WO2021230849A1

WO2021230849A1 - Pharmaceutical compositions prepared by dry milling method and containing celecoxib with increased dissolution rate

Info

Publication number: WO2021230849A1
Application number: PCT/TR2021/050619
Authority: WO
Inventors: Levent ÖNER; Hakan EROĞLU; Aslihan Arslan
Original assignee: Hacettepe Üni̇versi̇tesi̇
Priority date: 2020-10-26
Filing date: 2021-06-17
Publication date: 2021-11-18
Also published as: EP4232046A1; TR202017034A2; EP4232046A4

Abstract

The invention relates to a pharmaceutical composition prepared by dry milling containing celecoxib or pharmaceutically acceptable salt or hydrate thereof, povidone, mannitol and at least one pharmaceutically acceptable excipient and the weight ratio of celocoxib : povidone : mannitol in this composition, the celecoxib particle size and the dissolution rate of the composition.

Description

PHARMACEUTICAL COMPOSITIONS PREPARED BY DRY MILLING METHOD AND CONTAINING CELECOXIB WITH INCREASED DISSOLUTION RATE

Technical Field of the Invention

The invention relates to a pharmaceutical composition prepared by dry milling containing celecoxib or pharmaceutically acceptable salt or hydrate thereof, povidone, mannitol and at least one pharmaceutically acceptable excipient and the celecoxib particle size in this composition and the dissolution rate of the composition.

State of the Art of the Invention (Prior Art)

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drug class worldwide for the treatment of various diseases and relief of their symptoms. NSAIDs are non-steroidal drug class used to reduce pain and stiffness due to arthritis in diseases such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and used in the treatment of acute musculoskeletal pain, post-operative pain and dysmenorrhea.

Celecoxib has been described in the patent numbered US5466823 with a class of 1,5-diaryl pyrazoles and their salts and processes for the preparation of such substances.

The chemical name of celecoxib is

4-[5-(4-Methylphenyl)-3-(Trifluoromethyl)-lH-pyrazol-l-yl] benzene sulfonamide, its closed molecular formula is C17H14 F3N3O2S, its molecular weight is 381,38 and its chemical structure is as follows. In the patent numbered US5760068A, it is mentioned that 1,5-diaryl pyrazole class molecules, including celecoxib, can be used in the treatment of pain caused by rheumatoid arthritis and osteoarthritis.

Celebrex® is a product in oral capsule form containing celecoxib in strengths of 50 mg, 100 mg, 200 mg and 400 mg for use in the treatment of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acute musculoskeletal pain, chronic pain and post-operative pain.

Concensi® is a product in tablet form containing celecoxib and amlodipine besylate providing the treatment of pain from osteoarthritis and hypertension with a combined product. It has strengths of 200 mg/2.5 mg, 200 mg/5 mg, and 200 mg/10 mg, where 200 mg of celecoxib is combined with 2.5 mg, 5 mg, and 10 mg of amlodipine besylate, respectively. The fixed dose combination of celecoxib-amlodipine, which was licensed in 2018, is mentioned in detail in the patent numbered US9662315B2.

Elyxyb™ is a product in oral solution form in 25 mg/mL strength, indicated for the treatment of acute migraine with or without aura. The celecoxib oral solution form, which was developed and licensed in 2020 for celecoxib to be absorbed quickly and reach the maximum plasma concentration much faster than the Celebrex® product, is mentioned in detail in the patent numbered US9795620B2.

In addition to its anti-inflammatory effect, it is stated in the patent numbered EP2811833B 1 that celecoxib can be effective in the treatment of functional somatic syndromes observed in fibromyalgia, chronic fatigue syndrome and irritable bowel syndrome, by means of its use with

2 famciclovir, and the celecoxib-famciclovir combination has been protected by patent.

It is stated in the patent numbered EP2488170B1 that the use of co-crystals of celecoxib prepared together with tramadol is significantly more effective than only tramadol especially in reducing intense to moderate pain after surgical operations, and celecoxib-tramadol co-crystals has been protected by the patent.

In the patent numbered EP1296665B1, it is stated that celecoxib is combined with ibuprofen and this combined product can be administered by oral, rectal, intranasal, sublingual administration or by intravenous, intramuscular, intrastemal or subcutaneous injection. It has been mentioned that 25 mg to 200 mg strength of celecoxib can be combined with 50 mg to 800 mg strength of ibuprofen in this fixed dose combination.

All the mentioned information shows that celecoxib may be effective in different diseases as well as its efficacy in symptomatic treatment of diseases such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, acute pain, and the pharmacological effect of celecoxib continues to be investigated. For this reason, it is an important need to introduce pharmaceutical celecoxib compositions will be developed for any proven indication of celecoxib, to the use of patients as innovative products with new inventions.

In the patents numbered US8808751B2 (EP2054042A1 and A4), US8735450B2, EP2421525B1, US9095496B2, US9526734B2, it is mentioned that the dose used in order to be therapeutically effective, should be reduced in order to reduce the side effects of NS AID class drugs such as diclofenac, indomethacin, ibuprofen, naproxen, meloxicam and celecoxib, which are frequently used throughout the world in the treatment of diseases such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and in the relief of their symptoms. Although NS AIDs are generally used to provide symptomatic treatment, they reduce radiological progression without increasing toxicity when used continuously in the treatment of chronic diseases such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis. For this reason, patients must take NS AIDs continuously instead of using them only to reduce the signs and symptoms of the disease. However, as it is known, besides the benefits of NSAIDs, they have undesirable especially gastrointestinal side effects. The Food and Drug Administration (FDA) recommends the use of drugs at the lowest effective dose in the shortest time, in accordance with the target, in the treatments with all NSAIDs, so that patients do not encounter too many side effects while benefiting from NSAIDs. In order to reduce these undesirable side effects, the dose of the drug used should be reduced. Therefore, in the above-mentioned patents, it is stated that with the technology named SoluMatrix Fine Particle Technology™ (iCeutica Inc.), it has developed products that allow the use of three different NSAIDs, which are very common and chronically used in the treatment of arthritis, at lower doses compared to the dose used in the clinic.

In order to reduce the dose of a drug which is therapeutically effective, first of all, pharmacokinetic data should be improved according to the reference dose. Most of the NSAIDs that are frequently used in the clinic are molecules in the Class 2 group of the Biopharmaceutical Classification System (BCS), with very low water solubility but high permeability.

In order to improve the pharmacokinetic data of these molecules, it is necessary to increase their bioavailability consequently their solubility and dissolution properties. It is possible to increase the solubility, dissolution rate and bioavailability of BCS Class 2 molecules, which have a micron particle size in the market, by reducing the particle size to submicron (submicron, <2 pm) or nano sizes. In the patents numbered US8808751B2 (EP2054042A1 and A4), US8735450B2, EP2421525B1, US9095496B2, US9526734B2, it is mentioned that bioavailability is increased by reducing the particle size.

There are many different methods applied to eliminate solubility problems of active ingredients with low bioavailability; to increase dissolution, absorption and consequently in vivo efficacy. In order to increase the solubility and dissolution rate of the active ingredient, the surface area of the active ingredient in contact with the ambient liquid must be increased. The methods applied for this purpose are forming cyclodextrin complexes, preparing solid dispersions, microemulsion preparation methods and particle size reduction methods. Particle size reduction methods are divided into two groups as mechanically applied methods and methods of controlling particle size by engineering. In the process of mechanical particle size reduction (micronisation/nanonization), high-pressure homogenization methods are applied as well as milling with jet mills, high-energy ball mills and planetary ball mills. The methods in which particle size is controlled by engineering are the methods called cryogenic spraying method (creation of nano-structured amorphous drug particles with high porosity at very low temperatures), crystalline engineering (obtaining metastable polymorph, high-energy amorphous forms, ultra-thin particles by controlled crystallization process)

Among the methods mentioned above, the mechanical particle size reduction method is the most suitable method for the industry. For this reason, there are many molecules whose particle size is reduced, and their bioavailability is increased by this method. However, wet milling method is used in order to obtain more effective and positive results in order to reduce the particle size. The wet milling process is a laborious and long process in the production of solid dosage forms. Because the particles produced by the wet method must be converted into solid state by a technique such as spray drying or lyophilization.

Dry milling system can be used to facilitate the milling process, but in this case, the possibility of re-agglomeration of the milled particles arise. In recent studies, dry milling method with using excipients having function as stabilizer and surfactant is also preferred as an effective method.

With a technology called SoluMatrix Fine Particle Technology™ (iCeutica Inc.), substances are milled by dry milling method and submicron particles are obtained at the end of the milling process. In the patent document numbered EP 2421 510 Bl, which is one of the patents related to the dry milling method, substances such as lactose monohydrate, mannitol, tartaric acid, xylitol were used as the primary milling component, sodium lauryl sulfate and different substances as surfactant. In the dry co-milling trials with diclofenac, indomethacin and meloxicam, the most successful results were obtained with lactose and sodium lauryl sulfate, while in the milling with naproxen, mannitol was chosen as the primary milling component and sodium lauryl sulfate was used as the surfactant.

Excipients such as lactose, sorbitol, sodium lauryl sulfate, polyoxyl stearate, polyethylene glycol were used in dry milling compositions made for celecoxib in patents numbered US8808751B2 (EP2054042A1 and A4), US8735450B2, EP2421525B1, US9095496B2, US9526734B2. The particle size of celecoxib was reduced by milling with the mentioned excipients. Celecoxib is a BCS Class 2 molecule that is practically insoluble in water, is hydrophobic, and has high permeability. The very low water solubility of celecoxib results in high variation in absorption and low bioavailability after oral administration.

When celecoxib is taken orally in the form of capsule or tablet, it is not well absorbed, as it does not quickly distribute and dissolve in the gastrointestinal system. Therefore, it may take approximately 3 hours to reach the maximum plasma concentration following oral administration and delaying plasma concentration in this way causes the pharmacological effect to occur later. However, in cases such as migraines, acute pain, arthritis pain, dysmenorrhea, rapid pain relief effect is desired. In order to enable celecoxib to act more rapidly and to increase its bioavailability, it is necessary to improve its solubility and dissolution properties.

The medium in which celecoxib has the highest solubility is the pH 12 medium that does not simulate any physiological medium. Therefore, the dissolution method recommended by the FDA for the Celebrex® product is pH 12 medium containing 1% sodium lauryl sulfate. In order to improve the solubility and dissolution properties of celecoxib, it is not sufficient to increase its solubility only in the pH 12 medium. The gastrointestinal system pH values that celecoxib will be exposed to when taken orally are in the range of pH 1.2-6.8 and its solubility in these media should also be increased.

As given in the literature and patents numbered US8808751B2 (EP2054042A1 and A4), US8735450B2, EP2421525B1, US9095496B2, US9526734B2 for dry milling, co-milling the hydrophobic active ingredients with hydrophilic excipients can increase the solubility more compared to milling the active ingredient alone. For example, ibuprofen was milled in a planetary ball mill with excipients such as povidone, microcrystalline cellulose, hydroxypropyl methylcellulose, soluplus. Compared to ibuprofen milled alone; the solubility increased more as a result of milling ibuprofen with soluplus (Amjad Hussain et ak, Poster presentation, 2013).

In patents numbered US8808751B2 (EP2054042A1 and A4), US8735450B2, EP2421525B1, US9095496B2, US9526734B2; main milling excipients such as calcium carbonate, glucose, lactose anhydrate, lactose monohydrate, malic acid, maltitol, mannitol, sodium bicarbonate, sodium chloride, sorbitol, sucrose, tartaric acid, trisodium citrate dihydrate, xylitol; surface active agents such as Aerosil R972 silica, benzalkonium chloride, Brij700, Brij76, Cremophor EL, Cremophor RH-40, docusate sodium, kollidon 25, lecithin, poloxamer 188, microcrystalline cellulose, poloxamer 407, polyethylene glycol 3000, polyethylene glycol 8000, polyoxyl 40 stearate, povidone 30, primellose, primogel, sodium dodecyl sulfate, sodium octadecyl sulfate, Soluplus HS15, Tween 80 were used in the milling process of active pharmaceutical ingredients such as anthraquinone, celecoxib, cilostazol, ciprofloxacin, diclofenac acid, diclofenac, meloxicam, metaxalone, naproxen acid, naproxen sodium, progesterone, salbutamol.

Brief Description and Purposes of the Invention

In the present invention, a pharmaceutical composition comprising celecoxib active substance, which is practically insoluble in water, whose solubility is increased by using the dry milling method with povidone, mannitol and at least one pharmaceutically acceptable excipient, and whose particle size is reduced to submicron size by co-milling with pharmaceutical excipients is mentioned.

Celecoxib is a hydrophobic substance and has very low solubility and wettability in water. In the invention, a pharmaceutical composition has been developed that will allow rapid distribution and then dissolution in the gastrointestinal tract when it is taken orally as a solid dosage form such as a tablet or capsule.

Dry milling method, which is the most suitable method for the industry, was chosen for the particle size reduction of celecoxib. However, only celecoxib was not milled in the dry milling method. By taking advantage of dry co-milling, both the milling performance of celecoxib particles were increased and the solubility increased much more than the amount that would increase depending on the particle size reduction, by means of the pharmaceutical excipients in the milling composition.

During dry milling of celecoxib, rather hydrophilic excipients are preferred. As a result of the experiments, it has been determined that the highest solubility was provided at all physiological pHs when povidone and mannitol were used as the main milling component, and sodium lauryl sulfate was used as a surface-active agent. The solubility of the composition, which is specified for celecoxib in the patents numbered US8808751B2 (EP2054042A1 and A4), US8735450B2, EP2421525B1, US9095496B2, US9526734B2 and obtained as a result of dry milling of celecoxib with lactose monohydrate, sodium lauryl sulfate, polyoxyl stearate, at physiological pH is considerably lower than the composition presented in the invention. Although the particle size is reduced with dry milling and the solubility is increased significantly in pH 12 with lactose monohydrate, sodium lauryl sulfate, polyoxyl stearate substances, the solubility did not increase to the same extent at the pH values in the range of pH 1.2-6.8. Therefore, the ratio by weight of povidone and mannitol presented in the invention is very critical for increasing solubility.

In the pharmaceutical composition mentioned in the invention, the solubility of celecoxib at physiological pH values was increased. Using povidone and mannitol excipients in specific ratio in the pharmaceutical composition of celecoxib prepared by dry milling method, increased the solubility at all pH physiological values in addition to pH 12 medium. It is not known in the art how or weather the ratio by weight of povidone and mannitol in the milling composition affect solubility at physiological pHs.

In the experiments, it was seen that the ratio by weight of povidone and mannitol in the milling composition directly affects the solubility at physiological pHs. In dry milling of celecoxib, povidone and mannitol, the highest solute amount was obtained at 1:1:2 and 1:2:1 ratios when the milling parameters were kept constant at 500 rpm, 1 hour and 10:1 ball ratio. However, when the milling parameters were changed; the highest solute amounts were obtained at 1 : 1 : 1, 1:1.5:1.5, 1:0.5:1.5 and 1:1.5:0.5 ratios. When celecoxib, povidone, and mannitol were used in these weight ratios, the weight ratio of celecoxib and sodium lauryl sulfate was 1 and 0.2, respectively.

After celecoxib with an average particle size of 5-10 micrometers, homogeneously mixed with povidone, mannitol and sodium lauryl sulfate, it was milled in a planetary ball mill or high-energy ball mill. The pharmaceutical composition obtained at the end of dry milling was dispersed in water and the particle size was measured. Since povidone, mannitol and sodium lauryl sulfate in the pharmaceutical composition dissolve very well in water, the only insoluble substance in the prepared dispersion is celecoxib. As a result of the particle size measurement, the average particle size of celecoxib was found in the range of 200 nm-1500 nm. SEM image of celecoxib particles was given in Figure 1, SEM image of celecoxib particles in the composition obtained as a result of dry milling of celecoxib, povidone and sodium lauryl sulfate was given in Figure 2, and SEM image of celecoxib particles in the composition obtained as a result of dry milling of celecoxib, povidone, mannitol and sodium lauryl sulfate was given in Figure 3.

The solubility values were determined by preparing saturated solutions of the pharmaceutical composition prepared by dry milling from pH 1.2, pH 4.5 and pH 6.8 media containing 0.2% sodium lauryl sulfate. At the same time, the solubility values of raw celecoxib and Celebrex® were determined by preparing saturated solutions from pH 1.2, pH 4.5 and pH 6.8 media containing 0.2% sodium lauryl sulfate. Solubility values were given in Table 1.

Table 1. Solubility values of celecoxib at different pH values

* The composition developed within the scope of the invention is named as the test product.

Considering the solubility values of celecoxib in these media, situations where the sink condition was maintained or not have been created and a dissolution test has been carried out. Considering the solubility value of celecoxib, when the sink condition was maintained; the developed pharmaceutical composition had a dissolution rate such that at least 85% of celecoxib is dissolved in 30 minutes in dissolution media in the range of pH 1.2-pH 6.8 containing USP Apparatus 2 (Paddle), 50 rpm rotational speed, 1000 mL, 37°C, 0.2% sodium lauryl sulfate. The dissolution profiles of the Celebrex® product and the test product developed within the scope of the invention, of the dissolution test performed by maintaining sink condition are given in Figures 4, 5 and 6.

When the sink condition was not maintained; the developed pharmaceutical composition had a dissolution rate such that at least 40% of celecoxib was dissolved in 30 minutes in dissolution media in the range of pH 1.2-pH 6.8 containing USP Apparatus 2 (Paddle), 50 rpm rotational speed, 1000 mL, 37°C, 0.2% sodium lauryl sulfate; at least 70% of celecoxib is dissolved in 30 minutes in dissolution media in the range of pH 1.2-pH 6.8 containing 0.5% sodium lauryl sulfate. The dissolution profiles of the Celebrex® product and the test product were evaluated within the scope of the invention, of the dissolution test performed without maintaining the sink condition are given in Figures 7, 8 and 9.

The dry milling method, which is known and widely used in the field of pharmaceutical technology, is used not only for the purpose of reducing the particles by creating a mechanical effect, but also used as a solid dispersion preparation method in addition to the mechanical effect in the presented invention. According to the information in the literature, methods such as spray drying, solvent evaporation, hot melt extrusion, co-precipitation, electrospinning method, lyophilization method are generally used to prepare solid dispersion. However, the problems encountered in the scale-up and industrial application of these methods have not been overcome yet. Although co-milling method is not preferred as a solid dispersion preparation method, it is the most applicable to industry. With this invention, stable solid dispersions with increased solubility were produced by using the dry milling method. The developed production method is designed in way to be applied to the industry. The method specified in this invention is much less costly, contains less risk factors and is the most compatible with the industry than other methods applied to increase solubility known in the art.

Celecoxib used in dry milling in the invention is in the form of crystalline form-III. When celecoxib is milled alone in the dry milling process, there is no change in the polymorphic structure. However, as stated in the literature, when the solid dispersion of celecoxib with povidone is prepared, the crystalline form in beginning turns into an amorphous structure. It has been stated that when a solid dispersion of amorphous celecoxib is prepared with mannitol, mannitol can induce celecoxib crystalline growth. (Bhatt V et al., 2015, International Journal of Pharmaceutics, 495/1, 132-139). However, there is no information in the literature or other patents that it could prevent the crystalline structure of celecoxib from turning completely into amorphous as a result of adding mannitol in a specific ratio to the solid dispersion of the celecoxib prepared with povidone. Depending on the ratio by weight of povidone and mannitol in the pharmaceutical composition prepared by dry milling and containing celecoxib, povidone, mannitol and sodium lauryl sulfate in the milling composition, decrease in the crystalline structure as a result of milling varies. The pharmaceutical composition presented in the invention may be amorphous or crystalline or amorphous-crystalline mixture, depending on the weight ratio of povidone and mannitol in dry milling. X-ray diffraction patterns of the raw celecoxib, celecoxib milled alone with dry method, and the composition obtained as a result of co-milled celecoxib and povidone are given in Figure 10. The X-ray diffraction patterns of the compositions obtained as a result of co-milled celecoxib, povidone and mannitol in different weight ratios, and physical mixture of celecoxib, povidone, mannitol, and sodium lauryl sulfate are given in Figure 11.

Definitions of Figures Explaining the Invention Figure 1: SEM image of celecoxib particles.

Figure 2: SEM image of celecoxib particles in the composition obtained as a result of dry co-milled of celecoxib, povidone and sodium lauryl sulfate.

Figure 3: SEM image of celecoxib particles in the composition obtained as a result of co-milled of celecoxib, povidone, mannitol and sodium lauryl sulfate (PVP<MAN).

Figure 4: Dissolution rate profile of Celebrex® and the test product in the pH 1.2+0.2% SLS medium of the dissolution test by maintaining the sink condition

Figure 5: Dissolution rate profile of Celebrex® and the test product in the pH 4.5+0.2% SLS medium of the dissolution test by maintaining the sink condition

Figure 6: Dissolution rate profile of Celebrex® and the test product in the pH 6.8+0.2% SLS medium of the dissolution test by maintaining the sink condition

Figure 7: Dissolution rate profile of Celebrex® and test product in the pH 1.2+0.2% SLS medium without maintaining sink condition.

Figure 8: Dissolution rate profile of Celebrex® and test product in the pH 4.5+0.2% SLS medium without maintaining sink condition.

Figure 9: Dissolution rate profile of Celebrex® and test product in the pH 6.8+0.2% SLS medium without maintaining sink condition.

Figure 10: X-ray diffraction patterns of the raw celecoxib, celecoxib milled alone with dry method, and the composition obtained as a result of co-milled celecoxib and povidone.

Figure 11: X-ray diffraction patterns of the compositions obtained as a result of co-milled celecoxib, povidone and mannitol in different weight ratios, and physical mixture of celecoxib, povidone, mannitol, and sodium lauryl sulfate. Detailed Description of the Invention

Invention pharmaceutical composition prepared by dry milling method containing celecoxib or its pharmaceutically acceptable salt or hydrate, povidone, mannitol and at least one pharmaceutically acceptable excipient, is characterized by that celecoxib :povidone:mannitol has a weight ratio of at least 1 :0.5:0.5 and it contains celecoxib with a particle size in the range of 200 nm-1500 nm, and it has a dissolution rate such that at least 85% of celecoxib is dissolved in 30 minutes.

The inventive pharmaceutical composition contains celecoxib in the range of 30-200 mg.

The inventive pharmaceutical composition contains povidone in the range of 15-1000 mg.

The inventive pharmaceutical composition contains mannitol in the range of 15-1000 mg.

In the invention, at least one pharmaceutically acceptable excipient is selected from pharmaceutically acceptable surface-active agents, colorants, fillers, lubricants and glidants, dispersants, binding agents, or excipients consisting of combinations thereof. At least one pharmaceutically acceptable excipient used in dry milling in the invention is preferred as sodium lauryl sulfate in surface active agent function. In addition to sodium lauryl sulfate, at least one of the surface-active agents such as Brij700, Brij76, Cremophor EL, lecithin, poloxamer 188, poloxamer 407, polyethylene glycol 3000, polyethylene glycol 8000, polyoxyl 40 stearate, sodium dodecyl sulfate, sodium octadecyl sulfate, Soluplus HS15, Tween 80 can also be used as surface active agent. In addition to surface active agent, croscarmellose sodium is preferred for dispersant function and magnesium stearate for lubricant function.

The average particle size of celecoxib used in the invention is 5-10 micrometers and its crystalline structure is form-III. Since celecoxib is a hydrophobic substance, its wettability is very weak. For this reason, sodium lauryl sulfate is used in Celebrex® product to increase its wettability and solubility. Similarly, Concensi®, a celecoxib-amlodipine combined product, contains sodium lauryl sulfate in its composition. Elyxyb™, the oral solution product of celecoxib, contains glyceryl monocaprylate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil as emulsifier, and ethanol as co-solvent in its formulation. In order to increase the wettability and solubility of celecoxib, increasing the surface area by reducing the particle size is one of the most commonly used methods. Ball mills were also used in the invention to reduce the particle size of celecoxib. Wet and dry milling can be done in planetary ball mills or high-energy ball mills. These mills can be rotated at different rotational speeds, and they can mill in the desired time. The milling speed and time vary according to the properties of the substances to be milled. In milling with ball mills, the ratio of the amount of substance placed in the milling chamber to the weight of the ball to be used affects the milling performance. For this reason, the ball: substance ratio by weight should be at an optimum level for effective milling.

In the invention, celecoxib active ingredient was milled by using a planetary ball mill. Milling chamber of the ball mills and the balls; agate and zirconium oxide materials were chosen to minimize the interaction of celecoxib and other excipients with the milling chamber and balls. The main milling components and surface-active agents used in the celecoxib milling composition are given in Table 2. It can be operated at a rotational speed of 50 rpm-650 rpm in the ball mill. Speeds of 250 rpm and 500 rpm were used in the experiments presented in the invention. The milling time varies depending on the substances to be milled, but the experiments presented in the invention were made using a milling time of 1 hour to 4 hours. In ball mills, the amount of ball and powder was determined in ways that the raito by weight of the ball loaded into the milling chamber to powder is in the range of 1:1 to 19:1. The most successful results were achieved with a high ball: powder ratio, a more effective milling was achieved with the high ball amount. Table 2. Ingredients in the dry milling composition of celecoxib (CEL)

Dry milling experiments done by using the substances given in Table 2 and without using any excipients and the celecoxib pharmaceutical compositions obtained are given in Samples 1-24. The samples given in Table 3 were milled in a planetary ball mill at a rotational speed of 500 rpm for 4 hours. The amount of ball and powder was calculated as the ball: powder ratio of 15:1. 16 mm balls were used. The substance amounts given in Table 3 represent the ratio by weights of the substances in the total composition to celecoxib. For example, in Sample 4, the weight ratio of CEL:PVPK12:SLS is 1:1:02. Table 3. Celecoxib compositions prepared by dry milling

When the intrinsic dissolution rates of the samples given in Table 3, are tested at a rotational speed of 200 rpm by using 1000 mL, 0.04 M tribasic sodium phosphate buffer (pH 12), USP Wood Apparatus, the amounts dissolved after 60 minutes are given in Table 4.

Table 4. Dissolved amounts at 60^th minute in the intrinsic dissolution rate test and particle size results of Samples 1-24.

*A composition suitable for testing could not be obtained due to chemical interaction in dry milling in samples 10, 11, 12 and 24. Therefore, there is no analysis result.

When the intrinsic dissolution rates of samples 3, 15, 20, and 21 were tested using the Wood Apparatus at a rotational speed of 200 rpm in pH 1.2+0.2% SLS and pH 6.8+0.2% dissolution media, in addition to 0.04 M tribasic sodium phosphate buffer (pH 12) medium, pharmaceutical compositions containing mannitol were found to dissolve higher after 120 minutes.

As a result of milling with different excipients, it was determined that the highest solubility values in pH 1.2-6.8 medium containing 0.2% SLS in addition to pH 12 medium were obtained as a result of using povidone, mannitol and at least one pharmaceutical excipient, preferably sodium lauryl sulfate, in dry milling. When the intrinsic dissolution rates of the sample compositions were tested using 1000 mL, pH 1.2+0.2% SLS, USP Wood Apparatus at a rotational speed of 200 rpm, the dissolved amounts at the end of 120 minutes are given in Table 5.

Table 5. Components of different compositions and the dissolved amounts in the intrinsic dissolution rate test at 120^th minutes.

Composition Components Weight Ratios of the Dissolved Amount at 120^th Substances in the Minute (mg) Composition

In subsequent studies, different milling speeds, milling time and ball: powder ratio were applied by using the substances included in the milling composition at different weight ratios. Samples made to examine the effect of the raitos of weight of povidone and mannitol on the solubility of celecoxib and the dissolved amounts in 60 minutes in 0.04 M tribasic sodium phosphate buffer (pH 12) medium and the particle size analysis results are given in Table 6.

Table 6. Samples where different milling compositions and milling process parameters are applied.

When the amounts dissolved in 0.04 M tribasic sodium phosphate buffer (pH 12) medium at 60th minutes of the samples given in Table 6 are examined, the milling speed, milling time and ball: powder ratio directly affect the solubility of the composition obtained as a result of milling. At the same time, the raito of weight of povidone, mannitol and sodium lauryl sulfate in the milling composition are critical for solubility. When dry milling conditions are kept constant as 500 rpm milling speed, 1 hour milling time and 10:1 ball: powder ratio; the lowest dissolution was observed when the weight ratio of celecoxib:povidone:mannitol in dry milling was 1 :0.2: 1. When this ratio is 1 : 1 :0.2, the dissolved amount is higher than at 1 :0.2: 1 ratio, but still low. The highest dissolved amount was obtained at 1:1:2 and 1:2:1 ratio. However, when the milling parameters are changed; the highest dissolved amounts were obtained at 1:1:1, 1:1.5:1.5, 1:0.5:1.5 and 1:1.5:0.5 ratios. The high ball: powder ratio makes it possible to obtain high solubility by using lower ratios of povidone and mannitol. However, even if a high ball: powder ratio is used, the raito of weight of celecoxib:povidone:mannitol in the milling composition should be at least 1 :0.5:0.5. Below this ratio, high dissolved values are unlikely to be achieved even at the highest ball: powder ratio or milling speed or milling time. In addition to 0.04 M tribasic sodium phosphate buffer (pH 12) medium, the presence of mannitol in the milling composition is absolutely necessary in order to increase the solubility of the compositions obtained as a result of milling in water and physiological medium pH values such as pH 1.2, 4.5 and 6.8. The milling compositions of the samples in the 13-24 range contain only povidone and sodium lauryl sulfate. However, although the solubility values at pH 12 are high with these samples, the solubility in water and other physiological pH values is low. As a result of using different ratios of mannitol in the samples given in the Samples 1-12 range, the solubility in water and physiological pH values increased. For example, when the milling composition is celecoxib:povidone: sodium lauryl sulfate (1:1:0.2), the dissolved amount at physiological pH is 5 mg/1000 mL (120. min) maximum, when the milling composition is celecoxib:povidone: sodium lauryl sulfate: mannitol (1 : 1 :0.2: 1), the dissolved amount is at least 45 mg/1000 mL (120 min). The use of sodium lauryl sulfate in addition to povidone and mannitol in the milling composition provides to increase solubility, especially at physiological pH. Therefore, in order to increase its solubility, celecoxib:povidone:mannitol must be used in a weight ratio of at least 1:0.5:0.5 in a pharmaceutical composition prepaid by dry milling containing celecoxib, povidone, mannitol and at least one pharmaceutically acceptable excipient. It may be possible to increase the solubility by increasing this ratio, but if the ratios used in the milling composition increase, the unit weight of the pharmaceutical composition to be given to the patient will also increase. This situation may create an undesirable situation in terms of patient compliance. In addition, the maximum ratio determined from the experiments is 1:5:5, and in the case of using povidone and mannitol higher than this ratio, the solubility does not increase significantly and begins to decrease.

The production method applied to prepare a pharmaceutical composition after the dry milling experiments include the following process steps;

- Mixing homogeneously with celecoxib, povidone, mannitol and sodium lauryl sulfate,

- Milling the prepared powder mixture by using a planetary ball mill or high-energy ball mill used for dry milling,

- Mixing the ground powder mixture with croscarmellose sodium, then mixing with magnesium stearate,

- Compressing tablets with the prepared final powder or filling the final powder into capsules or filling the final powder into sachets. The above-mentioned production processes are performed for Sample 5 given in Table 6. The dissolution rate of the pharmaceutical composition obtained with Sample 5 is tested in dissolution media in the range of pH 1.2-pH 6.8 containing USP Apparatus 2 (Paddle), 50 rpm rotational speed, 1000 mL, 37°C, 0.2% sodium lauryl sulfate. The dissolution rate profiles of the dissolution test performed with maintaining sink condition are given in Figures 4, 5 and 6, and the dissolution rate profiles of the dissolution test without maintaining the sink condition are given in the Figures 7, 8 and 9.

Claims

1. A pharmaceutical composition prepared by dry milling, containing celecoxib or a pharmaceutically acceptable salt or hydrate thereof, povidone, mannitol and at least one pharmaceutically acceptable excipient, characterized in that; celecoxib :povidone:mannitol has a weight ratio of at least 1:0.5:0.5, it contains celecoxib with a particle size in the range of 200 nm-1500 nm, and it has a dissolution rate such that at least 85% of celecoxib is dissolved in 30 minutes.

2. A composition according to Claim 1, characterized in that; it contains celecoxib in the range of 30-200 mg.

3. A composition according to Claim 1, characterized in that; it contains povidone in the range of 15-1000 mg.

4. A composition according to Claim 1, characterized in that; it contains mannitol in the range of 15-1000 mg.

5. A composition according to Claim 1, characterized in that; said at least one pharmaceutically acceptable excipient is selected from pharmaceutically acceptable surface-active agents, colorants, fillers, lubricants and glidants, dispersants, binding agents or excipients consisting of combinations thereof.

6. A composition according to Claim 5, characterized in that; said surface active agent is sodium lauryl sulfate.

7. A composition according to Claim 5, characterized in that; said dispersant is croscarmellose sodium.

8. A composition according to Claim 5, characterized in that; said lubricant is magnesium stearate.

9. A composition according to Claim 1, characterized in that; micron-sized celecoxib particles before dry milling have a particle size in the range of 200 nm-1500 nm after dry milling.

10. A composition according to Claim 6, characterized in that; it has the lowest solubility of 130 pg/mL at physiological pHs in the range of pH 1.2-pH 6.8 containing 0.2% sodium lauryl sulfate.

11. A composition according to Claim 6, characterized in that; it has a dissolution rate such that at least 85% of celecoxib is dissolved in 30 minutes in dissolution media containing USP Apparatus 2 (Paddle) with sink condition, 50 rpm rotation speed, 1000 mL, 37°C, 0.2% sodium lauryl sulfate, pH 1.2-pH 6.8.

12. A composition according to Claim 6, characterized in that; it has a dissolution rate such that at least 40% of celecoxib is dissolved in 30 minutes in dissolution media containing USP Apparatus 2 (Paddle) without sink condition, 50 rpm rotation speed, 1000 mL, 37°C, 0.2% sodium lauryl sulfate, pH 1.2-pH 6.8.

13. A method of preparation a pharmaceutical composition according to any of the previous claims, characterized in that; it includes the following process steps;

- Compressing tablets with the prepared final powder or filling the final powder into capsules or filling the final powder into sachets.

14. A composition according to Claim 1, characterized in that; celecoxib is crystalline or amorphous or a crystalline-amorphous mixture.