A PROCESS FOR THE PREPARATION OF A STABLE LYOPHILIZED CEFOZOPRAN COMPOSITION FOR PARENTERAL ADMINISTRATION
The present invention relates to a stable lyophilized cefozopran composition for parenteral administration prepared by a lyophilization process and wherein the solvent system used in lyophilization process comprises aqueous solvent and at least two organic co-solvents.
Background
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.
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Our co-pending Indian patent application IN 205/DEI_/2010 discloses lyophilized parenteral dosage form of the cefozopran, which is prepared by using aqueous based solvent system comprising ethanol and water.
There is still a need for providing the alternate parenteral composition of cefozopran with aesthetically improved lyophilized product; prepared by a process which is simple, fast and economical and also wherein the composition remains stable enough for a commercial use.
Our scientists have now discovered a unique solvent system for cefozopran lyophilization which subsequently results in aesthetically improved lyophilized product with increased freezing temperature during freeze drying and reduced overall process time and is yet stable enough for a commercial use.
Summary of the invention
Hence, in one aspect, there is provided a stable lyophilized cefozopran composition for parenteral administration prepared by a process comprising:
a) dissolving cefozopran, isotonic agent and alkali metal salt in a solvent system to form a pre-lyophilization solution,
b) lyophilizing the pre-lyophilization solution;
wherein the solvent system comprises an aqueous solvent and at least two organic co-solvents.
In another aspect, there is provided a stable lyophilized cefozopran composition for parenteral administration prepared by a process comprising:
a) dissolving cefozopran, isotonic agent and alkali metal salt in a solvent system to form a pre-lyophilization solution,
b) lyophilizing the pre-lyophilization solution;
wherein the solvent system comprises water, tertiary butyl alcohol and ethanol.
In another aspect, there is provided a stable lyophilized cefozopran composition for parenteral administration prepared by a process comprising:
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a) dissolving cefozopran, sodium chloride and sodium carbonate in a solvent system to form a pre-lyophilization solution,
b) lyophilizing the pre-lyophilization solution;
wherein the solvent system comprises water, tertiary butyl alcohol and ethanol.
In another aspect, there is provided a stable lyophilized cefozopran composition for parenteral administration prepared by a process comprising:
a) dissolving cefozopran, sodium chloride and sodium carbonate in a solvent system to form a pre-lyophilization solution,
b) lyophilizing the pre-lyophilization solution;
wherein the solvent system comprises water, tertiary butyl alcohol and ethanol in a v/v ratio of 3:1:1.
In another aspect, there is provided a stable lyophilized cefozopran composition for parenteral administration prepared by a process comprising:
a) dissolving cefozopran in a solvent system ,
b) dissolving sodium chloride and sodium carbonate in water and mixing with the solution of step a),
c) cooling, filtering the solution and filling the solution in suitable vials,
d) freeze-drying the vials and sealing;
wherein the solvent system comprises water, tertiary butyl alcohol and ethanol in a v/v ratio of 3:1:1.
In one of the embodiments cefozopran is dissolved in the solvent system at a temperature of about 40 X to 55 °C.
In another embodiment sodium chloride and sodium carbonate are dissolved in water at a temperature of about 40 °C to 55 °C.
In another embodiment cooling of the solution is done by using conventional methods, for example ice bath, at a temperature of about 25 °C to 35 °C.
In another embodiment vials are frozen at a temperature of about -40 °C to -70 °C.
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Detailed description of the invention
The commercial product Firstcin® uses a non-aqueous based solvent system using ethanol as sole solvent to dissolve cefozopran and other ingredients during lyophilization. The use of non-aqueous based solvent system has several disadvantages. Lyophilization with non-aqueous based solvent system requires a much lower cooling temperature of about -85° C. However, lyophilization with the use of present solvent system comprising combination of aqueous solvent and at least two organic co-solvents, in particular combination of water, tertiary butyl alcohol and ethanol; require comparatively much higher freezing temperature of about -40 °C to about -70 °C, in particular at about -60 "C. The lyophilization process requires less time with the present solvent system, which results in less energy consumption thus making it more economical.
The final lyophilized product, with the use of present solvent system was surprisingly found out to be aesthetically improved over the previously known lyophilized products of cefozopran. The final lyophilized product is more fluffy, yellow colored powder 7 cake with increased surface area. Further, the final lyophilized products possess good stability and dissolution properties along with reduction in local reactions when injected.
The term "stable lyophilized cefozopran composition" as used herein relates to chemically stable composition which is less prone to degradation and wherein not more than 5% w/w of related substances are formed on storage of composition at 25 °C and 60 % RH for a period of 3 months. The stabilization of cefozopran in final dosage form is required as per the safety and regulatory requirements.
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.
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To prepare the parenteral composition with tonicity similar to normal physiological fluids in order to prevent post-administration swelling of the site 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, or mixtures thereof. In particular sodium chloride may be used. The administration of acidic parenteral formulations may cause irritation, itching, inflammation, pain, swelling, necrosis or bleeding. To overcome these problems, an alkali metal salt may be incorporated, 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; alkaline earth metal hydrogen carbonates such as magnesium hydrogen carbonate; alkali metal carbonates such as sodium carbonate, potassium carbonate; and alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate.
The solvent system used in the present invention comprises combination of an aqueous solvent and at least two organic co-solvents. Specific examples of organic solvents include ethanol, tertiary-butyl alcohol (t-butanol) isopropylalcohol, acetone, methanol, and the like. In particular, the solvent system of the present invention comprises combination of water, tertiary butyl alcohol and ethanol in a v/v ratio of from about 1:1:1 to about 6:1:1; in particular in a v/v ratio of 3:1:1.
Tertiary butyl alcohol possesses favorable properties to be utilized in aqueous co-solvent systems for the freeze drying of pharmaceutical products. The favorable properties of tertiary butyl alcohol include its high vapor pressure, low melting point (freezes completely in most freeze dryers with low expenditure of energy) and readily sublimes during the primary drying stage of the freeze-drying process. Additionally tertiary butyl alcohol also possessed low toxicity as an organic solvent.
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
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parenteral compositions. Examples include surfactants, buffers, preservatives, suspending agents, local anesthetics and stabilizers.
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 or mixture thereof^
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 or mixture thereof.
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.
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 or mixture thereof.
Specific examples of local anesthetics include: procaine hydrochloride, benzyl alcohol, lidocaine hydrochloride , mepivacaine hydrochloride or mixture thereof.
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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 or mixture thereof.
In one of the embodiments the stable cefozopran composition for parenteral administration may be prepared by a process comprising the steps of:
a) warming the solvent system (combination of water, tertiary butyl alcohol and ethanol) to about 40 to 55 °C,
b) adding and dissolving cefozopran in the solvent system of step a),
c) separately dissolving isotonic agent in water and mixing with the solution of step b) at about 40 to 55 °C,
d) dissolving alkali metal salt in water and mixing with the solution of step c) at about 40 to 55 X,
e) cooling the solution of step d) using ice bath to about 25 to 35 °C,
f) making up the volume with water and aseptically filtering the bulk through membrane filter,
g) filling the filtered solution of step f) in suitable vials,
h) freezing the vials at minimum temperature of about -40 °C to about -70 °C, i) freeze-drying the vials at maximum temperature of about 30 °C to about 50
°C, j) sealing the vials under vacuum/nitrogen atmosphere with stopper and flip-off
aluminium seals.
Cefozopran and other ingredients may be dissolved in present solvent system by using conventional method such as by stirring, sonicating or agitating. The solvent may be warmed at a temperature of about 30 to 60 °C in particular at 40 to 55 °C to facilitate the dissolution.
Cooling may be accomplished by using conventional methods known to those skilled in the art, for example, by using water bath, ice bath, dry ice bath or liquid nitrogen bath.
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Lyophilization may be accomplished by 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 about -40 °C to about -70 °C in particular at about -60 °C and freeze-drying the vials at maximum temperature of about 30 °C to about 50 °C in particular at about 40 "C.
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 or X-rays.
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
Ingredients Example 1 Example 2
Qty per vial (mg) Qty per vial (mg)
Cefozopran hydrochloride eq. 500 1000
to Cefozopran
Sodium Chloride 60 1^0
Sodium carbonate anhydrous 103 206
Solvent system 7.5 ml 15 ml
(water for injection: ethanol: tertiary butyl alcohol in a v/v ratio of 3 : 1 : 1)
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Procedure:
a) Solvent system was heated to about 49° C and cefozopran hydrochloride was dissolved by stirring,
b) Sodium chloride and sodium carbonate was dissolved in water at about 46 °C and this solution was mixed with the solution of step a),
c) The solution of step b) was cooled to 30 °C using ice bath,
d) The volume of bulk obtained in step c) was made up with water and the solution was filtered through a suitable filter,
e) The solution of step d) was filled in suitable vials and vials were freezed at about -60 °C
f) The vials of step e) were then freeze dried at maximum temperature of about 40 °C
g) The vials were sealed under vacuum/nitrogen atmosphere using stopper and flip-off aluminium seals.
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 2) were kept for accelerated stability studies under 25 X and 60 % RH for 3 months. The generated impurities (related substances) were evaluated initially (0 months) and after 3 months. The results of accelerated stability studies are reported below in table 2.
Table 2: Results of accelerated stability studies
Formulation Condition Initial 3 Months
(25X/ 60% relative
humidity)
Example 2 Any Individual Impurity 0.460 0.368
Strength: 1 gm (%w/w)
Total Impurities 3.616 3.983
(%w/w)
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WE CLAIM:
1. A stable lyophilized cefozopran composition for parenteral administration prepared
by a process comprising:
a) dissolving cefozopran , isotonic agent and alkali metal salt in a solvent system to form a pre-lyophilization solution,
b) lyophilizing the pre-lyophilization solution;
wherein the solvent system comprises an aqueous solvent and at least two organic co-solvents.
2. The stable composition of claim 1, wherein cefozopran comprises an acid addition salt selected from hydrochloride, hydrobromide, sulphate or phosphate salt.
3. The stable composition of claim 1, wherein the organic co-solvents are selected from one or more of ethanol, tertiary-butyl alcohol, isopropyl alcohol, acetone and methanol and wherein the aqueous solvent is water.
4. The stable composition of claim 3, wherein organic co-solvents are tertiary butyl alcohol and ethanol.
5. The stable composition of claim 3 and 4, wherein the solvent system comprises water, tertiary butyl alcohol and ethanol in v/v ratio of 3:1:1.
6. The stable composition of claim 1, wherein the isotonic agent is selected from sodium citrate, sodium chloride, glycerin, boric acid, calcium chloride, dextrose, and potassium chloride, arginine, histidine, glycine, sucrose, glucose and mannitol.
7. The stable composition of claim 1, wherein the alkali metal salt is selected from sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium hydrogen carbonate, sodium carbonate, potassium carbonate, magnesium carbonate and calcium carbonate.
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8. 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.
9. A process for the preparation of the stable lyophilized cefozopran composition for parenteral administration of claim 1, wherein the process comprises the steps of:

a) dissolving cefozopran in a solvent system ,
b) dissolving sodium chloride and sodium carbonate in water and mixing with the solution of step a),
c) cooling, filtering the solution and filling the solution in suitable vials,
d) freeze-drying the vials and sealing;
wherein the solvent system comprises water, tertiary butyl alcohol and ethanol in a v/v ratio of 3:1:1.
10. A stable cefozopran composition for parenteral administration and process of
preparation thereof, as disclosed and illustrated in the examples herein.