FIELD OF THE INVENTION

The present invention provides sterile composition of a cefepime with a pharmaceutically acceptable non-toxic organic and inorganic base obtained by co spray drying of aqueous solution of composition that contains non-sterile cefepime and non-sterile pharmaceutically acceptable non-toxic organic and inorganic bases. The present invention further relates to provide a process for preparation of the stable composition of cefepime and pharmaceutically acceptable base obtained by co spray drying. The stable composition of cefepime and pharmaceutically acceptable base obtained by co spray drying exist in an amorphous form.

BACKGROUND OF THE INVENTION The chemical entity, 7-[α- (2-aminothiazol-4-yl)-α-(Z)-methoxyiminoacetamido]-3- [(1- methyl-1-pyrrolidinio)methyl]-3-cephem-4-carboxylate, generically known as cefepime, is a semi synthetic, fourth generation injectable cephalosporin antibiotic effective against infections caused by both Gram-positive and Gram-negative organisms. The compound, which exists in the zwitterion form, is represented by formula (I).

cefepime, either because of its poor solubility in water or its inherent instability in zwitterionic form, is administrated in the form of acid addition salts. The marketed

MAXIPIME ^® formulation of cefepime contains cefepime dihydrochloride, monohydrate salt of formula Il as the active ingredient.

U.S. Pat. No. 4,406,899 discloses cefepime in the zwitterion form and the corresponding acid addition salts. However, there is neither any enabling disclosure for preparation of the acid addition salts nor any mention of the solid- state nature of the product in the specification.

Crystalline acid addition salts of cefepime such as the H ₂ SO ₄ , di-HNO ₃ , HCI, di- HCI, and sesqui-H ₃ Pθ ₄ salts and their solvates are disclosed in U.S. Pat. No. 4,910,301. The patent mentions that the zwitterion form disclosed in US '899 is unstable both as a dry powder and as an injectable composition and requires special packaging and storage conditions. In contrast, US '301 patent claims that the crystalline material obtained therein exhibits excellent thermal stability and is hence more suited for formulation into an injectable dosage form. This implies that the zwitterion form of US '899 is probably an amorphous like crystalline material which exhibits very poor stability on storage.

Further, US '301 patent discloses selective process for preparation of the crystalline acid addition salts which comprises of dissolving the zwitterion in a mineral acid and causing crystallization by addition of a solvent such as acetone or isopropanol, followed by filtration, washing and drying to obtain the acid addition salt. This process is usually conducted in sterile conditions and in an

aqueous medium resulting in an acidic solution thereby leading to extensive corrosion of the reactor vessel, which calls for the use of special corrosion- resistant reactors.

However, the abovementioned acid addition salts of cefepime cannot be administered directly after reconstitution with sterile water as they provide acidic solutions which provoke unacceptable irritation on intravenous administration and unacceptably painful sensation on intramuscular administration. Also some of the acid addition salts have reduced solubility's which are insufficient for typical injectable compositions. To overcome these limitations, the acid addition salt compositions are mixed with buffering agents during reconstitution to provide a pH of about 3.5 to about 7.

Another alternative to overcome the limitations associated with acidic solutions is utilizing the acid addition salts in physical admixture with a pharmaceutically acceptable base. Such a composition is disclosed in U.S. Pat. No. 4,994,451 and U.S. Pat. No. 5,244,891, wherein, injectable compositions of temperature stable acid addition salts of cefepime in physical admixture with a pharmaceutically acceptable non-toxic organic or inorganic base, specifically, arginine in proportions to provide a pH of about 3.5 to about 7 on dilution with water to injectable concentration, are described. The physical admixture is prepared by blending the sterile salt and the base into a uniform blend, e.g. utilizing a standard blender in a dry atmosphere, and is then preferably filled into a vial or other container, all under aseptic conditions.

The admixtures mentioned hereinabove require the use of sterile raw materials and totally aseptic and dry conditions, thus rendering the process expensive. Moreover, the physical admixtures of the crystalline, stable cefepime acid addition salts and L(+) arginine are known to exhibit poor solid state stability at elevated temperatures. Also, anhydrous L(+) arginine is extremely hygroscopic and it can accept two moles of water of crystallization. The physical admixtures need to be

vacuum-dried under a variety of conditions, preferably, using the lyophilization technique, to remove free extraneous water.

U.S. Pat. No. 4,808,617 claims a stable antibiotic composition consisting of amorphous cefepime zwitterion formed by lyophilization or co solvent precipitation of an aqueous solution of cefepime zwitterion and a salt or mixture of salts.

Solvent such as acetone or isopropanol is used to precipitate the zwitterion-salt complex. The salt is one wherein the cation is selected from the group consisting of sodium, lithium, calcium and magnesium and the anion is selected from chloride, bromide and iodide. This patent further claims a stable solvates of antibiotic composition as mentioned above.

U.S. Pat. No. 5,095,011 claims a stable, amorphous, lyophilized dihydrochloride salt of cefepime and a reconstituted, injectable composition which comprises an effective amount of the amorphous salt in an aqueous solution having a suitable organic or inorganic base wherein the pH of the resulting solution is between 3.0- 7.0. Although the patent claims that the amorphous form of cefepime is stable, it requires lyophilization or freeze-drying. Lyophilization is not cost-effective and universal since it involves the utilization of an expensive lyophilizer and moreover, the method is exclusive to only those manufacturers who have such a facility. Also the composition requires external addition of suitable base during reconstitution.

The US patent No. 3,984,403 discloses a method to provide composition comprising certain acid cephalosporins and bases such as l-arginine and l-lysine and to provide the process for their preparation. The process involves treatment of acid cephalosporin part (in the form of zwitterion or sodium salt) with base part (I- lysine or l-arginine) in approximately equivalent proportion in water, at or below room temperature to provide the reaction product in water followed by its isolation. The isolation method involves co-precipitation of mixture comprising cephalosporin acid and l-arginine by addition of ethanol, followed by filtration of solid and re dissolving the isolated solid in water and finally lyophilization of the aqueous solution to obtain amorphous composition The other isolation method

involves initial lyophilization of reaction mixture comprising cephalosporin acid and a l-arginine to get solid followed by dissolving the isolated solid in water, co- precipitation of composition by addition of ethanol and isolation of solid by filtration. Use of lyophilization method renders the process costlier and the multi- step work up makes it laborious.

From the foregoing, it would be apparent that the prior art methods for manufacture of a sterile powder composition of injectable cefepime suffer from the following limitations, viz. i) use of mineral acid under aqueous conditions which results in extensive corrosion of the reactor vessel by the acidic solution and calls for the use of special corrosion-resistant reactors, ii) requires dry, sterile conditions for blending, thus adding to the cost of the process. iii) requires sterile raw materials which render the method expensive. iv) not cost-effective since such methods involve lyophilization, requiring capital expenditure for installation of a lyophilizer. v) the methods do not have universal applicability since they are exclusive only to those manufacturers who have an in-house lyophilizer.

We have found that a stable composition cefepime and a pharmaceutically acceptable non-toxic organic or inorganic base can be obtained by spray drying the solution containing mixture of non-sterile of cefepime salt or solvates thereof and non-sterile non-toxic base. The spray ^" drying method does not have stringent requirements as that of prior art processes as described above. More over, the composition obtained by spray drying can be administered as an injectable directly after reconstitution with water.

SUMMARY OF THE INVENTION The present invention relates to sterile composition of a cefepime with a pharmaceutically acceptable non-toxic organic and inorganic base obtained by simple and cost effective method such as co spray drying of solution composition

that contains non sterile cefepime and non sterile pharmaceutically acceptable non-toxic organic and inorganic bases. The sterile composition obtained by the present invention has high purity, good thermal stability and obtained in amorphous or substantially amorphous form.

The term "co spray drying" utilised herein to mean spray drying of aqueous solution of composition containing cefepime and non-toxic base to give sterile mixture of both cefepime as well as non toxic base. The sterile composition thus obtained is termed as "co spray dried composition"

The process does not require separate facilities for the preparation of sterile acid addition salt of cefepime and of sterile pharmaceutically acceptable base, and a sterile blender to prepare their admixture.

Thus, in one aspect of the present invention, there is provided a co-precipitated injectable cefepime composition, which exhibits good stability.

In another aspect, the present invention provides a simple, cost-effective method for preparation of cefepime dihydrochloride-L (+) arginine mixture useful in the pharmaceutical composition.

In yet another aspect, the present invention provides a stable, composition of Cefepime with a pharmaceutically acceptable organic or inorganic base, which can be administered directly after reconstitution with sterile water without further pH adjustment.

The experimental conditions are simple and applicable to large-scale production.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a sterile and stable composition of cefepime acid addition salt with a pharmaceutically acceptable non-toxic organic or inorganic base that is obtained by spray drying.

In another aspect of the present invention, there is provided a process for manufacture of injectable cefepime composition by a spray drying which is comprising of, (i) dissolving a composition containing mixture of cefepime acid addition salt and a pharmaceutically acceptable non-toxic organic or inorganic base in water at 0-30 ⁰ C, preferably at 0-1O ⁰ C to obtain a clear aqueous solution having a pH in the range of 3.0-7.0,

(ii) filtration of aqueous solution through 0.2 micron membrane filter and (iii) subjecting the clear aqueous solution to spray drying, or

(i) dissolving a cefepime acid addition salt in water, (ii) dissolving a pharmaceutically acceptable non-toxic organic or inorganic base in water, (iii) addition of solution from operation (v) to solution from operation (iv) at 0-

3O ⁰ C, preferably at 0-10 ⁰ C to obtain a solution having a pH in the range of

3.0-7.0,

(iv) filtration of aqueous solution through 0.2 micron membrane filter and (v) subjecting the clear aqueous solution to spray drying.

The sterile dry powder can be filled into a vial or other container.

The cefepime acid addition salt and a pharmaceutically acceptable non-toxic organic or inorganic base employed in the process can be sterile or non-sterile.

Suitable acid addition salts of cefepime, which may be used in the composition according to the invention, include H ₂ SO ₄ , di-HNO ₃ , HCI, di-HCI, and sesqui- H ₃ PO ₄ salts and their solvates.

Suitable non-toxic organic or inorganic bases which may be used in the composition according to the invention include, for example, sodium citrate, potassium citrate, N-methylglucosamine, N-methylglucamine, L (+) lysine, L (+)

arginine tris(hydroxymethyl) aminomethane, NaHCO ₃ , Na ₂ CO ₃ , NaH ₂ PO ₄ , Na ₂ HPO ₄ , Na ₃ PO ₄ , KHCO ₃ , K ₂ CO ₃ , KH ₂ PO ₄ , K ₂ HPO ₄ and K ₃ PO ₄ . Most preferred bases in the composition are L (+) lysine and L (+) arginine.

The molar ratio of cefepime acid addition salt to the pharmaceutically acceptable base in the composition can be in the range of 1 :1 to 1:5, preferably in the range of 1: 2 to 1:3.

The composition containing mixture of non-sterile cefepime and a non-sterile pharmaceutically acceptable non-toxic organic or inorganic base was dissolved in water at 0-4O ⁰ C, preferably at 0-1O ⁰ C, most preferably at 0-5 ^Or O".

Using composition containing non-sterile cefepime and non-sterile base can also perform the invention. A non-sterile composition containing various crystalline acid additions salts of cefepime such as sulfuric, di-nitric, monohydrochloric, dihydrochloric, and di- and sesquiorthophosphoric acid addition salts or solvates thereof can be used for the process of present invention.

The composition of cefepime and L (+) arginine obtained by co spray drying was amorphous as per powder XRD pattern shown in figure 1.

The sterile composition obtained by spray drying method on reconstitution with sterile water, gives an injectable solution having pH in the range of 3.0-7.0, preferably in the pH range 4- 4.5, which is amenable for I. M. or I.V. administration directly without further pH adjustment. Such a sterile composition was found to be stable. The thermal stability data of amorphous composition containing cefepime and L (+) argnine in injection water is shown in Table 1.

Table 1 Thermal stability of amorphous composition containing cefepime and L (+) arginine in injection water.

Amorphous composition of cefepime hydrochloride and L- (+) arginine (gm) was dissolved in injection water and analyzed as per USP method.

Since the aqueous solution of cefepime acid addition salt and arginine has a pH of 4-6, it does not lead to corrosion of the reactor vessel unlike in prior-art methods.

The present invention is described in the following non-limiting examples.

The starting material i. e. composition containing admixture of crystalline cefepime dihydrochloride monohydrate and L (+) arginine available from the market was used. The spray drying was carried out by using Buchi mini spray dryer B-191.

Example 1

To water (250 ml) precooled to 0-5 ⁰ C, cefepime hydrochloride (63 gm) and L- (+) arginine (33 gm) was added and stirred for 10-15 minutes to get clear solution. A solution of L (+) arginine (5 gm) in water (35 ml) was added to obtain pH 4.7 slowly in 10- 15 minutes at 0-5 ⁰ C and stirred for 10-15 minutes. The clear solution was filtered through 0.2 micron membrane filter at 0-5 ⁰ C. Filtrate was subjected for spray drying in the following setting of spray dryer.

Yield of spray-dried composition was 82 gm and HPLC purity was 99.28% (by excluding peak for arginine).

Example 2

Composition containing cefepime dihydrochloride monohydrate and L-arginine (50 gm) was dissolved in demineralized water (50 ml) at 25-30 ⁰ C. The clear solution was filtered through 0.2 micron membrane filter. Filter was washed with water (10 ml). Combined filtrate was subjected for spray drying in the following setting of spray dryer.

Yield of spray-dried composition was 48 gm.