TECHNICAL FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical formulation for oral administration containing a therapeutically effective quantity of an oxazolidinone antibacterial agent such as Linezolid or pharmaceutical acceptable salt, derivative or polymorph thereof and a method for the preparation thereof.

BACKGROUND OF THE INVENTION Linezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria such as streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA) that are resistant to several other antibiotics. The main indications of Linezolid are infections of the skin and soft tissues and pneumonia (particularly hospital-acquired pneumonia), although off-label use for a variety of other infections is becoming popular.

Oxazolidinone antibiotics, such as Linezolid, have been known to contain the oxazolidinone ring in them structurally and hence their name. They are potent antibiotics which are saved as drugs of last resort against gram-positive bacteria. They are not to be used against bacteria which are sensitive to narrow spectrum antibiotics. Mechanistically oxazolidinone antibiotics show their action by inhibiting protein biosynthesis in the bacteria, which in turn causes cell death.

The oxazolidinones are protein synthesis inhibitors: they stop the growth and reproduction of bacteria by disrupting translation of messenger RNA (mRNA) into proteins in the ribosome. Although the mechanism of action is not fully understood, Linezolid appears to work on the first step of protein synthesis, initiation, unlike most other protein synthesis inhibitors, which inhibit elongation. It does so by preventing the formation of the initiation complex, composed of the 30S and 50S subunits of the ribosome, tRNA, and mRNA. Linezolid binds to the 23S portion of the 50S subunit (the center of peptidyltransferase activity). Due to this unique mechanism of action, cross-resistance between Linezolid and other protein synthesis inhibitors is highly infrequent or nonexistent.

The chemical name of Linezolid is (S)-N-({3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo- l,3-oxazolidin-5-yl}methyl)acetamide. The molecular formula is C ₁₆ H ₂₀ FN ₃ O ₄ corresponding to a molecular weight of 337.35. It is a white or almost white crystalline powder which is slightly soluble in water and freely soluble in methanol and methylene chloride.

Linezolid exhibits polymorphism and the main polymorphic forms that are known in the literature are form II and form III. Form II is more stable at temperatures below 85°C and thus, form III has the tendency of converting to form II when exposed to conditions of elevated temperature and humidity.

EP-B- 1248616 discloses taste masked antibiotic composition in the form of microcapsules comprising particles of Linezolid coated with an inner polymeric coating prepared by solvent coacervation of a microencapsulation polymer and an outer plasticised enteric polymer.

WO-A-2010/026597 discloses a pharmaceutical composition comprising a core containing Linezolid in the form of beadlet or pellet, manufactured by extrusion and spheronization method. Although each of the patents above represents an attempt to overcome the stability and solubility problems associated with pharmaceutical compositions comprising Linezolid, there still exists a need for a pharmaceutical composition which avoids such problems.

SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide an improved stable solid dosage formulation for oral administration containing an oxazolidinone antibacterial agent, and in particular Linezolid or pharmaceutical acceptable salt, derivative or polymorph thereof, as an active ingredient, which overcomes the deficiencies of the prior art and avoids polymorphic transformation of the active pharmaceutical ingredient resulting in longer shelf-life of the product.

Further object of the present invention is to provide a stable solid dosage formulation for oral administration containing Linezolid that overcomes the low water solubility of the active ingredient and has acceptable pharmacotechnical properties. It is another object of the present invention to provide an oral solid dosage formulation comprising Linezolid as an active ingredient, which is bioavailable and with sufficient self- life.

A further approach of the present invention is the selection of the appropriate active ingredient particle size distribution in order to obtain the optimum dissolution profile.

A major object of the present invention is the selection of the optimal combination of pharmaceutical acceptable excipients and method of preparation in order to achieve the appropriate dissolution profile and stability for the finished dosage form. Said dosage form affords predictable and reproducible drug release rates in order to achieve better treatment to a patient.

Another aspect of the present invention is to provide an oral solid dosage formulation comprising Linezolid which is manufactured through a fast, simple and cost-effective process.

In accordance with the above aspects of the present invention, a pharmaceutical composition for oral administration is provided comprising Linezolid or pharmaceutical acceptable salt, derivative or polymorph thereof, as an active ingredient, and an effective amount of the non- ionic surfactant Poloxamer to enhance the active ingredient's solubility.

According to another embodiment of the present invention, a process for the preparation of a stable, solid dosage form for oral administration, containingan oxazolidinone antibacterial agent such as Linezolid is provided, which comprises the following steps: -weighing of Linezolid and all excipients and sieving

-mixing Linezolid and the excipients of the internal phase until complete uniformity

-roller compacting or slugging the bulk mixture

-sizing of the granules

-mixing the granules with lubricant

-compressing the resulted mixture into a tablet dosage form; and

-optionally, applying a film-coating on the core.

The composition of the present invention may be alternatively manufactured by a direct compression process.

Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the dissolution profile of Formulation Trial 2.

Fig. 2 shows the dissolution profile of Formulation Trials 3 A-C.

Fig. 3 shows the dissolution profile of Formulation Trial 4.

Fig. 4 shows the dissolution profile of Formulation Trial 5.

Fig. 5 shows the dissolution profile of Formulation Trial 6.

Fig. 6 shows the dissolution profile of Formulation Trial 7.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient (e.g. Linezolid) is considered to be "stable" if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.

As already mentioned the main object of the present invention is to provide an immediate release composition of Linezolid or pharmaceutical acceptable salt, derivative or polymorph thereof that is simple to manufacture, bioavailable, cost effective, stable and possesses good pharmacothechnical properties.

Particle size is having a pronounced effect on the absorption of drugs with low aqueous solubility. Due to the poor solubility of Linezolid the influence of its particle size distribution on its dissolution was extensively studied in order to achieve the objects of the present invention.

In order for a drug to have its effect after oral administration it must go into solution and then diffuse through the gut wall into the body. The first step in that process is the disintegration of the dosage form followed by dissolution of the active ingredient. One way to increase dissolution rate of poorly soluble drugs such as Linezolid is to increase the surface available for dissolution by reducing particle size.

The bioavailability of poorly soluble drugs, for example Linezolid, may be increased by using specific excipients able to enhance the active ingredient's solubility. Poloxamer is the excipient of choice for dissolution problems with solid oral dosage forms.

Poloxamers are non-ionic polyoxyethylene-polyoxypropylene copolymers. When the concentration of the poloxamers in the system increases, this results in the formation of multimolecular aggregates. Polypropylene oxide usually forms central hydrophobic cores wherein methyl groups interact via Van der Waals forces with the substance undergoing solubilisation. However, water solubility is believed to be due to the polyethylene oxide block by hydrogen bonding interactions of ether oxygen with water molecules.

The presence of the non-ionic surfactant Poloxamer in the formulation might help:

a) The swelling of the system.

b) The penetration of the dissolution medium inside the system due to its surfactant properties.

c) The wetting of the active ingredient.

d) The diffusion of the dissolved active ingredient. In such cases, the formation of a monolayer film of Poloxamer makes the particle surface hydrophobic in nature which swells in contact or by penetration of an aqueous environment. The swelling of such particles may control active ingredient release from gel-structured cavities.

The non-ionic surfactant poloxamer is present in the preferred composition of the present invention in an amount of more than 1% (w/w) and less than 10% (w/w). Most preferably, poloxamer is present in an amount of more than 1% (w/w) and less than 5% (w/w).

The solubility properties of water-soluble drugs result in rapid and high-level drug release, but with poorly soluble drugs such as Linezolid, other ingredients in the formulation, including the disintegrant, play a key role in determining the drug dissolution characteristics exhibited by the finished formulation. To aid dissolution, conventional tablet formulations generally require rapid disintegration, which can be facilitated by the addition of superdisintegrants. Commonly used superdisintegrants, such as crospovidone, croscarmellose sodium and sodium starch glycolate, are highly efficient at low concentration levels in tablet formulations at facilitating the rate and extent of tablet disintegration.

Sodium starch glycolate as disintegrant provides the necessary force to rapture and eventually disintegrate the tablets. Specifically, due to its extremely large swelling capacity in aqueous solution it enhances the forces needed to push particles apart within tablet pores exerted by the water, resulting in rapid tablet disintegration. The disintegrant efficiency of sodium starch glycolate is unimpaired in the presence of hydrophobic excipients, such as lubricants unlike many other disintegrants. Increasing the tablet compression pressure also appears to have no effect on disintegration time. Moreover, tablets prepared with sodium starch glycolate have good storage properties. Sodium starch glycolate is present in the preferred composition of the present invention in an amount of more than 1% (w/w) and less than 10% (w/w). Most preferably, sodium starch glycolate is present in an amount of more than 5% (w/w) and less than 10% (w/w). It has been surprisingly found that the objects of the present invention are achieved when the formulation is prepared using Linezolid with specific particle size, in particular wherein Ο ₉₀ <75μπι, as measured using laser light scattering techniques such as with a Malvern Mastersizer machine. The small particle size of the active ingredient in combination with the use of the surfactant Poloxamer enhances Linezolid' s solubility and improves the dissolution properties of the tablets. Tableting is preferred production method because is faster, easier, adds fewer steps to the process, is the most economical and ensures a high production yield. The excipients in the formulation were chosen carefully to give appropriate dissolution rate and stability of the finished dosage form. The tablets of the present invention were tested for dissolution of Linezolid in 1000ml of buffer as dissolution media in USP II apparatus and rotated at 50rpm. The preferred composition of the present invention releases at least 80% of Linezolid in 45 minutes. Most preferably at least 80% of Linezolid is released in 30 minutes. A composition for tableting may be prepared by wet granulation. In wet granulation, the active ingredient and the excipients in powder form are blended and then further mixed in the presence of a liquid that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.

A tableting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients may be compacted into a slug and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.

As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray-dried lactose and colloidal silica.

The pharmaceutical compositions of the present invention may also contain one or more additional formulation excipients such as diluents, disintegrants, binders, lubricants, glidants, colorants and flavouring agents, provided that they are compatible with the active ingredient of the composition, so that they do not interfere with it in the composition and in order to increase the stability of the drug and the self-life of the pharmaceutical product.

Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose, dextrates, dextrose, fructose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, xylitol, maltose, maltodextrin, maltitol, lactose.

Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose function include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include alginic acid, carbomer, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, methylcellulose, polydextrose, polyethylene oxide, polyvinylpyrroline. The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include sodium starch glycolate, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmelose sodium, guar gum, methylcellulose, polacrilin potassium, sodium alginate, crospovidone.

Glidants can be added to improve the ftowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, calcium silicate, calcium phosphate tribasic. When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause surface irregularities to the product. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include talc, magnesium stearate, calcium stearate, glycerylbehenate, hydrogenated castor oil, stearic acid, sodium lauryl sulfate.

Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers are, for example, mint powder, menthol, cherry flavour, xylitol, vanillin, aspartame, acesulfame potassium, saccharin. Solid compositions may optionally be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

Tablets may be coated with coating compositions such as Opadry® to impart aesthetic appeal. Such a coating may comprise about 3% by weight of the tablet.

A number of immediate release tablets comprising different excipients were tested as presented in the following examples to achieve the optimal properties with respect to the objectives of the present invention.

EXAMPLES Example 1 : Table 1: Formulation trial 1

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Internal Phase

Linezolid 71,43

Lactose monohydrate 15,57

Microcrystalline cellulose 8,00

Aerosil 2,00

Sodium starch glycolate 2,00

External Phase

Mg stearate 1,00

Total for uncoated tablet 100,00 Due to the large amount of Linezolid in the tablet and its bad flow properties, wet granulation using water as solvent was selected at first as the most suitable manufacturing process.

Linezolid immediate release tablets of Example 1 were prepared according to the following manufacturing process: Linezolid was mixed with the excipients of the internal phase. The granulation liquid, water, was added to the mixture. The wetted mass was dried. The external phase was added to the obtained granule. The powder mixture was compressed into tablets.

The physicochemical characteristics achieved are presented in the following table:

Table 2: Results of Formulation trial 1

From the results above it can be concluded that the amount of Sodium starch glycolate is quite low since the tablets were not able to disintegrate. Thus, no dissolution profile could be obtained for Formulation trial 1. Example 2:

In order to significantly improve the tablet's disintegration properties, the amount of Sodium starch glycolate was increased to 6%. Moreover, to enhance the active ingredient's solubility the non-ionic surfactant Poloxamer was used in an amount of 2%.

Table 3: Formulations trial 2

The tablets were prepared with the same manufacturing process as in example 1. The physicochemical characteristics achieved are presented in table 4 and in Fig. 1. Table 4: Results of Formulation trial 2

The results above indicate that the increase in the amount of Sodium starch glycolate in combination with the presence of Poloxamer provided desirable disintegration properties to the tablet since it was able to disintegrate within few minutes. Example 3:

In order to further enhance the tablet's disintegration properties, the amount of Sodium starch glycolate was slightly increased to 8%. In addition, in order to optimize the amount of Poloxamer in the formulation, which is necessary for the appropriate dissolution rate and extent of Linezolid, it was decreased to 1%, and also Aerosil was excluded from the formulation. Table 5: Formulations trial 3 A-C

Linezolid immediate release tablets of Example 3 were prepared according to the following manufacturing process: Poloxamer was dissolved in water. Linezolid was mixed with the excipients of the internal phase. The poloxamer solution was added to the mixture. The wetted mass was dried. The external phase was added to the obtained granule. The powder mixture was compressed into tablets.

The physicochemical characteristics achieved are presented in table 6 and in Fig. 2. Table 6: Results of Formulation trials 3 A-C

RESULTS

TEST PARAMETERS

Formulation trial 3 A Formulation trial 3B Formulation trial 3C

Hardness 90 N 84 N 76 N

Disintegration 2Ί5" 2Ό6" 2'24"

Carr's index 35% 37% 35%

t (min) % Released % Released % Released

5 80.54 67.76 71.75

Dissolution 10 83.27 71.47 73.88

(buffer pH

15 90.00 72.62 78.06

6.8, 1000

20 90.80 74.10 79.76

mL, 50rpm)

30 91.89 74.99 81.30

45 94.23 75.89 84.22 As seen in the table above there is a great improvement in the release of the drug substance achieved in formulation trial 3 A in which all the excipients are kneaded with the active ingredient apart from the lubricant, magnesium stearate.

Example 4:

In Formulation trial 4, Aerosil was included in the formulation in order to evaluate its role in the flow properties of the bulk mass and in general the tablet's properties. In addition, the following formulation was prepared by using active ingredient with different particle size distribution in order to study its influence in the drug release and the physical characteristics of the tablets. Table 7: Formulation trial 4

The tablets were prepared with the same manufacturing process as in example 3. The physicochemical characteristics achieved are presented in table 8 and in Fig. 3. Table 8: Results of Formulation trial 4

As shown in the table above, active ingredient with two different particle size distributions was used (D9 ₀ = 40 μπι and D9 ₀ = 200μπι). The results indicate the great influence of the particle size distribution of Linezolid on its dissolution properties since micronized Linezolid with D90 =40 μπι exhibits a higher release rate and extent compared to the active ingredient with larger particles.

Formulation trial 4 was also studied regarding its chemical stability. After storage of tablets in chambers under normal (25°C/ 60 % RH), intermediate (30°C/ 65 % RH) and accelerated conditions (40°C/ 75 % RH), for 3 months, no raise of impurities was observed (Table 9).

Table 9: Stability data of Formulation trial 4 with API with D ₉₀ = 40 μιη

Example 5: In Formulation trial 5 direct compression of micronized Linezolid (Dgo =40 μπι) with the same excipients as in Formulation 4 was also applied.

Table 10: Formulation trial 5

Linezolid immediate release tablets of Example 5 were prepared according to the following manufacturing process: Linezolid was mixed with the excipients of the internal phase. The external phase was added to the obtained mixture. The powder mixture was compressed into tablets.

The physicochemical characteristics achieved are presented in table 11 and in Fig.4.

Table 11: Results of Formulation trial 5

TEST PARAMETERS RESULTS

Hardness 90 N

Disintegration 0'59"

Carr's index 33%

t (min) % Released

5 60.04

10 76.15

Dissolution (buffer pH 6.8, 15 82.62

1000 mL, 50rpm)

20 85.60

30 87.57

45 89.95 Although the disintegration of the tablets was very fast, the dissolution profile was not the desirable and had to be improved.

Example 6:

In order to improve the physicochemical characteristics of tablets obtained by direct compression, the amount of Poloxamer was increased to 3% and Polyvinylpyrrolidone (PVP) was added in the formulation as a binder. Moreover, Lactose monohydrate was substituted by Lactose spray-dried in order to improve the flow properties of the bulk mixture since it is more suitable for direct compression or dry granulation.

Table 12: Formulation trial 6

The tablets were prepared with the same manufacturing process as in example 5. The physicochemical characteristics achieved are presented in table 13 and in Fig.5. Table 13: Results of Formulation trial 6

TEST PARAMETERS RESULTS

Hardness 106 N

Disintegration 0'46"

Carr's index 28%

t (min) % Released

5 69.76

10 81.69

Dissolution (buffer pH 6.8, 15 84.25

1000 mL, 50rpm)

20 86.09

30 88.14

45 89.48 The results above indicate that although disintegration was very rapid, the extent of the active ingredient's dissolution was not the desirable and thus it needed further improvement.

Example 7:

To improve the solubility of Linezolid the amount of Lactose spray-dried was increased whereas the amount of Microcrystalline cellulose and Sodium starch glycolate was slightly decreased. In addition, the same formulation was prepared using Linezolid with higher particle size (D9 ₀ = 200 μιη) in order to evaluate its impact on the dissolution properties of tablets prepared by direct compression.

The preferred immediate release composition according to the present invention is illustrated in Table 14 below:

Table 14: Formulation trial 7

The tablets were prepared with the same manufacturing process as in example 5.

The physicochemical characteristics achieved are presented in table 15 and in Fig.6. Table 15: Results of Formulation trial 7

The results above indicate that the physical properties as well as the dissolution rate and extent of the active ingredient were the desirable without further need for optimization of the formulation. In addition, the formulation prepared using Linezolid with higher particle size 200 μιη) exhibited lower dissolution profile as already observed in wet granulation method.

The above formulation was also manufactured by dry granulation method either using slugging or roller compaction showing equivalent results. In addition, the tablets obtained from the above formulation were further film coated without affecting the dissolution profile and their physical and chemical stability was examined after 6 months storage under normal(25°C/ 60 % RH), intermediate (30°C/ 65 % RH) and accelerated conditions (40°C/ 75 % RH). Table 16: Stability data of Formulation trial 7 with API with D ₉₀ = 40 μπι

From the results demonstrated above we can conclude that the preferred tablet composition of the present invention exhibits the desirable dissolution rate and extent as well as physical and chemical stability.

While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims