MECHANISM

FIELD OF INVENTION

The present invention relates to a solid oral pharmaceutical composition comprising gemifloxacin or a pharmaceutically acceptable hydrate, crospovidone, povidone and at least one pharmaceutically acceptable excipient, wherein the weight ratio of crospovidone to povidone in the composition is about 4.5: 1.0 and the composition is prepared by fluid -bed granulation.

BACKGROUND OF THE INVENTION

Gemifloxacin is a synthetic broad- spectrum antibacterial agent for oral administration and it is a compound related to the fluoroquinolone class of antibiotics. The fluoroquinolone class is expected to work by blocking the action of two bacterial enzymes called DNA gyrase and topoisomerase IV, which are needed to make and repair bacterial DNA.

The chemical name of gemifloxacin is (i?,S)-7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)-l- pyrrolidinyl]-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-l,8-n aphthyridine-3-carboxylic acid. The empirical formula of gemifloxacin is C18H20FN5O4 and molecular weight is 389.38 g/mole. The chemical structure of gemifloxacin is:

Formula I

Commercially, gemifloxacin is used as its mesylate salt in the sesquihydrate form. The The empirical formula of gemifloxacin mesylate salt is C18H20FN5O4.CH4O3S and its molecular weight is 485.49 g/mole, and the mesylate salt is a white to light brown powder. The chemical structure of gemifloxacin mesylate is:

Formula II

Gemifloxacin mesylate sesquihydrate has one asymmetric centre at C3, it is developed as the racemate. It has equal amounts of enantiomers. Enantiomers are identified with sensitive analytical methods like IR, UV and NMR.

Gemifloxacin base and its pharmaceutically acceptable salts first have been declared in EP688772 by LG Chemical LTD in which it also discloses the process for the preparation of gemifloxacin mesylate anhydrous, monohydrate, sesquihydrate, and trihydrate.

The hydrate forms of gemifloxacin mesylate, especially sesquihydrate is known as having good physicochemical properties such as high water solubility and stability. EP0981527 specifically discloses the sesquihydrate form of gemifloxacin mesylate.

Gemifloxacin mesylate was subsequently developed by SmithKline Beecham (later on GSK) and Oscient Pharmaceutical Co. for the treatment of urinary and respiratory tract bacterial infections. It was approved by Food and Drug Administration (FDA) in April 2003 and it has been launched in the film-coated tablet form under the name of the FACTIVE ^® in the strength of 320 mg. FACTIVE ^® is used for the treatment of acute exacerbation of chronic bronchitis (AECB) and community acquired pneumonia (CAP) of mild to moderate severity including multi-drug resistant strains Streptococcus pneumoniae (MDRSP). The recommended dose in both indications is one 320 mg tablet administered once daily for 5 days with the possibility to extend treatment to 7 days in cases of CAP due to known or suspected MDRSP.

Gemifloxacin is a quinolone or fluoroquinolone antibiotic, bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. In addition to the blocking of the bacterial DNA replication, it is active against both Gram- positive and Gram-negative bacteria due to being broad-spectrum antibiotic. FACTIVE ^® is in the form of film-coated tablet contains gemifloxacin mesylate as active ingredient and crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, titanium dioxide as pharmaceutically acceptable excipients. Gemifloxacin as an oral tablet is considered to be freely soluble at neutral pH (350 pg/mL at 37°C, pH 7.0). Thus, it is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of gemifloxacin were observed between 0.5 and 2 hours following oral tablet administration and the absolute bioavailability of the 320 mg tablet averaged approximately 71%. In the state of art there are many patents/patent applications which are summarized below.

EP2491921 relates to a pharmaceutical composition comprising anhydrous gemifloxacin or pharmaceutically acceptable salt thereof manufactured by using various manufacturing processes such as dry granulation, wet granulation and direct compression including organic solvent. The content of organic solvent should be monitored carefully in the pharmaceutical composition for the use of drug product in safe.

EP2491920 relates to an effervescent tablet, sachet and dry syrup form of pharmaceutical formulation comprising gemifloxacin or pharmaceutically acceptable salt thereof and an excipient or mixtures of excipients, is in the form of an effervescent tablet, sachet and dry syrup. One of the disadvantages for these dosage forms is that the content of drug product requires to be dissolved in a liquid before administration.

CN102949369 relates a pharmaceutical composition comprising gemifloxacin mesylate manufactured by wet granulation wherein the manufacturing method comprising two steps; the first step is related with using high speed mixer wherein gemifloxacin and appropriate pharmaceutical excipients are mixed and then granulated with pre-binder; the second step is related with using fluidized bed granulation wherein another binder is sprayed over the obtained composition in the first step and then the obtained granule is dried and screened through proper sieved. However, granulation process is carried out within two steps which requires more time and amount of pharmaceutically acceptable excipients compared to one step granulation process while performing the manufacturing. There is a need to develop an immediate release tablet composition which is more advantageous in terms of manufacturing process and formulation design presenting suitable dissolution profile and disintegration mechanism.

SUMMARY OF THE INVENTION

The object of the invention is to develop compositions comprising gemifloxacin as gemifloxacin mesylate preferably sesquihydrate form that presents an improved release pattern and disintegration mechanism.

The present invention relates to a solid oral pharmaceutical composition comprising gemifloxacin mesylate or a pharmaceutically acceptable hydrate, crospovidone, povidone and at least one pharmaceutically acceptable excipient, wherein the weight ratio of crospovidone to povidone in the composition is about 4.5: 1.0 and the composition is prepared by fluid-bed granulation.

The present invention also relates to a wet granulation process for the preparation of a solid pharmaceutical composition according to the invention comprising the steps of: a) Gemifloxacin mesylate, preferably in the form of sesquihydrate, Microcrystalline cellulose and Crospovidone are transferred into fluid-bed granulator by screening through a proper sieve and stirred, b) Povidone is dissolved in a sufficient amount of deionised water until it is completely dissolved , c) The solution in Step (b) is sprayed onto the powder blend prepared in Step (a) to perform granulation process, d) The granule prepared in Step (c) is dried and sifted through a proper sieve, e) Magnesium stearate is added to the granules prepared in Step (d) by screening through a proper sieve and stirred for 3 minutes to obtain a uniform final blend, f) Tablet compression is performed with the final blend in Step (e), g) Tablets are coated with a defined coating agent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a solid oral pharmaceutical composition comprising gemifloxacin mesylate or a pharmaceutically acceptable hydrate, crospovidone, povidone and at least one pharmaceutically acceptable excipient, wherein the weight ratio of crospovidone to povidone in the composition is about 4.5: 1.0 and the composition is prepared by fluid-bed granulation.

The present invention relates to a solid oral pharmaceutical composition comprising gemifloxacin or a pharmaceutically acceptable salt thereof, preferably mesylate salt, more preferably mesylate salt in sesquihydrate form with a high load drug due to presenting 320 mg gemifloxacin as pure in the finished drug product. Therefore, the object of this invention is relates to develop an immediate release tablet composition that has high load gemifloxacin mesylate sesquihydrate, approximately about 80% by weight of the total composition.

Preferably, the dosage form of the composition is an immediate release tablet.

The term an "immediate release tablet" refers to dosage forms disintegrate rapidly after administration with enhanced rate of dissolution. Moreover, in the case of solid dosage it should dissolve or disintegrate in the stomach within a short period. It should present rapid dissolution and absorption of drug, which may produce rapid onset of action.

In one embodiment, the gemifloxacin mesylate used in the composition is in sesquihydrate form.

Based on the prior art, gemifloxacin has hygroscopic characteristics that is known to be freely soluble at neutral pH. Thus, it tends to show segregation during the powder blending and that gives rise to obtain granule blend with non-homogeneity characteristics.

The powder blending comprising gemifloxacin mesylate sesquihydrate may not be manufactured by using conventional methods such as direct compression and dry granulation with the current formulation due to segregation characteristic properties of gemifloxacin and also, being in high doses per unit which means the powder characteristics of the blend is dominated by gemifloxacin. These problems further cause to obtain non -homogeneous tablets which present non-homogenous release pattern and in conclusion present inappropriate dissolution and disintegration time results.

One of the excipient that should be located in the formulation design of an immediate release tablet composition is disintegrant to achieve targetted dissolution profiles. Disinetgrant is the agent added to tablet formulations to promote the breakup of the tablet into smaller fragments in an aqueous environment thereby increasing the available surface area and promoting a more rapid release of the drug substance.

Another excipient that should be located in the formulation design of an immediate release tablet composition is binder to achieve targetted dissolution profiles. Binder promotes cohesiveness, the binders, also called adhesives, help the other ingredients in a tablet to mix together. Thus, tablet binders are used to turn powder to granules; this is achieved through the process of granulation. The type and amount of binder affects dissolution profile directly in case of having an important role in physicochemical properties of tablet. Therefore, two types of wet granulation method was evaluated to decide the most proper one.

In vitro dissolution is one of the vital tools for characterization of biopharmaceutical quality of a dosage form of drug development. In vitro dissolution data helps in the evaluation and interpretation of the possible effects on bioavailability. The in vitro dissolution curves depend on the release characteristics of the formulation and manufacturing process. In the said invention of the immediate release tablet further comprises filler, disintegrant, binder, lubricant and solvent.

The filler can be selected from phosphate dihydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and mixtures thereof. Preferably, the filler is microcrystalline cellulose.

The disintegrant can be selected from croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose and mixtures thereof. Preferably, the disintegrant is crospovidone. The binder can be selected from hypromellose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol and mixtures thereof. Preferably, the binder is povidone.

The lubricant can be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. Preferably, the lubricant is magnesium stearate. The solvent can be selected from deionized water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide and their mixtures thereof. Preferably, the solvent is water.

First embodiment in accordance with the present invention was designed with adjusted quantitative formulation composed of pharmaceutically acceptable ingredients mentioned above. The embodiment, Example 1, was manufactured by using wet granulation method, particularly high shear granulation method due to the advantage of high-shear granulation that the process is completed within a short period of time in comparison with fluid-bed granulation process.

The proposed embodiment based on the invention provides an immediate release tablet composition wherein the amounts in w/w% by weight of the total composition are as stated below:

Example 1: Unit Formula The manufacturing process of the immediate release tablet composition, identified as Example 1 comprising gemifloxacin, preferably gemifloxacin mesylate sesquihydrate as an active ingredient, comprises the following steps: i. Gemifloxacin mesylate sesquihydrate, microcrystalline cellulose, crospovidone and povidone were weighed, transferred into mixer through screening with a proper sieve and stirred, ii. Sufficient quantity of deionised water was added to the powder blend prepared in Step (i) to perform granulation process in the high- shear mixer, iii. The granules prepared in Step (ii) were dried in fluid bed dryer and sifted through a proper sieve, iv. Magnesium stearate was added to the powder granulation prepared in Step (iii) through screening with a proper sieve and stirred, v. The powder blend in Step (iv) was sifted through a proper sieve to obtain a homogenous final blend, vi. Tablet compression was performed with the final blend obtained in Step (v).

The immediate release tablet that was prepared by high-shear granulation as a type of wet granulation method, wherein the amount ratio of crospovidone as disintegrant to povidone as binder was 3.75:1. The obtained tablets were subjected to in vitro dissolution study under the conditions that are set by US FDA. Dissolution media is 0.01N HC1 based on the information. Other conditions are defined as; volume of dissolution media is 900 ml, temperature is 37°C±0.5°C, rotation speed is 50 rpm, Apparatus II (Paddle) and the duration of dissolution study is 45-minute.

Table I: The results of dissolution study for Example 1 Based on the results presented in Table I above;

Firstly, Example 1 couldn’t release the active ingredient gemifloxacin in a similar dissolution profile with reference drug product.

Secondly, disintegration time was 20 minutes in average. In conclusion; dissolution profile should be accelerated and disintegration time should be reduced to comply with ICH guidelines in which the acceptable specification for disintegration time is not more than 15 minutes for tablet dosage form.

The most effective parameters on dissolution release profile are disintegrant and binder used in the formulation. The disintegrant and binder have a functional reverse correlation between them. As known from state of art, increase in disintegrant can reduce the wetting time of tablet dosage form and regulates the dissolution release profile to act faster. However, since the binder has reverse function of disintegrant, it was considered to obtain an equilibrium for the release versus time. Therefore, another example was proposed, by doing the modifications below; - the amount of the crospovidone as disintegrant was planned to be increased, and the amount of povidone as binder was planned to be decreased by keeping the final tablet weight constant through adjusting the amount of filler and using the same manufacturing method with Example 1.

Example 2: Unit Formula

Manufacturing process comprises the following steps: i. Gemifloxacin mesylate sesquihydrate, microcrystalline cellulose, crospovidone and povidone were weighed, transferred into mixer through screening with a proper sieve and stirred, ii. Sufficient quantity of deionised water was added to the powder blend prepared in Step (i) to perform granulation process in the high- shear mixer, iii. The granules prepared in Step (ii) were dried in fluid bed dryer and sifted through a proper sieve, iv. Magnesium stearate was added to the powder granulation prepared in Step (iii) through sifting with a proper sieve and stirred, v. The powder blend in Step (iv) was sifted through a proper sieve to obtain a homogenous final blend, vi. Tablet compression was performed with the final blend in Step (v).

Table II: The results of dissolution study for Example 2 Although dissolution release profile and disintegration time of Example 1 was considered to be accelerated by increasing the amount of crospovidone and decreasing the amount of povidone, targeted dissolution profile was not achieved.

It was surprisingly realized by observing both embodiments that the synergetic effect of crospovidone and povidone was superior to the individual amounts of them on the release pattern of the formulation.

Based on the results presented in Table P above, dissolution profile and disintegration time of Example 2 were considered to be improved by designing another embodiment with doing modifications on the amount ratio of crospovidone to povidone. The amount ratio of crospovidone to povidone used in Example 2 was 6.0: 1.0. The most proper ratio was the one has the best correlation based on the functions in the formulation and Example 3 was proposed to get this relationship.

Example 3: Unit Formula

Manufacturing process comprises the following steps: i. Gemifloxacin mesylate sesquihydrate, microcrystalline cellulose, crospovidone and povidone were weighed, transferred into mixer through screening with a proper sieve and stirred, ii. Sufficient quantity of deionised water was added to the powder blend prepared in Step (i) to perform granulation process in the high-shear mixer, iii. The granules prepared in Step (ii) were dried in fluid bed dryer and sifted through a proper sieve, iv. Magnesium stearate was added to the powder granulation prepared in Step (iii) through screening with a proper sieve and were stirred, v. The powder blend in Step (iv) was sifted through a proper sieve to obtain a homogenous final blend, vi. Tablet compression was performed with the final blend in Step (v). The amount ratio of crospovidone to povidone was 4.5:1.

Table III: The results of dissolution study for Example 3

Based on the results presented in Table III above, dissolution profiles of Example 3 were accelerated in comparison with the dissolution profile of Example 2. Improvement in the release profile of active ingredient was achieved. In accordance with FDA regulations, similarity of two drug products can be compared based on the results of in vitro dissolution profile studies of these drug products.

In the present embodiment, the similarity factor between dissolution profiles of reference drug product and Example 3 was calculated and evaluated in accordance with FDA regulations. If the value of the similarity factor is between 50 - 100, the dissolution profiles of two drug products in comparison are concluded as similar. Moreover, the similarity factor was calculated as the value of 50 which means the developed formulation was suitable, but very close to the lower limit of acceptance criteria and a few improvements were still required.

In spite of the improved dissolution release, the disintegration time was still an unsolved problem, because the result of disintegration time was found 19 minutes.

As stated above to develop a drug product with proper quality attributes, two parameters have significant roles. Up to now, formulation design was modified and improvements were provided at a specified level.

Thus, the other most significant parameter influences the disintegration time as well as dissolution release is manufacturing process incorporated with a suitable formulation design. The manufacturing method particularly formalize the structure of the granule on the disintegration mechanism. Based on the state of art, it is absolutely clear that subtle variations in processing parameters result in significant changes for the disintegration process.

Moreover, a detailed understanding of the interplay between process parameters, structure and disintegration behaviour will be critical for high quality immediate -release products manufactured by continuous processing with active feedback loops controlling the process.

For the reasons mentioned above, the type of the wet granulation method was changed from high-shear granulation to fluid-bed granulation, in developing the granule structure of the powder blend.

In the state of art high-shear granulation allows the mixing of various powder materials and their subsequent granulation and wherein the growth of the granules is ensured by addition of the liquid either contains a binder or not, and by the stochastic movement of the powder in the device.

In the present invention, the granules obtained after a granulation process by using high-shear granulation process was not homogenous and fine as it should be. Thus, this kind of granule structure caused high disintegration time due to requiring long time for wetting. It was considered that fluid-bed granulation process may help to overcome these problems.

In fluid-bed granulation, the spraying of the solvent onto a powder granule increase the bond link between each other with the achieving the desired size of the granule. As a result, the obtained smaller and narrower particle size with fluid-bed granulation may improve the overall quality of the final product. Another embodiment was proposed that has the same qualitative and quantitative formulation with Example 3 in which the manufacturing method was fluid-bed granulation.

Example 4: Unit Formula Manufacturing process comprises the following steps: i) Gemifloxacin mesylate as sesquihydrate, Microcrystalline cellulose and Crospovidone were transferred into fluid-bed granulator by screening through a proper sieve and stirred, ii) Povidone was dissolved in a sufficient amount of deionised water till to dissolve completely, iii) The solution in Step (ii) was sprayed into the powder blend prepared in Step (i) and granulation process was performed. iv) The granules prepared in Step (iii) was dried and sifted through a proper sieve. v) Magnesium stearate was added to the granules prepared in Step (iv) by screening through a proper sieve and the powder blend is stirred for 3 minutes to obtain a uniform final blend. vi) Tablet compression was performed with the final blend in Step (v). vii) Further, tablets were coated with a defined coating agent.

The amount ratio of crospovidone to povidone was 4.5:1.

Table IV: The results of dissolution study for Example 4

Disintegration time of Example 4 was found 12 minutes on average.

Based on the results presented in Table IV above, dissolution profiles of Example 4 were accelerated in comparison with that of Example 3. In addition, disintegration time of Example 4 was reduced to 12 minutes that met also ICH requirements by being not more than 15 minutes.

Moreover, the similarity between dissolution profiles of reference product and Example 4 was better. The similarity factor between dissolution profiles of reference drug product and Example 4 was 72, which means that the modifications done were served as it was intended.

Finally, the release profile and disintegration mechanism of developed immediate release tablet dosage form manufactured in accordance with fluid-bed granulation process and formulation design comprising crospovidone and povidone with the specific amount ratio of 4.5: 1.0 was optimized.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

The present invention also provides a wet granulation process for the preparation of a solid pharmaceutical composition according to any one of the preceding claims, wherein the process comprising the steps of: a) Gemifloxacin mesylate, preferably in the form of sesquihydrate, Microcrystalline cellulose and Crospovidone are transferred into fluid-bed granulator by screening through a proper sieve and stirred, b) Povidone is dissolved in a sufficient amount of deionised water until it is completely dissolved , c) The solution in Step (b) is sprayed onto the powder blend prepared in Step (a) to perform granulation process, d) The granule prepared in Step (c) is dried and sifted through a proper sieve, e) Magnesium stearate is added to the granules prepared in Step (d) by screening through a proper sieve and stirred for 3 minutes to obtain a uniform final blend, f) Tablet compression is performed with the final blend in Step (e), g) Tablets are coated with a defined coating agent.