A PROCESS FOR THE PREPARATION OF AN ORAL PHARMACEUTICAL COMPOSITION CONTAINING QUINOLONE ANTIBACTERIAL AGENTS
The present invention relates to a process for the preparation of an oral pharmaceutical composition containing a quinolone antibacterial agent or its pharmaceutically acceptable salt. More particularly the present invention provides a quinolone antibacterial agent or its pharmaceutically acceptable salt in a fine particulate ready-to-use suspension dosage form which is taste masked and has a high bioavailability.
Orally administered dosage forms include solid dosage forms such as tablets or capsules, and liquid dosage forms such as solutions, suspensions or emulsions. Certain category of patients such as infants, children, elderly, disabled or seriously ill patients are unable to swallow the solid dosage forms. Therefore, a chewable solid dosage form may be provided for patients who are able to chew the dosage form, however, it is apparent that a liquid dosage form is especially preferred and in many instances is the only mode of oral administration for the above category of patients. Patients, may be more inclined to comply to their medication instruction if the dosages are easier to ingest. The present invention particularly provides a process for the preparation of an oral pharmaceutical composition containing a quinolone antibacterial agent in a liquid dosage form, however, the composition may also be provided as a semisolid dosage form.
Since the discovery of sulphonamides for antimicrobial therapy during the 1930's, there has been an on-going quest for more effective antibacterial agents having a broad spectrum of activity. Nalidixic acid, the prototype quinolone, was first disclosed in 1962 through Belgium Patent No. 612,258. Since then a large number of 4-quinolone antibacterial agents belonging to the chemical class of quinoline carboxylic acid derivatives have become known. Examples include sparfioxacin, cinoxacin, enrofloxacin, ciprofloxacin, fleroxacin, temafloxacin, difloxacin, oflaxacin, lomefloxacin, pefloxacin, norfloxacin, amifloxacin, sarafloxacin, enoxacin, and rosoxacin. It is well known to those skilled in the art that for quick onset of action and for achieving high peak concentration of the antibacterial agent at the site of infection it is desirable that the active ingredient dissolves at a fast rate resulting in rapid absorption. Furthermore, for drugs which are absorbed only from the upper gastrointestinal tract, a slow dissolution may result in incomplete bioavailability. For example, Harder et.al. (Br. J. Clin. Pharmac, 1990, 30, 35-39) reported that the main absorption site of the quinolone antibacterial agent, ciprofloxacin, is upper gastrointestinal tract upto the jejunum. Moreover, dosage forms are transported in a short time from the upper gastrointestinal tract to lower parts of the gastrointestinal tract. Therefore, the dosage form should be formulated such that it is retained for longer periods in the upper parts of the gastrointestinal tract or such that it provides a high rate of dissolution of active ingredient thus resulting in rapid and complete absorption from the upper gastrointestinal tract and therefore a high bioavailablility. The present invention provides a process for the preparation of an oral pharmaceutical composition having a high bioavailability of the quinolone antibacterial agent.
Although liquid dosage forms, in general, are suited for the purpose of rapid absorption of active ingredient, a significant drawback is that these dosage forms usually permit perceptible exposure of the active ingredient to taste buds resulting in an unacceptable taste because of bitterness of many drugs. This may, in turn lead to poor patient acceptance and compliance to the dosage regimen.
The quinolone antibacterial agents are characterised by a bitter taste, particularly, ciprofloxacin, norfloxacin, ofloxacin and enoxacin.
United States Patent No. 5152986 claimed a complex between quinoline carboxylic acid derivatives and a weak carboxyl containing cation exchange resin, the said complex being useful in masking the bitter taste of the quinoline carboxylic acid derivative.
European Patent No. 0551820 disclosed pharmaceutical compositions containing active ingredients which are flavour masked by microencapsulation having rapid release of active ingredient and high bioavailability. The microcapsules consisted of a capsule wall of water insoluble polymethacrylic acid polymers or ethylcellulose, optionally containing water soluble polymers, plasticizers, wetting agents and other customary auxiliaries. It is well known to those skilled in the art that a layer of water insoluble polymers over drug containing units results in a decrease in the rate of dissolution. Furthermore, European Patent No. 0551820, discloses microcapsules which have a size of 10 to 800 µm.
The presence of relatively large particles in taste masked liquid formulations is undesirable because they may be retained in the mouth cavity and/or get crushed between the teeth. It would thus be of benefit to provide ciprofloxacin in a very fine particulate suspended dosage form. The present invention provides a process for the preparation of an oral pharmaceutical composition containing suspended quinolone antibacterial agent in a fine particle form such that the suspension has a high bioavailability, and furthermore the bitter taste of the active ingredient is suitably masked so as to result in a palatable composition without the need to coat the drug particles with water insoluble polymers.
Currently, an oral ciprofloxacin suspension for reconstitution is known. It consists of two separate container-closure systems, one containing microcapsules of ciprofloxacin and the second containing an oil based vehicle. The suspension is reconstituted by mixing the contents of the two containers and the reconstituted suspension is stored over the duration of therapy and multiple doses are withdrawn from it. It would be of benefit to provide a pourable ready suspension of the active ingredient in a single container closure system. Not only, would it avoid the inconvenience of the suspension but more importantly it would decrease the size of product package, the storage, shipping and packaging costs and therefore the cost of the dosage form. The present invention provides a process for the preparation of the taste masked oral liquid formulation as a ready-to-use suspension.
It is an objective of the present invention to provide a process for the preparation of an oral pharmaceutical composition containing a quinolone antibacterial agent in a fine particle form such that the suspension has a high bioavailability, and furthermore, the bitter taste of the active ingredient is suitably masked so as to result in a palatable composition.
Accordingly the present invention provides a process for the preparation of an oral pharmaceutical composition comprising:
(a) a therapeutically effective amount of quinolone antibacterial agent, as herein described, or its pharmaceutically acceptable salt;
(b) an aqueous phase emulsified in an oil phase with the help of one or more emulsifier(s) and/or suspending agent(s), such as herein described, such that a water in oil emulsion is formed; and
(c) An effective amount of taste masking pharmaceutically acceptable excipients, such as herein described, to provide a palatable taste to the said composition.
The quinolone antibacterial agents to be used in the process according to the present invention include sparfloxacin, cinoxacin, ciprofloxacin, fleroxacin, temafloxacin, difloxacin, ofloxacin, lomefloxacin, pefloxacin, norfloxacin, amifloxacin, sarafloxacin, enoxacin, and rosoxacin. In one preferred embodiment of the invention, the quinolone antibacterial agent is ciprofloxacin or its pharmaceutically acceptable salt used in an amount equivalent to about 50 mg to 500 mg, more preferably from 125 to 250 mg of ciprofloxacin base per 10 ml of the composition.
According to the present invention, the oral pharmaceutical composition contains one or more suspending agent(s) and/or emulsifying agents. Suspending agents stabilise suspensions and emulsions in various ways which are well known to those skilled in the art. Apart from their stabilisation function they may have a role in taste masking such as by interaction or complexation with dissolved bitter active ingredient, by forming a highly viscous film over the surface of particles of the bitter active ingredient, or by interaction with water, thereby restricting the amount of water available for dissolution of the active ingredient.
Suspending agents are well known in the pharmaceutical art and examples include gums such as acacia, agar, carrageenan, guar, karaya, locust bean, pectin, propyleneglycol alginate, sodium alginate, tragacanth, xanthan gum; cellulose polymers such as carboxymethyl cellulose sodium, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, and hydroxypropyl methylcellulose, cross-linked acrylic acid polymers such as available under the brand name Carbopol 93 4P, clays such as bentonite and colloidal magnesium aluminium silicate, chitosan, polyethyleneglycols, gelatin, polyvinylpyrrolidone, polyvinyl alcohol and the like. According to a preferred embodiment of the invention, the suspending agent is anionic in nature, for example, alginates, propylene glycol alginate, gum arabic, carageenan, guar gum, gum karaya, gum tragacanth, and xanthan gum. In a more preferred embodiment of the invention the suspending agent is acrylic acid polymer cross-linked with allyl sucrose such as is available under the brand name Carbopol 934P.
The suspending agents, described herein, have also been traditionally used as emulsifying agents.
According to the present invention, the oral pharmaceutical composition contains one or more suspending agent(s) and/or emulsifying agents. The emulsifying agents may be selected from, but are not limited to, esters of fatty acids with alcohols such as glycerol, sorbitol, propylene glycol and polyethyleneglycols; polyglycolyzed glycerides; polyoxyethylene derivatives of fatty acid esters such as polyoxyethylene sorbitan fatty acid ester; fatty acids
such as oleic acid, lauric acid and their salts; alcohols such as cholesterol and cetyl alcohol; polyoxyethylene-polyoxypropylene copolymers; polyoxyethylene alkyl ethers; anionic surfactants such as sodium dioctyl sulfosuccinate and sodium lauryl sulphate; and the like. The factors to be considered in selection of emulsifiers are well known to those skilled in the art. The emulsifiers or combination of emulsifiers best suited for the water-in-oil emulsion are those that have the right balance of oil solubility and water solubility so as to concentrate at the interface as well as the ability to form a strong film over the surface of water droplets. Polyglycolyzed glycerides have been beneficially used in the composition, although other emulsifiers could also be used. Polyglycolyzed glycerides are made by alcoholysis reaction of natural oils with polyethylene glycols. A polyglycolyzed glyceride that may preferably be used in the composition is a polyglycolyzed medium chain glyceride or a C8 - C10 ethoxylated glyceride such as is available under the brand name Labrafac WL-1219. The suggested Cosmetic Toiletry & Fragrance Association (CTFA) name for Labrafac WL- 1219 is glyceryl caprylate/caprate PEG-4 complex. It has a Hydrophilic Lipophilic Balance (HLB) number of 4 to 5. Polyoxyethylene castor oil derivatives are also beneficially used in the invention. Polyoxyethylene castor oil derivatives are a series of materials obtained by reacting varying amounts of ethylene oxide with castor oil or hydrogenated castor oil. A polyoxyethylene castor oil derivative that may preferably be used in the composition is polyoxyl 40 hydrogenated castor oil which has a HLB number of 14-16. The more preferred emulsifier system comprises of polyoxyl 40 hydrogenated castor oil at a concentration in the range from about 0.1% to 0.4%w/v, preferably 0.25% w/v and polyglycolyzed medium chain glycerides such as available under the brand name of Labrafac Hydro WL-1219 at a concentration in the range from about 1.0% to 4.0% w/v, preferably 2.5% w/v of the composition.
The emulsifying agents as described herein have also been used traditionally in suspensions as wetting and dispersing agents.
According to the present invention the oral pharmaceutical composition contains an aqueous phase. It would be well recognized by those skilled in the art that the amount of water in the pharmaceutical composition would affect the amount of the quinolone antibacterial agent dissolved and therefore the taste of the composition. It would further be recognized by those skilled in the art that the amount of aqueous phase emulsified in the oil phase affects the viscosity of the emulsion which in turn affects the characteristics of the composition such as its physical stability, pourability, body, and appearance.
In preferred embodiments of the invention, the water content is in the range from about 25% to 60% w/w, more preferably from about 35% to 45% w/w of the composition.
According to a preferred embodiment of the invention, the quinolone antibacterial agent is present in the form of a fine particulate suspension. In a preferred embodiment of the invention the quinolone antibacterial agent used has a particle size such that 90% particles are less than 125 um, more preferably less than 25 urn, and further more preferably less than 10um, when measured by laser diffraction technique.
It is well known to those skilled in the art that adjustment of the pH of the aqueous phase of a pharmaceutical composition to a pH range such that the solubility of the active ingredient is minimised helps in masking taste by limiting the amount of dissolved bitter active ingredient that can interact with the taste bud receptors. In preferred embodiments of the invention the
aqueous phase contains one or more pH modifying agents such that the pH is adjusted to within one pH unit from the pH at which the solubility of the quinolone antibacterial agent is at its minimum. In a particular embodiment of the invention the active ingredient is ciprofloxacin and the pH of the aqueous phase is in the range from about 6.0 to 7.5.
In preferred embodiments of the invention, the amount of oil phase is from about 40 to 75%w/w of the composition. In more preferred embodiments of the invention, the amount of oil phase is from about 55 to 65% w/w of the composition. According to the invention, the oil phase contains an oil. Examples of oils include coconut oil, corn oil, soybean oil, sunflower oil, sesame oil, arachis oil, rice-bran oil, rapeseed oil, mineral oil, and the like. The oil phase
may contain oil soluble pharmaceutically acceptable excipients such as oil soluble emulsifiers, flavour oils, racementhol, preservatives, stabilisers and the like.
According to the invention, the oral pharmaceutical composition contains taste masking excipients. The methodology of flavouring a pharmaceutical composition so as to mask the unacceptable taste of the composition is well known to those skilled in the art. Thus, for example, a bitter tasting compound may be blended with sweet, sour or salty compounds. Examples of sweetening agents include sugar, saccharin sodium, aspartame, sorbitol, sodium cyclamate, and the like. Examples of sour tasting compounds include acids such as citric and tartaric acids and/or their salts. Taste masking excipients include compounds that have a cooling effect and desensitize the taste buds, for example, menthol and sodium glycerrhyzinate. Taste masking excipients also include flavours like orange, mango, pineapple, toffee, and the like. In preferred embodiments of the invention the taste masking excipients include saccharin sodium in a range from about 0.3 to 0.6%w/v, preferably 0.4% w/v of the composition.
In a preferred embodiment of the invention, the oral pharmaceutical composition does not contain sugar.
The oral pharmaceutical composition also contains preservatives. Preservatives useful in the present invention include, but are not limited to, sodium benzoate, potassium sorbate, salts of ethylene diamine tetraacetic acid, and p-hydroxy benzoic acid esters such as methyl paraben. Methods of evaluating the efficacy of preservatives in pharmaceutical formulations are well known to those skilled in the art and suitable preservatives or their combinations may be selected on the basis of such evaluations. One such preferred preservative system includes methyl paraben sodium in concentration from about 0.1 to 0.25 % w/v, more preferably 0.18 %w/v, and propyl paraben sodium in a concentration from about 0.01 to 0.03% w/v, more preferably 0.02%w/v of the composition.
The oral pharmaceutical composition may also, if desired, contain additional ingredients such as defoaming agents, electrolytes , sequestering agents and anticaking agents.
The invention will now be illustrated below by way of examples using the quinolone antibacterial agent, ciprofloxacin. The examples are not intended to limit the scope of the present invention but read in conjunction with the details and general description above, provide further understanding of the present invention and an outline of a preferred process for preparing the composition of the invention.
EXAMPLE 1
This example illustrates the process of preparation of an oral suspension containing suspended ciprofloxacin (125mg/10ml). The ingredients contained in the suspension are as follows
(Table Removed)

Manufacturing Process :
1. Fractionated coconut oil was heated at 80-90°C for 3 hrs and cooled to room temperature.
2. 400ml purified water was taken in an appropriate sized stainless steel vessel. 1.8 g methyl paraben sodium, 0.2 g propyl paraben sodium, 2 g disodium edetate, 1.2 g citric acid monohydrate, 16 g disodium hydrogen phosphate, 4 g saccharin sodium and 1.0 g sodium chloride were added and dissolved under continuous stirring.
3. Carbopol 934P was dispersed by stirring for 30 min. in the solution of Step 2.
4. To the bulk of step 3, 2.5 g of Polyoxyl 40 hydrogenated castor oil was added under high speed stirring and stirred further for 15 minutes.
5. pH of bulk of step 3 was recorded. pH was either between 6.6 to 7.2 or was adjusted using 10% w/v citric acid solution or 5% sodium hydroxide solution to a pH between 6.6 to 7.2
6. 26.1 g of ciprofloxacin USP was added and dispersed in the bulk of step 5, using a high shear mixer for 30 minutes.
7. 25 g of Labrafac Hydro WL 1219 was dissolved in fractionated coconut oil, 525mL.
8. The oil phase of step 7 was added to the bulk of aqueous phase of step 5 and homogenized for 15 min.
9. 0.5 g of racementhol was dissolved under stirring, in 10 mL of mango ripe flavour and 4ml of Devon butter toffee flavour. The solution was transferred to the bulk of step 8.
10. pH of bulk of step 9 was checked. If pH was not between 6.8 to 7.2, it was adjusted with 10% w/v citric acid solution or 5% w/v sodium hydroxide solution.
11. Volume was made up using fractionated coconut oil to yield a homogeneous suspension.
Three different ciprofloxacin suspensions were made according to the process outlined above using ciprofloxacin consisting of particles having a particle size such that 90% of the particles were less than 125 urn, 25 µm, and 10 |xm, respectively, in the three suspensions. The suspensions were pourable and had a palatable taste. The mouthfeel of the suspension improved with decrease in particle size.
The resulting ciprofloaxacin oral suspensions were physically stable (no jflocculation or separation) at accelerated conditions of temperature and humidity i.e 40°C/75%RH for 30 days. The suspensions had a pH of 7.10 and viscosity of 500 - 1200 centipoise (Brookefield LV viscometer, RV Spindle 3, 20 rpm).
EXAMPLE 2
This example illustrates the process of preparation of an oral suspension containing suspended ciprofloxacin (250mg/10ml). The ingredients contained in the suspension are as follows:
(Table Removed)
Manufacturing Process
The ingredients were mixed together following the procedure set forth in Example 1. Three different ciprofloxacin suspensions were made according to the process outlined in example 1 using ciprofloxacin consisting of particles having a particle size such that 90% of the particles were less than 125 µm, 25 µm, and 10 µm, respectively, in the three suspensions. The suspensions were pourable and had a palatable taste.
The resulting suspensions were physically stable at accelerated conditions of temperature & RH i.e. 40°C/75%RH for 30 days. The suspensions had a pH of 6.65 and viscosity of 800 -1500 cps (Brookefield LV viscometer, RV spindle 3, 20 rpm).
The bioavailability of ciprofloxacin from 20 ml of the suspension and ciprofloxacin tablets containing 500 mg of ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin base were compared in a bioavailability study. The study was conducted on 8 young healthy male volunteers who were fasted prior to oral administration of the two products. The plasma concentration profile is given in Figure 1.of the accompaning drawings.
Although ciprofloxacin base has poor solubility in water and ciprofloxacin is absorbed only from upper gastrointestinal tract, the bioavailability study showed that the suspension containing ciprofloxacin base gave the same extent and marginally slower rate of absorption as compared to the tablets containing ciprofloxacin hydrochloride. It may be noted that when an aqueous suspension containing ciprofloxacin base was orally administered to human volunteers it was found that the bioavailability of ciprofloxacin from such a ciprofloxacin suspension was low as compared to tablets containing ciprofloxacin hydrochloride. This demonstrates that the oral pharmaceutical composition prepared according to the process of the present invention not only had an acceptable taste but also resulted in a high bioavailability of ciprofloxacin.
The Oral pharmaceutical composition prepared according to the present invention is not a mere admixture but has properties different from the sum total of the properties of its ingredients.

We claim :
1. A process for the preparation of an oral pharmaceutical composition comprising :
(a) A therapeutically effective amount of quinolone antibacterial agent,as herein
described, or its pharmaceutically acceptable salt; (b)An aqueous phase emulsified in an oil phase with the help of one more
emulsifier(s) and/or suspending agent(s), such as herein described, such that a
water in oil emulsion is formed ; and (c) An effective amount of taste masking pharmaceutically acceptable excipients,
such as herein described, to provide a palatable taste to the said composition.
2. A process as claimed in claim 1 wherein the oil phase comprises of fractionated coconut oil.
3. A process as claimed in any of claims 1 and 2 wherein the content of water in the aqueous phase is in a range from 35 to 45% w/w of the composition..
4. A process as claimed in any of claims 1 to 3 wherein one or more pH modifying agents are added such that the pH of the aqueous phase is adjusted to within one pH unit from the pH at which the solubility of the quinolone antibacterial agent is at its minimum.
5. A process as claimed in claims 1 to 5 wherein the suspending agent is an acrylic acid polymer cross-linked with allyl sucrose.
6. A process as claimed in any of claims 1 to 5 wherein the emulsifiers are selected from polyoxethylene castor oil derivatives and polyglycolyzed glycerides.
7. A process as claimed in claim 6 wherein the polyoxyethylene castor oil derivative is polyoxyl 40 hydrogenated castor oil.
8. A process as claimed in claim 6 wherein the polyglycolyzed glyceride is a polyglycolyzed medium chain (C8-C10) glyceride having a HLB number in the range from 4 to 5.
9. A process as claimed in any of claims 1 to 8 wherein the quinolone antibacterial agent used has a particle size such that 90 % particles are less than 125 µm when measured by laser diffraction technique.
10. A process as claimed in any of claims 1 to 8 wherein the quinolone antibacterial agent used has a particle size such that 90 % particles are less than 25 µm when measured by laser diffraction technique.
11. A process as claimed in any of claims 1 to 8 wherein the quinolone antibacterial agent used has a particle size such that 90 % particles are less than 10 urn when measured by laser diffraction technique.
12. A process as claimed in any of claims 1 to 11 wherein the quinolone antibacterial agent is ciprofloxacin.
13. A process as claimed in claim 12 wherein one or more pH modifying agents are added such that the pH of the aqueous is in the range from pH 6.0 to 7.5.
14. A process for the preparation of an oral pharmaceutical composition of claims 1 to 13 substantially as herein described and illustrated by the examples herein.