A PROCESS FOR THE PREPARATION OF A STABLE CEFOZOPRAN
COMPOSITION
The technical field of the present invention relates to a stable cefozopran composition for parenteral administration wherein the composition is prepared by aqueous based lyophilization.
Cefozopran is a potent cephalosporin antibiotic which is administered parenterally. It is useful against a variety of clinical pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae. It is indicated in acute and chronic respiratory tract infections, urinary tract infections, thigh muscle infections and meningitis.
Parenteral administration of acidic compounds such as acidic salts of cefozopran is associated with pain at the site of administration.
As an approach to resolve this problem, example 1 of Japanese patent application no. 53-29936 discloses a composition containing cefotiam hydrochloride and sodium carbonate in an equivalent ratio of about 1:1. Further US 4,161,527 and US 4,933,334 describe pharmaceutical antibiotic composition of a cephalosporin which is produced by admixing cephalosporin with a pharmaceutically acceptable carbonic acid salt. The use of sodium carbonate has another advantage that, at the time of reconstitution in water for injection, carbon dioxide gas is evolved and the dissolution of the formulation is considerably hastened by its agitating effect.
One such parenteral composition of cefozopran is available commercially in Japan under the trade name Firstcin®. It is manufactured by admixing cefozopran, sodium carbonate and other pharmaceutically acceptable excipients in the presence of ethyl alcohol. The admixture is further subjected to lyophilization to produce an injectable powder composition. Removal of ethanol during lyophilization involves a complex, time consuming and expensive process.
There is thus a need for providing the parenteral dosage form of the cefozopran, which is prepared by using aqueous based solvent systems that can provide, several added advantages over non-aqueous solvent systems.
Hence, in one aspect, there is provided a stable cefozopran composition for parenteral administration comprising:
a) cefozopran,
b) isotonic agent, and
c) alkali metal salt
wherein the composition is prepared by aqueous based lyophilization.
In another aspect, there is provided a stable cefozopran composition for parenteral administration comprising:
a) cefozopran,
b) sodium chloride, and
c) sodium carbonate
wherein the composition is prepared by aqueous based lyophilization.
In another aspect, there is provided a stable parenteral cefozopran composition prepared by the process comprising the steps of:
a) dissolving Cefozopran in an aqueous solvent and lyophilizing the solution,
b) re-dissolving the lyophilize obtained in step a), in an aqueous solvent
c) dissolving isotonic agent and alkali metal salt in water and mixing with the solution of step b),
d) filtering and filling the solution in suitable vials,
e) lyophilizing the vials at a temperature of about -30 °C to about -60 °C to form a stable cefozopran composition.
In another aspect, there is provided a stable parenteral cefozopran composition prepared by the process comprising the steps of:
a) dissolving Cefozopran in an aqueous solvent and lyophilizing the solution,
b) re-dissolving the lyophilize obtained in step a), in an aqueous solvent,
c) dissolving sodium chloride and sodium carbonate in water and mixing with the solution of step b),
d) filtering and filling the solution in suitable vials,
e) lyophilizing the vials at a temperature of about -30 °C to about -60 °C to form a stable cefozopran composition.
The commercial product Firstcin® uses a non-aqueous solvent system to dissolve cefozopran and other ingredients during lyophilization. The use of non-aqueous solvent system has several disadvantages. Lyophilization with alcohol based solvent system requires a much lower cooling temperature of about -85 °C. However, the aqueous based lyophilization may be carried out at a comparatively higher temperature of about -60 °C to about -30 °C, in particular at about -40 °C. The lyophilization process requires less time if the solution is aqueous based and this results in less energy consumption. Further in the removal of alcohol the special arrangement of liquid nitrogen trap is required. The use of aqueous based system do not affect the physiological properties of composition and still the formulation has good stability and dissolution properties along with reduction in local reactions when injected.
The term "stable cefozopran composition" as used herein relates to chemical stability of cefozopran against degradation wherein not more than 5% of related substances are formed on storage of composition at 40 °C and 75 % RH for a period of 2 months. The stabilization of cefozopran in final dosage form is required as per the safety and regulatory requirements. Our preliminary study has revealed that the addition sequence of cefozopran and alkaline substance have a profound effect on stability of the final composition. The stability of the composition is lower if the alkali substance is added in the solution along with the addition of cefozopran. However, the stability of the composition improved significantly if the alkali substance is added along with isotonic agent at a later stage to the solution of lyophilized cefozopran.
The term "cefozopran" as used herein relates to cefozopran base and its acid addition salts including hydrochloride, hydrobromide, sulphate, phosphate, in particular cefozopran hydrochloride. The term also includes polymorphs, complexes, salts, solvates, hydrates, isomers and other derivatives thereof. The amount of cefozopran as used herein may vary from 250 mg per vial to 2000 mg per vial.
To prepare the parenteral composition having tonicity, similar to normal physiological fluids in order to prevent post-administration swelling or rapid absorption of the composition because of differential ion concentrations between the composition and physiological fluids, one or more isotonic agent may be included into the composition in the range of about 4.0 % (w/w) to about 20.0 % (w/w) of the final composition. Suitable examples include sodium citrate, sodium chloride, glycerin, boric acid, calcium chloride, dextrose, and potassium chloride, arginine, histidine, glycine, sucrose, glucose, mannitol, and the like. In particular sodium chloride may be used.
The administration of acidic parenteral formulations may cause irritation, itching, inflammation, pain, swelling, necrosis or bleeding. An alkali metal salt may be incorporated to overcome these problems in the range of about 5.0 % (w/w) to about 25.0 % (w/w). Specific examples of alkali metal salt include alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like; alkaline earth metal hydrogen carbonates such as magnesium hydrogen carbonate; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; and alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate and the like.
The lyophilization may be carried out in an aqueous based solvent system. The aqueous solvent comprises at least about 50-80 % (v/v) water, preferably about 60-70 % (v/v) water and optionally one or more water miscible solvents. Specific examples of water miscible solvents include ethanol, isopropylalcohol, acetone, methanol, and the like. Examples include the aqueous solvent system comprising 70 % (v/v) water and 30 % (v/v) ethanol.
The stable cefozopran composition for parenteral administration may further comprise one or more pharmaceutically acceptable excipients that include all physiologically inert excipients used in the pharmaceutical art for dispensing of parenteral compositions. Examples include surfactants, buffers, preservatives, suspending agents, local anesthetics, stabilizers and the like.
Surfactant(s) may be added in a parenteral composition to solubilize the drug and other components so that a single phase system is formed. Suitable examples of
surfactants include polyethylene glycol (400) monolaurate, polyoxyethylene (4) sorbitan monolarate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) oleyl ehter, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) cetyl ehter, polyoxyethylene (40) stearate, sodium oleate, polyoxyetyhlene (100) stearate, potassium oleate, sodium lauryl sulphate and the like.
Buffers may be added in a parenteral composition to maintain the pH of the composition at the desired levels. Specific examples of buffers include: acetic acid, adipic acid, benzoic acid, sodium benzoate, citric acid, lactic acid, maleic acid, potassium phosphate, sodium phosphate monobasic, sodium phosphate dibasic, sodium acetate, sodium bicarbonate, sodium carbonate, sodium citrate, sodium tartrate, tartaric acid and the like.
Preservative(s) may be added in the parenteral compositions to prevent microbial contamination and growth upon storage. Specific examples of preservatives includes benzoic acid and salts, sorbic acid and salts, propionic acid, chlorobutanol, formaldehyde, Hexamethylene tetramine, phenol, cresol, benzyl alcohol, chlorothymol, chlorohexidine and salts, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, phenylmercuric acetate and phenylmercuric nitrate, and the like.
Suspending agents help to maintain the viscosity of the parenteral composition and one or more suspending agents may be incorporated as desired. Specific examples include: gelatin, methylcellulose, pectin, polyethylene glycol 4000, sodium carboxymethylcellulose, croscarmellose sodium and hydroxypropyl cellulose, sorbitol solution and the like.
Specific examples of local anesthetics include: procaine hydrochloride, benzyl alcohol, lidocaine hydrochloride , mepivacaine hydrochloride and the like.
Specific examples of stabilizers include: sodium sulphite, sodium metabisulphite, sodium bisulphite, sodium thiosulphate, sodium formaldehyde sulfoxylate, sulfur dioxide, ascorbic acid, isoascorbic acid, thioglycerol, thioglycolic acid, cysteine hydrochloride, acetylcysteine, edetate disodium, edetate calcium disodium, edetate
tetrasodium, creatinine, glycine, niacinamide, sodium acetyltryptophanate, sodium caprylate, sodium saccharin and the like.
In one of the embodiments the stable cefozopran composition for parenteral administration may be prepared by a process comprising the steps of:
a) dissolving Cefozopran in an aqueous solvent and lyophilizing the bulk in trays,
b) adding and dissolving lyophilized Cefozopran of step a) in an aqueous solvent at 42 °C,
c) adding and dissolving isotonic agent and alkali metal salt in water and mixing with the bulk of step b),
d) making up the volume of bulk of step c) with aqueous solvent and filtering the solution through a suitable filter,
e) filling the solution of step d) in suitable vials and lyophilizing the vials to form a dry powder mass.
Cefozopran and other ingredients may be dissolved in aqueous solvent by using conventional method such as by stirring, sonicating, agitating and the like. If desired the solvent may be warmed at a temperature of about 30 to 60 °C in particular at 35 to 45 °C to facilitate the dissolution.
Lyophilization may be accomplished using conventional methods known to those skilled in the art, for example, by filling the solution in vials and then rapidly freezing by cooling at -30° C to -60° C and removing moisture, while supplementing heat necessary for removal of moisture.
The vials may also be sterilized by using conventional methods known to those skilled in the art, for example, thermal sterilization, gas sterilization, UV light sterilization, radiation sterilization with gamma rays, electron beams, X-rays, and the like.
At the time of administration the composition may be reconstituted with saline water or any other intravenous fluid that may be administered to the mammal in need thereof, as per the dosage requirements.
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention in any way.
Examples
Table 1: Cefozopran HCI parenteral composition

(Table Removed)
Procedure:
a) Aqueous solvent was heated to about 42° C and cefozopran hydrochloride was dissolved by stirring.
b) The solution of step a) was bulk lyophilized in trays.
c) The lyophilized Cefozopran of step a) was dissolved in Aqueous solvent at 42 °C,
d) Sodium chloride and sodium carbonate was dissolved in Aqueous solvent. The bulk of step c) was added to the bulk of step b),
e) The volume of bulk obtained in step d) was made up with Aqueous solvent and the solution was filtered through a suitable filter,
f) The solution of step e) was filled in suitable vials and vials were lyophilized.
The cefozopran composition prepared in above examples may be reconstituted with saline water (100 ml) and injected intravenously.
Accelerated stability studies:
The formulations prepared by the above process (example 1) and the commercially available cefozopran formulation (Firstcin®) were kept for accelerated stability studies under 40 °C and 75 % RH for 3 months. The generated impurities (related substances) were evaluated at a difference of 1 month for about 2 months. The results of accelerated stability studies are reported below in table 2.
Table 2: Results of accelerated stability studies
(Table Removed)

WE CLAIM:
1. A stable cefozopran composition for parenteral administration comprising: cefozopran, isotonic agent and an alkali metal salt, wherein the composition is prepared by aqueous based lyophilization.
2. The stable composition of claim 1, wherein cefozopran is an acid addition salt selected from hydrochloride, hydrobromide, sulphate or phosphate salt.
3. The stable composition of claim 1, wherein the isotonic agent is selected from one or more of sodium citrate, sodium chloride, glycerin, boric acid, calcium chloride, dextrose, and potassium chloride, arginine, histidine, glycine, sucrose, glucose and mannitol.
4. The stable composition of claim 1, wherein the alkali metal salt is selected from one or more of sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium hydrogen carbonate, sodium carbonate, potassium carbonate, magnesium carbonate and calcium carbonate.
5. The stable composition of claim 1, wherein the composition may further comprise one or more pharmaceutically acceptable excipients selected from buffers, preservatives, antioxidants, suspending agents, surfactants, local anesthetics, chelating agents and stabilizers.
6. A process for the preparation of the stable cefozopran composition of claim 1, wherein the process comprises the steps of:

a) dissolving Cefozopran in an aqueous solvent and lyophilizing the solution,
b) re-dissolving the lyophilize obtained in step a) in an aqueous solvent,
c) dissolving isotonic agent and alkali metal salt in water and mixing with the solution of step b),
d) filtering and filling the solution in suitable vials,
e) lyophilizing the vials at a temperature of about -30 to about -60 °C to form a stable cefozopran composition.
7. The process as claimed in claim 6, wherein the aqueous solvent is a mixture comprising water and one or more water miscible solvents.
8. The process as claimed in claim 7, wherein the water miscible solvents are selected from one or more of ethanol, isopropylalcohol, acetone and methanol.
9. The process as claimed in claim 7, wherein the aqueous solvent is a mixture comprising 70 % (v/v) water and 30 % (v/v) of ethanol.
10. A stable cefozopran composition for parenteral administration and process of preparation thereof, as disclosed and illustrated in the examples herein.