PRE-FILLED SYRINGE CONTAINING MOXIFLOXACIN

Abstract

The present invention relates to a pre-filled syringe containing Moxifloxacin has a plunger, a barrel, a needle with gauge, kits having this syringe and the use of the syringe for the administration of Moxifloxacin for postsurgical bacterial endophthalmitis after cataract surgery.

Claims

1-15. (canceled)

16. A pre-filled syringe containing a liquid formulation of Moxifloxacin and comprising a syringe barrel, wherein the syringe barrel is made of plastic or glass and is silicone-free.

17. The pre-filled syringe of claim 16, wherein Moxifloxacin concentration is 0.1 to 500 mg/ml.

18. The pre-filled syringe of claim 16, containing less than 50 particles per ml of the liquid formulation having a diameter of 10 m or greater.

19. The pre-filled syringe of claim 16, containing less than 5 particles per ml of the liquid formulation having a diameter of 25 m or greater.

20. The pre-filled syringe of claim 16, having a gliding force of less than or equal to about 10N.

21. The pre-filled syringe of claim 16, further comprising a a silicone-free stopper.

22. The pre-filled syringe of claim 16, wherein the syringe barrel is made of polymer, cycloolefin, or glass.

23. The pre-filled syringe of claim 16, wherein the syringe barrel comprises an internal coating other than a silicone coating.

24. The pre-filled syringe according to claim 16, further comprising a staked needle.

25. A kit comprising the pre-filled syringe of claim 16.

26. A method for treating postsurgical endophthalmitis prophylaxis or other related eye diseases and conditions comprising: administering a liquid formulation of Moxifloxacin in the pre-filled syringe of claim 16 to a patient with postsurgical endophthalmitis prophylaxis or other related eye diseases and conditions.

27. The method of claim 26, wherein a volume of 1 to 500 m of the liquid formulation is administered to the patient by intracameral injection into the anterior chamber.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 shows an example of a pre-filled syringe of the present invention for intracameral injection of Moxifloxacin. The pre-filled syringe composes of plunger head, plunger, needle, needle cap, needle guard activation clip, needle guard wings, label, syringe barrel, viewing window, dose marking.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The detailed description is merely exemplary in nature and is not intended to limit application and uses. The following examples further illustrate the present invention without, however, limiting the scope of the invention thereto. Various changes and modifications can be made by those skilled in the art on the basis of the description of the invention, and such changes and modifications are also included in the present invention. Unless indicated otherwise, all ingredient concentrations are presented in units of % weight/volume % w/v).

[0019] Moxifloxacin is preferably present in the compositions of the present invention in the form of a pharmaceutically acceptable salt. Most preferably, moxifloxacin is present in the form of moxifloxacin hydrochloride. The compositions contain moxifloxacin in an amount equivalent to about 0.5% as the free base. The amount of moxifloxacin hydrochloride in the compositions of the present invention is 0.5-0.6%, and is most preferably 0.545%, which is equivalent to 0.5% moxifloxacin as base.

[0020] The compositions of the present invention may contain boric acid in an amount from 0.2-0.4%, preferably 0.3%.

[0021] In a certain embodiment of the present invention, Edetate &sodium is present in the compositions of the present invention in an amount of 0.005-0.02%. Most preferably, the edetate disodium is present in an amount of 0.01%.

[0022] An ionic tonicity adjusting agent is added to the compositions of the present invention in an amount sufficient to cause the final composition to have an osmolality of 270-330 mOsm/Kg. Preferably, the ionic tonicity adjusting agent is sodium chloride and is present in an amount of 0.5-0.8%. Most preferably, the compositions of the present invention contain 0.65% NaCl.

[0023] The compositions of the present invention further contain an otically and ophthalmically acceptable non-ionic surfactant, such as a polysorbate surfactant, a block copolymer of ethylene oxide and propylene oxide surfactant (e.g., a pluronic or tetronic surfactant), or tyloxapol. Preferably, the compositions contain the non-ionic surfactant in an amount of 0.04-0.06%. Most preferably, the non-ionic surfactant is tyloxapol and the amount of tyloxapol in the compositions of the present invention is 0.05%.

[0024] The compositions can contain a preservative ingredient or a preservation-enhancing ingredient selected from the group consisting of benzalkonium chloride and sorbitol. Preferably, the compositions of the present invention contain benzalkonium chloride if they are intended for topical otic administration and sorbitol if they are intended for topical ophthalmic administration. If present, the amount of benzalkonium chloride in the compositions is 0.005-0.015%, preferably 0.01%. If present, the amount of sorbitol in the compositions of the present invention is 0.1-0.3%, preferably 0.2%. In addition, the compositions can be preservative free and sterile formulation.

[0025] The pH of the aqueous solutions of the present invention is adjusted with an ophthalmically acceptable pH-adjusting agent. Ophthalmically acceptable pH adjusting agents are known and include, but are not limited to, hydrochloric acid (HCl) and sodium hydroxide (NaOH). The compositions of the present invention preferably contain NaOH or HCl to obtain the desired pH. The compositions of the present invention are formulated and maintained within a narrow pH range in order to keep the compositions stable over a commercially acceptable shelf-life period. The compositions of the present invention have a pH of 5.0-9.0, and most preferably 7.8-8.0.

[0026] The compositions of the present invention are preferably packaged in prefilled syringes or multi-dose plastic containers designed to deliver drops to the eye. Preferably pre-filled syringe containing a liquid formulation of Moxifloxacin and comprising a syringe barrel, wherein the syringe barrel is made of plastic/glass and is silicone-free.

[0027] Preferably, the pre-filled syringe is a disposable and for one dose to avoid contamination.

EXAMPLES

[0028] The following examples are intended to illustrate, but not limit, the present invention. While the invention has been described with respect to the specific embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the listed claims.

Example 1. Ophthalmic Solution Containing Moxifloxacin Hydrochloride Eq. to Moxifloxacin (0.3% w/v Dissolved) in Prefilled Syringe

[0029]

TABLE-US-00001 TABLE 1 No. Pharmaceutical Ingredients Quantities (%) 1 Moxifloxacin Hydrochloride 0.3 2 Benzalkonium Chloride 0.01 3 Boric acid 0.2 4 Mannitol 4.0 5 EDTA 0.01 6 Hydrochloric Acid and/or pH adjustment to Sodium Hydroxide, NF 5.5 7 Water for injection q.s. to 100

[0030] A formulation as shown in table 1 is prepared as follows:

[0031] (a) Accurately weigh quantity of Moxifloxacin Hydrochloride and required quantity of Disodium edetate (EDTA) are introduced into suitable container and dissolved it in sufficient water for injection and stirred until clear colorless solution is obtained.

[0032] (b) Required quantity of Boric acid and Mannitol are dissolved in sufficient quantity of water for injection in separate container and stirred until clear solution is obtained; this solution is added to solution of step (a) with stirring.

[0033] (c) Required quantity of Benzalkonium Chloride is dissolved in sufficient quantity of water for injection in separate container and stirred until clear solution is obtained; this solution is added to solution of step (a) with stirring to obtain a final solution.

[0034] (d) The pH of final solution obtained as per step (c) is adjusted to 5.5 with required quantity of 1 N NaOH or 0.1 N HCL stock solution and final volume of desired batch size is made up with sufficient quantity of water for injection.

[0035] (e) The solution of step (d) is then filtered through 0.22 m sterile filter.

[0036] (f) The filtered sterilized Moxifloxacin solution of step (e) is used to fill the prefilled syringes.

[0037] Example 2. Ophthalmic Solution Containing Moxifloxacin Hydrochloride Eq. to Moxifloxacin (0.5% w/v Dissolved) in Prefilled Syringe

TABLE-US-00002 TABLE 2 No. Pharmaceutical Ingredients Quantities (%) 1 Moxifloxacin Hydrochloride 0.5 2 Benzalkonium Chloride 0.01 3 Boric acid 0.1 4 Sodium Chloride 0.8 5 EDTA 0.01 6 Hydrochloric Acid and/or pH adjustment to Sodium Hydroxide, NF 6.5 7 Water for injection q.s. to 100

[0038] A formulation as shown in table 2 is prepared as follows:

[0039] (a) Accurately weigh quantity of Moxifloxacin Hydrochloride and required quantity of Disodium edetate (EDTA) are introduced into suitable container and dissolved it in sufficient water for injection and stirred until clear colorless solution is obtained.

[0040] (b) Required quantity of Boric acid and Sodium Chloride are dissolved in sufficient quantity of water for injection in separate container and stirred until clear solution is obtained; this solution is added to solution of step (a) with stirring.

[0041] (c) Required quantity of Benzalkonium Chloride is dissolved in sufficient quantity of water for injection in separate container and stirred until clear solution is obtained; this solution is added to solution of step (a) with stirring to obtain a final solution.

[0042] (d) The pH of final solution obtained as per step (c) is adjusted to 6.5 with required quantity of 1 N NaOH or 0.1 N HCL stock solution and final volume of desired batch size is made up with sufficient quantity of water for injection.

[0043] (e) The solution of step (d) is then filtered through 0.2.2 m sterile filter.

[0044] (f) The filtered sterilized Moxifloxacin solution of step (e) is used to fill the prefilled syringes.

Example 3. Ophthalmic Solution Containing Moxifloxacin Hydrochloride Eq. to Moxifloxacin (0.6% w/v Dissolved) in Prefilled Syringe

[0045]

TABLE-US-00003 TABLE 3 No. Pharmaceutical Ingredients Quantities (%) 1 Moxifloxacin Hydrochloride 0.6 2 Benzalkonium Chloride 0.01 3 Boric acid 0.1 4 Sodium Chloride 0.7 5 Sorbitol 0.1 5 EDTA 0.01 6 Hydrochloric Acid and/or pH adjustment to Sodium Hydroxide, NF 7.5 7 Water for injection q.s. to 100

[0046] A formulation as shown in table 3 is prepared as follows:

[0047] (a) Accurately weigh quantity of Moxifloxacin Hydrochloride and required quantity of Disodium edetate (EDTA) are introduced into suitable container and dissolved it in sufficient water for injection and stirred until clear colorless solution is obtained.

[0048] (b) Required quantity of Boric acid and Sodium Chloride and Sorbitol are dissolved in sufficient quantity of water for injection in separate container and stirred until clear solution is obtained; this solution is added to solution of step (a) with stirring.

[0049] (c) Required quantity of Benzalkonium Chloride is dissolved in sufficient quantity of water for injection in separate container and stirred until clear solution is obtained; this solution is added to solution of step (a) with stirring to obtain a final solution.

[0050] (d) The pH of final solution obtained as per step (c) is adjusted to 7.5 with required quantity of 1 N NaOH or 0.1 N HCL stock solution and final volume of desired batch size is made up with sufficient quantity of water for injection.

[0051] (e) The solution of step (d) is then filtered through 0.22 m sterile filter.

[0052] (f) The filtered sterilized Moxifloxacin solution of step (e) is used to fill the prefilled syringes.

Example 4. Preservative Free Ophthalmic Solution Containing Moxifloxacin Hydrochloride Eq. to Moxifloxacin (0.5% w/v Dissolved) in Prefilled Syringe

[0053]

TABLE-US-00004 TABLE 4 No. Pharmaceutical Ingredients Quantities (%) 1 Moxifloxacin Hydrochloride 0.5 2 Boric acid 0.1 3 Sodium Chloride 0.8 4 Hydrochloric Acid and/or pH adjustment to Sodium Hydroxide, NF 7.5 5 Water far injection q.s. to 100

[0054] A formulation as shown in table 4 is prepared as follows:

[0055] (a) Accurately weigh quantity of Moxifloxacin Hydrochloride is introduced into suitable container and dissolved it in sufficient water for injection and stirred until clear colorless solution is obtained.

[0056] (b) Required quantity of Boric acid and Sodium Chloride are dissolved in sufficient quantity of water for injection in separate container and stirred until clear solution is obtained; this solution is added to solution of step (a) with stirring.

[0057] (c) The pH of final solution obtained as per step (b) is adjusted to 7.5 with required quantity of 1 N NaOH or 0.1 N HCL stock solution and the final volume of desired hatch size is made up with sufficient quantity of water for injection.

[0058] (d) The solution of step (c) is then filtered through 0.22 m sterile filter.

[0059] (e) The filtered sterilized Moxifloxacin solution of step (d) is used to fill the prefilled syringes.

Example 5. Preservative Free Ophthalmic Solution Containing Moxifloxacin Hydrochloride Eq. to Moxifloxacin (0.6% w/v Dissolved) in Prefilled Syringe

[0060]

TABLE-US-00005 TABLE 5 No. Pharmaceutical Ingredients Quantities (%) 1 Moxifloxacin Hydrochloride 0.6 2 Sodium Chloride 0.8 3 Hydrochloric Acid and/or pH adjustment to Sodium Hydroxide, NF 7.5 4 Water for injection q.s. to 100

[0061] A formulation as shown in table 5 is prepared as follows:

[0062] (a) Accurately weigh quantity of Moxifloxacin Hydrochloride is introduced into suitable container and dissolved it in sufficient water for injection and stirred until clear colorless solution is obtained.

[0063] (b) Required quantity of Boric acid and Sodium Chloride are dissolved in sufficient quantity of water for injection in separate container and stirred until clear solution is obtained; this solution is added to solution of step (a) with stirring.

[0064] (c) The pH of final solution obtained as per step (b) is adjusted to 7.5 with required quantity of 1 N NaOH or 0.1 N HCL stock solution and final volume of desired batch size is made up with sufficient quantity of water for injection.

[0065] (d) The solution of step (c) is then filtered through 0.22 m sterile filter.

[0066] (e) The filtered sterilized Moxifloxacin solution of step (d) is used to fill the prefilled syringes. Example 6. Determination of Particles of Different Sizes

[0067] The particle size of particles in different plastic and glass syringes containing Moxifloxacin solution and subjected to different conditions is determined by a Horiba laser light scattering particle sizer. The appropriate amount of Moxifloxacin solution is transferred from the prefilled syringes to liquid sampling cell and the particle sizes and distribution are determined by the particle sizer.

Example 7. Determination of Moxifloxacin Stability

[0068] Samples in different plastic and glass prefilled syringes are subjected to stress conditions to study the stability of Moxifloxacin formulation. The following storage condition are used: 4 C./35% RH, 25 C./40% RH, 25 C./40% RH Horizontal, 30 C/65% RH, 40 C./<25% RH, freeze-thaw cycle. Each cycle consisted of 24 hours at 20 C. followed by 24 hours at room temperature.

Example 8. Determination of Gliding Forces in Different Plastic and Glass Syringes Containing Moxifloxacin Solution

[0069] The glide force (F) can be determined by the following equation:

F=[l/r.sup.4]* A

where A is the area of barrel lumen; r is radius of tube; is viscosity; is the laminar flow through a tube (Poiseuille's Law):

=[r.sup.4/8]*[(P)/l]

where P is the pressure differential; and l is the length of the tube.

[0070] The gliding force and break loose force can be determined by a Tensile Compression Testing Machine. The relationship between compression load (N) and compression extension (mm) can be plotted after measurement. The break loose force and gliding force can be therefore determined from the plot. The syringeability can be optimized based on the break loose force and gliding force.