JP5021934B2 - Pharmaceutical composition having improved solubility - Google Patents

Description

The present invention relates to a pharmaceutical composition and a method for producing the same.
This application was converted from US Provisional Application No. 60 / 390,881 (filed Jun. 21, 2002, incorporated herein by reference in its entirety). This application also includes US Provisional Application No. 60 / 426,275 (filed on November 14, 2002), US Provisional Application No. 60 / 427,086 (filed on November 15, 2002), and US Provisional Application No. 60 / 429,515. (Filed November 26, 2002), US provisional application 60 / 437,516 (filed December 30, 2002) and US provisional application 60 / 456,027 (filed March 18, 2003) (see full text) Claim it here).

  Celecoxib (Celecoxib, 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide) has the structural formula (I)

A substituted pyrazolylbenzenesulfonamide represented by the formula:

  Celecoxib belongs to the general class of nonsteroidal anti-inflammatory drugs (NSAIDs). Unlike conventional NSAIDs, celecoxib is a selective inhibitor of cyclooxygenase II (COX-2) that causes few side effects when administered to patients. The synthesis and use of celecoxib is further described in U.S. Pat. ). An orally administrable liquid formulation of celecoxib is discussed in US 2002/0107250 (incorporated herein by reference in its entirety).

  Other COX-2 inhibitors are similar to celecoxib, which forms part of the large group of drugs, all of which are benzenesulfonamides. These include deracoxib, 4- [3-fluoro-4-methoxyphenyl) -3-difluoromethyl-1H-pyrazol-1-yl] benzenesulfonamide, valdecoxib, 4- [5- Methyl-3-phenylisoxazol-4-yl] benzenesulfonamide, rofecoxib, 3-phenyl-4-[-(methylsulfonyl) phenyl] -5H-furan-2-one and etoricoxib, 5- Chloro-3- (4-methylsulfonyl) phenyl-2- (2-methyl-5-pyridinyl) pyridine, these drugs are described in more detail in W001 / 78724 and W002 / 102376.

  In the form marketed as CELEBREX ™, celecoxib is a neutral molecule that is essentially insoluble in water. Celecoxib generally exists as needle-like crystals and tends to aggregate and form a mass. Aggregation occurs even when celecoxib is mixed with other materials, resulting in a heterogeneous mixture. These properties are common to other pyrazolyl benzenesulfonamides and are a significant problem in the manufacture of pharmaceutical formulations of drugs, particularly oral formulations.

  It would be advantageous to improve the properties of drugs with low water solubility, particularly in oral formulations, to provide new forms. In particular, when an active pharmaceutical ingredient (API) having low water solubility is supplied in a form with improved water solubility, when API dissolution is required, for example, API is diluted in the digestive tract The problem still remains after being taken as an oral formulation (where the terms “API” and “drug” are used interchangeably herein). Under this circumstance, APIs with low water solubility tend to emerge from solution. When this happens, for example, due to crystallization or precipitation processes, the bioavailability of the API is significantly reduced. Therefore, it is desirable to improve the properties of API-containing formulations that increase the bioavailability of the API in oral dosage forms, thereby resulting in a more rapid onset of therapeutic effect.

  It has now been found that stable crystalline salts and co-crystals of celecoxib can be synthesized. The celecoxib composition of the present invention has greater solubility, solubility, total bioavailability (area under the curve or AUC), lower Tmax, peak serum level arrival time and higher Cmax, maximum serum concentration compared to neutral celecoxib. Have. In addition, the celecoxib composition of the present invention includes a composition that is less hygroscopic and more stable. When the celecoxib salt of the present invention is in a crystalline form, it is converted to an amorphous free form of celecoxib by neutralization of the salt, and then converted to a neutral metastable crystal form, or directly to a neutral metastable crystal. Convert to shape. These amorphous or metastable crystalline forms of neutral celecoxib are more readily available forms of API than neutral celecoxib currently on the market. Neutral crystalline celecoxib is currently marketed as CELEBREX ™ and is designed as “neutral” to distinguish it from the ionized salt form of celecoxib. In addition, acidification or neutralization of the celecoxib salt solution yields amorphous celecoxib at that site, which is then converted to a metastable crystalline form or ultimately converted to a stable neutral celecoxib. Converts directly to neutral metastable crystalline form of neutral celecoxib.

  In one aspect of the invention, the time that can be maintained as a supersaturated solution before precipitation from solution based on the solubility, solubility and / or solubility of the API (either as part of the pharmaceutical composition or alone) It is related with the method of increasing. The increase in solubility (or concentration as a function of time) can thus be expressed as bioavailability, ie an increase in AUC, resulting in a decrease in time to Tmax or an increase in Cmax. The method produces a salt or co-crystal of an active pharmaceutical ingredient (eg free acid) and the salt or co-crystal is optionally a precipitation inhibitor and optionally a precipitation inhibition enhancer (hereinafter referred to as enhancer). Mixing. The precipitate is either a crystalline or amorphous solid form that separates or comes out from solution. The salt may be amorphous or crystalline, but is preferably crystalline. Usually, the salt or co-crystal form used is a crystalline form that dissolves and then recrystallizes and precipitates out of solution, where the term “crystal” inhibitor is “precipitated” for greater selectivity. This is why it may be used instead. The term “crystal” inhibitor can also be used to identify salts or co-crystals that are in an amorphous form prior to dissolution and that precipitate from solution in crystalline form after dissolution. Crystalline salts are superior to amorphous salts as initial compounds, and amorphous salts are superior to neutral amorphous or crystalline forms. The form of the free acid is not preferred as the initial compound unless the initial solution in the solubilizer is a liquid formulation containing a precipitation inhibitor and optionally an enhancer. The precipitation inhibitor is often a surfactant and preferably repeats at least 2 or 3 times, preferably an ether functional group, preferably a repeating ether group, for example an oxygen atom separated by two carbon atoms. A surfactant having an ether group. Further preferred surfactants have an interfacial tension of less than 10 dyne / cm when measured at 25 ° C. at a concentration of 0.1% w / w in water and / or the surface tension of a precipitation inhibitor (eg poloxamer) Is less than 42 dyne / cm when measured at 25 ° C. in water at a concentration of 0.1% w / w. The combination of salt or co-crystal, precipitation inhibitor and optionally enhancer (or precipitation inhibitor, optionally enhancer and other forms) is an aqueous solution, preferably water or an average human stomach fasted for 12 hours. Precipitation of supersaturated solution in gastric fluid conditions such as gastric fluid or simulated gastric fluid (SGF) for more than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes or 1 hour Is preferably prevented or delayed. In order to allow the composition to move from the stomach to a higher pH environment, it is preferred that the solution remain supersaturated for more than 15, 20, or 30 minutes. SGF may be diluted 2, 3, 4, 5, 6, 7, 8, 9, 10 times to reproduce water intake. For example, SGF may be diluted 5 times assuming that the patient drinks a glass of water when taking the composition of the invention orally. The degree of increase in solubility, solubility and / or supersaturation is 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%, etc., or neutral celecoxib in the same solution (e.g., 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 40 times, 50 times, 75 times than free acid) 100 times, 125 times, 150 times, 175 times, 200 times, 250 times, 300 times, 350 times, 400 times, 500 times, 1000 times, 10,000 times, or 100,000 times may be specified. The increase in solubility may be further defined by the time that the composition remains as supersaturated.

  The enhancer preferably comprises a cellulose ester such as hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC). Thus, the method of the present invention enhances the degree of drug dissolution at supersaturated concentrations and / or gastric fluid conditions (eg, SGF) where the drug can be maintained in a dissolved state.

  Typically, the enhancer does not improve, or only improves (less than 10%) the length of time that the active pharmaceutical ingredient remains supersaturated unless additional precipitation inhibitors are added. The method of the present invention provides greater solubility, solubility and bioavailability, AUC, reduced time to Tmax, time to reach peak serum levels and higher Cmax when compared to neutral form or salt alone. Used to form a pharmaceutical formulation with the highest serum concentration. AUC is the area under the plot of plasma concentration of drug against time after drug administration (not logarithm of concentration). The area is appropriately measured by the “trapezoidal law”. That is, the data points are connected by a straight line segment, a perpendicular line is drawn from the abscissa to each data point, and the total area of the triangle and trapezoid thus configured is calculated. If the final measured concentration (Cn, at tn) is not zero, the AUC from tn to infinity is approximated by Cn / kel.

AUC is specifically used to estimate drug bioavailability and estimate total drug clearance (Cl _T ). After a single intravenous dose, AUC = D / Cl _T (where D is the dose) in a single compartment system following first order elimination kinetics, or AUC = C ₀ / kel (where kel is Drug elimination rate constant). For routes other than vein, in such a system, AUC = FD / Cl _T (where F is drug availability).

  Furthermore, the present invention relates to combining a precipitation inhibitor and optionally a potentiator with a medicament already in the form of a salt or co-crystal. The invention further relates to combining a precipitation inhibitor and optionally a potentiator with a medicament in the form of a salt or co-crystal solvate, desolvate, hydrate, dehydrate or anhydride.

Accordingly, in a further aspect, the present invention provides (a) a pharmaceutically active ingredient having low aqueous solubility or solubility, preferably in gastric fluid conditions,
Provided is a pharmaceutical composition comprising (b) a precipitation inhibitor, and (c) optionally an enhancer.

In a further aspect, the present invention provides:
(A) a pharmaceutically active ingredient having low aqueous solubility or solubility, preferably under gastric fluid conditions;
(B) A pharmaceutical composition comprising a precipitation inhibitor having an interfacial tension of less than 10 dyne / cm or a surface tension of less than 42 dyne / cm, and (c) optionally an enhancer.

In a further aspect, the present invention provides (a) a pharmaceutically active ingredient having low aqueous solubility or solubility, preferably in gastric fluid conditions,
Provided is a pharmaceutical composition comprising (b) a surfactant, and (c) optionally an enhancer.

In a further aspect, the present invention provides (a) a pharmaceutically active ingredient having low aqueous solubility or solubility, preferably in gastric fluid conditions,
Provided is a pharmaceutical composition comprising (b) a poloxamer having an interfacial tension of less than 10 dyne / cm or a surface tension of less than 42 dyne / cm, and (c) optionally an enhancer.

In a further aspect, the present invention provides (a) a pharmaceutically active ingredient having low aqueous solubility or solubility, preferably in gastric fluid conditions,
A pharmaceutical composition comprising (b) a surfactant and (c) a cellulose ester is provided.

In a further aspect, the present invention provides (a) a pharmaceutically active ingredient having low aqueous solubility or solubility, preferably in gastric fluid conditions,
(B) a surfactant having an interfacial tension of less than 10 dyne / cm or a surface tension of less than 42 dyne / cm, and (c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC)
A pharmaceutical composition is provided.

In a further aspect, the present invention provides (a) a pharmaceutically active ingredient having low aqueous solubility or solubility, preferably in gastric fluid conditions,
(B) poloxamer, and (c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC)
A pharmaceutical composition is provided.

In a further aspect, the present invention provides (a) a pharmaceutically active ingredient having low aqueous solubility or solubility, preferably in gastric fluid conditions,
(B) a poloxamer having an interfacial tension of less than 10 dyne / cm or a surface tension of less than 42 dyne / cm, and (c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC)
A pharmaceutical composition is provided.

In a further aspect, the present invention provides (a) celecoxib,
(B) a poloxamer having an interfacial tension of less than 10 dyne / cm or a surface tension of less than 42 dyne / cm at a concentration of 0.1%, and (c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC)
A pharmaceutical composition is provided.

In a further aspect, the present invention provides a process for the preparation of a pharmaceutical composition for providing a supersaturated concentration of a drug having low aqueous solubility, preferably in gastric fluid conditions, the process comprising the above aspects or other herein Including thorough mixing with the ingredients at the site.
In a further aspect, the surfactant dissolves in the dissolution medium to yield 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3% %, 0.2% or less than 0.1% concentration or 0.1% (w / w) concentration.

The present invention further provides a method for producing a pharmaceutical composition, the method comprising:
(1) Prepare multiple containers,
(2) Prepare multiple excipient solutions,
(3) A plurality of compound solutions are prepared, each of which has a pharmaceutical compound dissolved therein,
(4) Distribute one of the excipient solutions to each container together with one of the compound solutions to form a complete mixture, the properties of each mixture being different in different containers,
(5) Incubate the mixture,
(6) Confirm the appearance of solid nucleation or precipitation,
(7) Select a pharmaceutical compound / excipient combination in which the occurrence of solid nucleation is suppressed,
(8) producing a pharmaceutical composition comprising the pharmaceutical compound / excipient combination.

  Applicants will determine which properties of the pharmaceutical compound / excipient combination inhibit (inhibit) solid nucleation (here used to indicate the onset of solidification) in a quick and simple manner, It has been found that it is possible to screen a mixture comprising a pharmaceutical compound and an excipient to determine whether it is amorphous or crystalline. The term “solid nucleation” as used herein refers to the onset of solidification, whether amorphous or crystalline, but can be specified as amorphous or crystalline. In this way, other properties of these excipients or combinations thereof are selected for the production of a pharmaceutical composition in which the active pharmaceutical ingredient remains in solution for a sufficient time after being administered to the patient. can do. In this way, pharmaceutical compositions that reach at least the minimum bioavailability of the active pharmaceutical ingredient can be readily produced based on direct in vitro screening.

  Various properties of the pharmaceutical composition affect the development or precipitation of solid nucleation of the active pharmaceutical ingredient. Such properties include the identity or amount of excipients in the composition and the identity or amount of pharmaceutical compounds. Other properties may include other diluent amounts or carrier amounts such as salts or buffer compounds. If it can be polymorphic, the pharmaceutical compound itself can be screened in various forms of variation. Furthermore, according to the present invention, various salts, solvates, hydrates, co-crystals and other forms of active pharmaceutical ingredients can be screened.

The present invention can be readily applied to screening numerous variations of various excipients. Accordingly, in a preferred aspect, the present invention provides a method for producing a pharmaceutical composition, the method comprising:
(1) Prepare multiple containers,
(2) Prepare multiple excipient solutions,
(3) A plurality of compound solutions are prepared, each of which has a pharmaceutical compound dissolved therein,
(4) Distributing one of the excipient solutions to each container together with one of the compound solutions to form a complete mixture, each excipient being different in a different container;
(5) incubating the mixture,
(6) Confirm the appearance of solid nucleation or precipitation,
(7) Select an excipient in which the expression of solid nucleation is suppressed,
(8) producing a pharmaceutical composition comprising a pharmaceutical compound and a selected excipient.

According to this embodiment, the excipient is changed. Different excipients may be used in different containers, a single excipient may be used, or a combination of multiple excipients, eg, a combination of two, three, three or more components May be.
In a further aspect, the present invention provides a pharmaceutical composition obtained by the method of the present invention. The pharmaceutical composition may further comprise an excipient, diluent or carrier. In a preferred aspect, the pharmaceutical composition is formulated for oral administration.

Furthermore, the present invention provides a method for assessing excipient mediated delays in solid nucleation or precipitation of pharmaceutical compounds, the method comprising:
(1) Prepare multiple containers,
(2) Prepare multiple excipient solutions,
(3) A plurality of compound solutions are prepared, each of which has a pharmaceutical compound dissolved therein,
(4) Distribute one of the excipient solutions to each container together with one of the compound solutions to form a complete mixture, the properties of each mixture being different in different containers,
(5) Incubate the mixture,
(6) Confirm the appearance of solid nucleation or precipitation,
(7) ranking the properties of the mixture according to the onset time of solid nucleation or precipitation.

In a further aspect, the present invention provides a method of screening an excipient that inhibits solid nucleation or precipitation of a pharmaceutical compound, the method comprising:
(1) Prepare multiple containers,
(2) Prepare multiple excipient solutions,
(3) A plurality of compound solutions are prepared, each of which has a pharmaceutical compound dissolved therein,
(4) Distribute one of the excipient solutions to each container together with one of the compound solutions to form a complete mixture, each excipient being different in different containers;
(5) Incubate the mixture,
(6) Confirm the appearance of solid nucleation or precipitation,
(7) ranking the excipients by the onset time of solid nucleation or precipitation.

  In general, the active pharmaceutical ingredient (API) can be present, usually in a supersaturated solution, preferably in an aqueous based medium. The active pharmaceutical ingredients may be their free acids, free bases, co-crystals or salts or solvates, hydrates or dehydrates. The present invention is particularly applicable to pharmaceutical compositions containing active pharmaceutical ingredients that are likely to precipitate or crystallize out of solution during nucleation events when contacted with bodily fluids such as gastric or intestinal fluids. Accordingly, the present invention is particularly directed to pharmaceutical compositions that have a relatively low solubility or solubility when contacted with body fluids, as shown herein, but that have a relatively high solubility or solubility under suitable in vitro conditions. Can be applied.

  According to the present invention, the compound solution can be a solution that solubilizes the compound, or it can be a non-aqueous solution or an aqueous solution having a pH adjusted to accommodate the compound. For example, to achieve high solubility of a compound, a free base type compound is dissolved in an aqueous solution at an acidic pH, while a free acid type compound is dissolved in an aqueous solution at a basic pH. It will be. Therefore, the compound solution may be a supersaturated solution or preferably a supersaturated solution when compared with water, gastric juice or intestinal fluid. It is also preferred for the excipient to be formed with water, usually a solution containing deionized water or other aqueous based solution. In one aspect, the mixture mimics gastric fluid (SGF) or intestinal fluid (SIF, 0.68% potassium dihydrogen phosphate, 1% pancreatin and sodium hydroxide (final solution pH is 7.5)) From a point of view, it is preferred that excipients be added to solutions that mimic these body fluids. Alternatively, additional additives may be added to the solution to form a mixture that normally creates a suitable environment for the screening to be performed.

One advantage of the present invention is that multiple containers can exist in multiple well plate format or block and tube format so that at least 24, 48, 96, 384 or 1536 samples are analyzed in parallel. It can be done. Analyze multiple blocks and tubes or multiwell plates to analyze a total sample of at least 1000, 3000, 5000, 7000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000 or 100000 Can do. This is useful because the method can be operated in a semi-automatic or automatic manner using an apparatus that has multiple well plate formats. At least the dispensing step can be performed with an automatic liquid handling device. Therefore, a method such as high throughput screening can be performed. In addition, the use of multiple well plate formats results in a relatively low degree of screening. For example, each sample can be 100 mg, 50 mg, 25 mg, 10 mg, 5 mg, 750 microgram, 500 microgram, 250 microgram, 100 microgram, 75 microgram, 50 microgram, 25, depending on the active pharmaceutical ingredient, sample size, etc. Micrograms, 10 micrograms, 1 microgram, 750 ng, 500 ng, 250 ng, 100 ng or less than 50 ng may be included. This therefore minimizes the amount of active pharmaceutical ingredient needed to confirm the nature of the excipient or excipient combination that inhibits the development of excipients or nucleation. Thus, improved speed and relatively low cost are advantages.
The complete mixture formed in that way can be achieved by any of the conventional methods, such as using a mixer, during or after solution dispensing. Once the mixture is formed, it is generally advantageous to incubate the mixture at a constant temperature, such as about 37 ° C., to mimic in vivo conditions.

  Measurement of solid nucleation or precipitation can be performed, for example, by measuring light scattering of the mixture. This can be done by any conventional light scattering measurement, such as the use of a nephelometer. It may also include a further step of measuring the crystallization of the solid nucleation or precipitation product. This step is commonly performed prior to selecting the pharmaceutical compound / excipient combination for use in the pharmaceutical composition. Crystallization can be measured, for example, by birefringence screening.

Neither light scattering measurement nor birefringence screening is an open measurement technique. Advantageously, part or all of the sample solution need not be transferred to the second container, and the container or well can be sealed with a transparent seal that allows the use of these techniques.
In its most general aspect, the present invention relates to a pharmaceutical composition comprising an active pharmaceutical ingredient having low aqueous solubility or solubility (or as disclosed herein). In general, in this application, low aqueous solubility refers to compounds having a solubility in water of not more than 10 mg / ml, preferably not more than 1 mg / ml when measured at 37 ° C. The present invention particularly relates to drugs having a solubility of 0.1 mg / ml or less. Furthermore, the present invention relates to compounds that cannot be maintained as supersaturated solutions with stomach or intestinal fluid or with SGF or SIF. Such drugs include sulfonamide drugs such as benzenesulfonamide, in particular the pyrazolyl benzenesulfonamide mentioned above, including COX-2 inhibitors. Disclosed herein are stable crystalline metal salts of pyrazolylbenzenesulfonamides such as celecoxib. Such metal salts include alkali metal or alkaline earth metal salts, preferably sodium, potassium, lithium, calcium and magnesium salts.

  The pharmaceutical composition is preferably formulated for oral administration. The drug of the present invention is a time until it reaches the onset of a therapeutic effect (a time during which a drug administration effect can be confirmed or judged, for example, when a patient starts to feel fever or pain reduction). Can be shortened and the bioavailability can be increased. Accordingly, the pharmaceutical composition of the present invention is particularly suitable for administration to human patients.

2 shows the reproducibility of the differential scanning calorimetry (DSC) thermogram of celecoxib sodium salt prepared in Example 1 from 50 ° C. to 110 ° C. FIG. The reproducibility of the thermogravimetric thermogram of the sodium salt of celecoxib produced in Example 1 was shown and was performed at about 30 ° C. to about 160 ° C. The reproducibility of the PXRD diffractogram of the sodium salt of celecoxib produced in Example 1 is shown. 4- [5- (4-Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide obtained according to the protocol detailed in Example 4 and used in sodium salt The pharmacokinetics in male Sprague-Dawley rats after oral administration of 5 mg / kg of celecoxib crystal form obtained. 4- [5- (4-Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide obtained according to the protocol detailed in Example 4 and used in sodium salt The pharmacokinetics in male Sprague-Dawley rats after oral administration of 5 mg / kg of celecoxib crystal form obtained. The formulation and mean pharmacokinetic parameters (and their standard deviations) of celecoxib in male dog plasma with a single oral or single intravenous administration of celecoxib or celecoxib sodium are shown. The formulation and mean pharmacokinetic parameters (and their standard deviations) of celecoxib in male dog plasma with a single oral or single intravenous administration of celecoxib or celecoxib sodium are shown. A linear volume response in the AUC vs. volume plot is shown. The average concentration of celecoxib in serum by a single oral administration of celecoxib or celecoxib sodium to a male dog or a single intravenous administration of celecoxib is shown. FIG. 5 shows the effect of changing the ratio of ethylene glycol to propylene glycol subunits within the poloxamer at the concentration of celecoxib sodium salt in solution. Same weight cellulose (hydroxypropylcellulose (HPC, 100,000 kDa), low viscosity hydroxypropylmethylcellulose (low density HPMC, viscosity 80 to 120 cps), high viscosity hydroxypropylmethylcellulose (high density HPMC, viscosity 15,000 cps), fine Figure 3 shows the effect of various celluloses on the solubility of various compositions including crystalline cellulose (Avicel PH200)), d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TGPS) and celecoxib sodium. FIG. 6 shows the solubility at 37 ° C. of compositions comprising various weight ratios of d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TGPS), hydroxypropylcellulose and celecoxib sodium salt. Figure 5 shows the solubility profile of celecoxib sodium salt in simulated gastric fluid (SGF) from a solid mixture containing excipients at room temperature. The legend shows the weight ratio of excipients and excipients to celecoxib sodium (1: 1 unless otherwise noted). Excipients include polyvinylpyrrolidone (PVP), poloxamer 188 (P 188), poloxamer 237 (P237), d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TGPS) and Gercia (Gelucire ™) 50 / Includes 13. Avicel microcrystalline cellulose in the solubility of a mixture of celecoxib sodium salt, d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TGPS) and hydroxypropylcellulose (HPC) in simulated gastric fluid (SGF) at 37 ° C The effect of silica gel is shown. The legend indicates the weight ratio of the components. Celecoxib sodium salt in simulated gastric juice diluted 5-fold with excipients including d-alpha-tocopher polyethylene glycol-1000 琥珀 ester (vitamin E TPGS), hydroxypropyl cellulose (HPC) and poloxamer 237 The solubility is shown. The legend indicates the weight ratio of the components. FIG. 4 shows a PXRD diffractogram for the sodium salt of celecoxib produced by the method of Example 6. 2 shows the Raman spectrum for the sodium salt of celecoxib produced by the method of Example 6. 2 shows a differential scanning calorimetry (DSC) thermogram of celecoxib lithium salt MO-116-49B. 1 shows a thermogravimetric analysis (TGA) thermogram of celecoxib lithium salt MO-116-49B. The Raman spectrum of celecoxib lithium salt MO-116-49B is shown. PXRD diffractogram of celecoxib lithium salt MO-116-49B is shown. 1 shows a differential scanning calorimetry (DSC) thermogram of celecoxib potassium salt MO-116-49A. 1 shows a thermogravimetric analysis (TGA) thermogram of celecoxib potassium salt MO-116-49A. The Raman spectrum of celecoxib potassium salt MO-116-49A is shown. PXRD diffractogram of celecoxib potassium salt MO-116-49A is shown. 1 shows a thermogravimetric analysis (TGA) thermogram of celecoxib potassium salt MO-116-55D. 2 shows the Raman spectrum of celecoxib potassium salt MO-116-55D. 1 shows a PXRD diffractogram of celecoxib potassium salt MO-116-55D. 1 shows a thermogravimetric analysis (TGA) thermogram of celecoxib calcium salt MO-116-62A. The Raman spectrum of celecoxib calcium salt MO-116-62A is shown. PXRD diffractogram of celecoxib calcium salt MO-116-62A is shown. 1 shows a PXRD diffractogram of commercially available celecoxib. The Raman spectrum of a commercially available celecoxib is shown. Fig. 2 shows the crystallization inhibition time of celecoxib as a function of an excipient in simulated gastric fluid (SGF). Figure 3 shows the interfacial tension in water of selected PLURONIC excipients. It shows that PLURONIC concentrations equal to or higher than CMC are preferred for the effectiveness of precipitation inhibition. Figure 3 shows the solubility of celecoxib sodium hydrate from a composition comprising PLURONIC P123 and F127. Figure 5 shows the solubility of celecoxib sodium hydrate from PLURONIC P123, F127 and F87 in the presence of HPC. Figure 6 shows the solubility of celecoxib sodium hydrate using PLURONIC F127, HPC and granule fluid. Figure 2 shows the solubility of celecoxib sodium hydrate using PLURONIC F127 and HPC in a dense formulation. The dissolution profile of a spring with and without a parachute is shown. 2 shows a flow chart outlining the method according to the invention. A plate map of an automatic liquid distributor is shown. Figure 5 shows a light scatter trace over time in the analysis of the present invention. Figure 2 shows a thermogravimetric analysis (TGA) thermogram of a propylene glycol solvate of celecoxib sodium salt. FIG. 3 shows a PXRD diffractogram of a propylene glycol solvate of celecoxib sodium salt. FIG. 3 shows a PXRD diffractogram of a propylene glycol solvate of celecoxib sodium salt. FIG. 3 shows a PXRD diffractogram of a propylene glycol solvate of celecoxib sodium salt. FIG. 3 shows a PXRD diffractogram of a propylene glycol solvate of celecoxib sodium salt. 1 shows a thermogravimetric analysis (TGA) thermogram of a propylene glycol solvate of celecoxib potassium salt. FIG. 4 shows a PXRD diffractogram of a propylene glycol solvate of celecoxib potassium salt. 1 shows a thermogravimetric analysis (TGA) thermogram of a propylene glycol solvate of a celecoxib lithium salt. 2 is a thermogravimetric analysis (TGA) thermogram of celecoxib sodium salt propylene glycol trihydrate prepared according to Example 21. FIG. FIG. 4 shows a PXRD diffractogram of the sodium salt propylene glycol trihydrate of celecoxib produced according to Example 21. FIG. 3 shows a thermogravimetric analysis (TGA) thermogram of the sodium salt propylene glycol trihydrate of celecoxib prepared according to Example 21. FIG. FIG. 4 shows a PXRD diffractogram of the sodium salt propylene glycol trihydrate of celecoxib prepared according to Example 21. 2 shows a DSC thermogram of isopropyl alcohol solvate of sodium salt of celecoxib prepared according to Example 22. FIG. 9 shows a thermogravimetric analysis (TGA) thermogram of the isopropyl alcohol solvate of the sodium salt of celecoxib prepared by Example 22, which was performed at about 30 ° C. to about 160 ° C. FIG. FIG. 4 shows a PXRD diffractogram of isopropyl alcohol solvate of celecoxib sodium salt prepared according to Example 22. FIG. 4 shows a PXRD diffractogram of a propylene glycol solvate of celecoxib lithium salt produced by Example 20. FIG. 5 shows a PXRD diffractogram of celecoxib: nicotinamide cocrystal produced by Example 23. FIG. 4 shows a PXRD diffractogram of celecoxib sodium salt hydrate under 17% RH prepared according to Example 24. FIG. 5 shows a PXRD diffractogram of celecoxib sodium salt hydrate under 31% RH prepared according to Example 24. FIG. 6 shows a PXRD diffractogram of celecoxib sodium salt hydrate under 59% RH prepared according to Example 24. FIG. 4 shows a PXRD diffractogram of hydrated celecoxib sodium salt under 74% RH prepared according to Example 24. FIG. 4 shows a PXRD diffractogram of a hydrate of propylene glycol solvate of celecoxib sodium salt prepared according to Example 24 under 17% RH. FIG. 4 shows a PXRD diffractogram of the hydrate of propylene glycol solvate of celecoxib sodium salt prepared according to Example 24 under 31% RH. FIG. 4 shows a PXRD diffractogram of a hydrate of propylene glycol solvate of celecoxib sodium salt prepared according to Example 24 under 59% RH. FIG. 4 shows a PXRD diffractogram of the hydrate of propylene glycol solvate of celecoxib sodium salt prepared according to Example 24 under 74% RH. FIG. 4 shows a PXRD diffractogram of multiple celecoxib sodium salt samples of various hydration states produced according to Example 25. 2 shows a PXRD diffractogram of celecoxib sodium salt prepared according to Example 2. FIG. 1 is a thermogravimetric analysis (TGA) thermogram of a hydrate of celecoxib potassium salt. 1 shows a PXRD diffractogram of a hydrate of celecoxib potassium salt. Figure 2 shows a thermogravimetric analysis (TGA) thermogram of the sodium salt of celecoxib made with sodium chloride. FIG. 5 shows a PXRD diffractogram of celecoxib sodium salt made with sodium chloride. Figure 5 shows the dissolution profile of sodium salt hydrate of celecoxib. Figure 5 shows in vitro dissolution data for a sustained release formulation of celecoxib. The change in the PXRD diffractogram of celecoxib sodium salt hydrate by the change of the atmospheric relative humidity is shown. Figure 7 shows the change in the PXRD diffractogram of celecoxib sodium salt propylene glycol solvate with changes in atmospheric relative humidity. 2 shows dynamic vapor absorption data for celecoxib sodium salt hydrate. The dynamic vapor absorption data of celecoxib potassium salt are shown. PXRD data for celecoxib potassium salt is shown. Figure 5 shows dynamic vapor absorption data for celecoxib sodium propylene glycol solvate. Figure 5 shows dynamic vapor absorption data for celecoxib sodium propylene glycol solvate. 2 shows a comparison of PXRD diffractograms of celecoxib sodium propylene glycol solvate. Figure 5 shows dynamic vapor absorption data for celecoxib potassium propylene glycol solvate. 2 shows a comparison of PXRD diffractograms of celecoxib potassium propylene glycol solvate. Figure 5 shows dynamic vapor absorption data for celecoxib lithium propylene glycol solvate. 2 shows a comparison of PXRD diffractograms of celecoxib lithium propylene glycol solvate. 3 shows dynamic vapor absorption data for celecoxib: nicotinamide co-crystals. 1 shows a DSC thermogram of amorphous celecoxib potassium salt. The Raman spectrum of the amorphous celecoxib potassium salt is shown. 1 shows a PXRD diffractogram of amorphous celecoxib potassium salt. Figure 2 shows a thermogravimetric analysis (TGA) thermogram of celecoxib: 18-crown-6 co-crystal. 1 shows a DSC thermogram of celecoxib: 18-crown-6 co-crystal. The PXRD diffractogram of a celecoxib: 18-crown-6 co-crystal is shown. Figure 2 shows a thermogravimetric analysis (TGA) thermogram of celecoxib: 15-crown-5 solvate. FIG. 5 shows a DSC thermogram of celecoxib: 15-crown-5 solvate. FIG. 5 shows a PXRD diffractogram of celecoxib: 15-crown-5 solvate. Figure 2 shows a thermogravimetric analysis (TGA) thermogram of celecoxib diglyme solvate. 2 shows a DSC thermogram of celecoxib diglyme solvate. FIG. 4 shows a PXRD diffractogram of celecoxib diglyme solvate. 1 shows a thermogravimetric analysis (TGA) thermogram of valdecoxib: 18-crown-6 co-crystal. 1 shows a PXRD diffractogram of valdecoxib: 18-crown-6 co-crystal. The single crystal packing figure of valdecoxib: 18-crown-6 co-crystal is shown. Figure 2 shows a TGA thermogram of celecoxib NMP solvate. A Raman spectrum of celecoxib NMP solvate is shown. PXRD diffractogram of celecoxib NMP solvate is shown. A packing diagram of celecoxib NMP solvate at 100K is shown. Figure 5 shows a packing diagram of celecoxib NMP solvate at 571K. 1 shows a thermogravimetric analysis (TGA) thermogram of celecoxib sodium salt synthesized from 2-propanol. 2 shows a DSC thermogram of celecoxib sodium salt synthesized from 2-propanol.

  In its most general aspect, the present invention relates to a pharmaceutical composition comprising an active pharmaceutical ingredient having, for example, low aqueous solubility in gastric juice conditions. In general, the low aqueous solubility described in this application relates to compounds having a solubility in water of 10 mg / ml or less, preferably 5 mg / ml or 1 mg / ml or less when measured at 37 ° C. Furthermore, “low aqueous solubility” is 900, 800, 700, 600, 500, 400, 300, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30 when measured at 37 ° C. 20 μg / ml or even less than 10, 5 or 1 μg / ml, or even 900, 800, 700, 600, 500, 400, 300, 200, 150, 100, 90, 80, 70, 60, 50, 40 , 30, 20, or 10 ng / ml or less than 10 ng / ml. In addition, aqueous solubility can also be measured in simulated gastric fluid (SGF) instead of water. The SGF of the present invention (undiluted) is prepared by mixing 1 g / L Triton X-100 and 2 g / L NaCl in water and adjusting the pH at 20 mM to obtain a solution with a final pH of 1.7. Made. The pH is 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, It may be specified as 4, 4.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5 or 12.

  Active pharmaceutical ingredients having a solubility of 0.1 mg / ml or less are benzenesulfonamides, in particular any sulfonamide drug (including COX-2 inhibitors) such as these pyrazolylbenzenesulfonamides mentioned above, etc. include. Disclosed herein are stable crystalline metal salts and co-crystals of pyrazolylbenzenesulfonamides such as celecoxib. Such metal salts include alkali metal or alkaline earth metal salts, especially sodium, potassium, lithium, calcium and magnesium salts.

In one aspect of the invention, the active pharmaceutical ingredient with low aqueous solubility is formulated with a precipitation inhibitor and optionally a precipitation inhibition enhancer. The precipitation inhibitor used in the present invention can be selected from a wide range of surfactants (see, for example, FIG. 30). In an embodiment, it comprises a nonionic surfactant or an ionic surfactant. In an embodiment of the invention, the precipitation inhibitor (eg, poloxamer) has an interfacial tension of less than 10 dyne / cm and / or when measured as a concentration of 0.1% w / w in water compared to mineral oil at 25 ° C. Alternatively, the precipitation inhibitor (eg, poloxamer) has a surface tension of less than 42 dyne / cm when measured as a concentration of 0.1% w / w in water. In other embodiments of the invention, the interfacial tension is less than 15, 14, 13, 12, 11, 9, 8, 7 or 6 dyen / cm, or the surface tension is 45, 44, 43, 41, 40, Less than 39, 38, 37, 36 or 35 dyne / cm. In other embodiments, the surfactant is a poloxamer. The poloxamer comprises a block copolymer of ethylene oxide-propylene oxide, preferably having the structure (PEG) _x- (PPG) _y- (PEG) _z (where x, y and z are integers) x is usually equal to z). A preferred form of poloxamer is that obtained from BASF designated “PLURONIC®”. However, the present invention is not limited to the PLURONIC series, and similar poloxamers obtained from other suppliers may be used. Examples of PLURONIC poloxamers according to the present invention include PLURONIC L122, PLURONIC P123, PLURONIC F127 (Poloxamer 407), PLURONIC L72, PLURONIC P105, PLURONIC LP2, PLURONIC P104, PLURONIC F108 (Poloxamer 338), PLURONIC P103, PLURONIC L44 , PLURONIC F68 (poloxamer 188) and PLURONIC F87 (poloxamer 237). A particular poloxamer and its corresponding PLUROIC, ie generic name and trade name, can be used interchangeably throughout.

In one embodiment, the present invention provides:
(A) an active pharmaceutical ingredient and (b) a polyethylene block copolymer comprising an A-type linear polymer moiety bonded to one end of a B-type linear polymer moiety (wherein the A-type moiety has a relatively hydrophilic character. And the repeating unit gives an average Hansch-Leo fragmentary constant of about −0.4 or less, has a molecular weight of about 30 to about 500, and the B-type moiety is a relatively hydrophobic feature. Wherein the repeat unit provides an average Hansch-Leo fragmental constant of about −0.4 or greater, has a molecular weight of about 30 to about 500, and each repeat unit of the polymer portion. At least about 80% of the linkages are ether linkages.)
A pharmaceutical composition is provided. In a preferred first embodiment, the polyether block copolymer has the formula
ABA '(i)
AB (ii)
BAB '(iii) or
L (R ¹ ) (R ² ) (R ³ ) (R ⁴ ) (iv)
Wherein A and A ′ are A-type linear polymer moieties, B and B ′ are B-type linear polymer moieties, R ¹ , R ² , R ³ and R ⁴ are formulas (i), (ii ) Or (iii) a block copolymer or hydrogen, L is a linking group, provided that no more than ^{two of} R ¹ , R ² , R ³ or R ⁴ are hydrogen.
A polyether block copolymer selected from the group consisting of:

  In other embodiments, the composition comprises or forms block copolymer micelles during administration or subsequent course. Preferably, at least about 0.1% of the active pharmaceutical ingredient is more preferably incorporated into the micelles, more preferably at least about 1% of the active pharmaceutical ingredient, more preferably at least about 5% of the active pharmaceutical ingredient.

In other embodiments, the hydrophobic fraction of the copolymer of the composition is preferably at least about 50% or more, at least about 60%, more preferably 70%.
In still other embodiments, the hydrophobic weight of the copolymer is at least about 900, preferably at least about 1700, more preferably at least about 2000, and even more preferably at least about 2300.

  In still other embodiments, the hydrophobic weight of the copolymer is at least about 2000 and the hydrophobic percentage is at least about 20%, preferably 35%, or the hydrophobic weight is at least about 2300 and the hydrophobic proportion is at least about 20%, preferably 35%.

  The optional third component of the pharmaceutical composition according to the present invention comprises a precipitation inhibition enhancer. An enhancer is a compound that can enhance the action of a precipitation inhibitor in inhibiting, preventing or at least reducing the precipitation of a drug with low aqueous solubility, usually when diluted for the following oral administration: . In one embodiment, the enhancer does not work with the precipitation inhibitor alone. In other embodiments, the enhancer does not have any effect or negative effect on in vitro precipitation analysis, but increases the action of the precipitation inhibitor in in vivo or in vitro solubility analysis. Cellulose esters such as hydroxypropylcellulose are particularly useful enhancers according to the present invention. Cellulose esters change the chain length of their cellulose skeleton and, as a result, change their viscosity when measured, for example, at 2% strength by weight in water at 20 ° C. A lower viscosity is usually preferred over a higher viscosity in the present invention. In embodiments of the invention, the cellulose ester, such as HPC, has a viscosity in water of 2%, about 100 to about 100,000 cP, or about 1000 to about 15,000 cP. In other embodiments, the viscosity is 1,500,000, 1,000,000, 500,000, 100,000, 75,000, 50,000, 35,000, 25,000, 20,000, 17,500, 15,000, 12,500, 11,000, 10,500, 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, It has a viscosity of less than 2,000, 1,000, 750, 500 or 250 cP, or a range selected from the above two integers.

  The enhancer is also useful for delaying Tmax and / or increasing the time that the active pharmaceutical ingredient concentration exceeds 1/2 Tmax, and thus smoothing the serum concentration versus time curve. Preferred enhancers increase the time over which the active pharmaceutical ingredient concentration exceeds 1/2 Tmax by 25%, 50%, 75%, 100%, more than 3 times. In a preferred embodiment, the composition reduces the time to Tmax and maintains 1/2 Tmax longer than the free acid or than in a similar composition except that the salt or co-crystal is replaced by the free acid. .

  The component ratio a: b: c (active pharmaceutical ingredient: precipitation inhibitor: enhancing agent) exemplified here is about 1: 1: 1 (precipitation inhibitor and enhancing agent is +/− 0.2). However, the ratio can be adjusted to suit the application. For example, the amount of precipitation inhibitor or enhancer may need to be reduced, and should be reduced below the optimal concentration to reduce the amount of excipients in the dosage form of a composition such as a tablet or capsule. might exist. In one embodiment, the unit dosage form is a precipitation inhibitor (surfactant) in water or SGF in an amount required or greater than that required to reach its critical micelle concentration (CMC). Agent). Although poloxamers may not form intrinsic micelles, care is taken to form similar structures that are considered micelles for the purposes of the present invention.

  In addition, the composition may include a pharmaceutically acceptable diluent, excipient or carrier, and such additional ingredients are described in further detail below. One such additional component includes a granulating fluid such as poloxamer 124, PEG 200 or PEG 400. It forms complete contact between the active pharmaceutical ingredient, the precipitation inhibitor and optionally the enhancer by dissolving the bonds or parts thereof. Embodiments mention that the composition is at least 25%, 50%, 75%, or almost or completely dissolved, but it is preferred that the composition remain solid, semi-solid or pasty. . Any pharmaceutically acceptable liquid can be used provided it is solid and does not cause conversion to the free acid in salt or co-crystal form. Some non-limiting examples include methanol, ethanol, isopropanol, higher alcohols, propylene glycol, ethyl caprylate, propylene glycol laurate, PEG, diethyl glycol monoethyl ether (DGME), tetraethylene glycol dimethyl ether, triethylene glycol Contains ethylene glycol monoethyl ether and polysorbate 80. The presence of the granulating fluid-like liquid increases the solubility of the active pharmaceutical ingredient by delaying the contact between the active pharmaceutical ingredient and the dissolution medium as much as possible until the surfactant is dissolved in large quantities. This delays precipitation. The use of a granulating fluid-like liquid is particularly useful when the pharmaceutically active ingredient and the precipitation accelerator are solid.

As an alternative embodiment for increasing the supersaturation of the active pharmaceutical ingredient, the pharmaceutical composition is in a compressed form by compressing the ingredients together during the manufacturing process of the pharmaceutical composition. The compression is performed in the same way as is done with the granulating fluid. Suppression of precipitation or smoothing the serum concentration versus time curve can be limited, if necessary, by using a disintegrant during compression.
In a further embodiment, the active pharmaceutical ingredient and the precipitation inhibitor (and optionally the enhancer) when combined form a paste or non-aqueous solution. If a paste is utilized, a viscous mass of the ingredient may be produced, which is thought to delay the dissolution of the active pharmaceutical ingredient by first dissolving the surfactant. This is believed to promote supersaturation of the active pharmaceutical ingredient.

Usually, the compounds and compounds of the present invention are closely related as pharmaceutical compositions. In this context, “close relationship” means, for example, a drug mixed with a precipitation inhibitor, a drug embedded or incorporated in the inhibitor, a compound that forms a coating of drug particles, or vice versa, and the entire compound Including a drug dispersed substantially uniformly throughout.
According to a further aspect of the present invention, there is provided a method for treating a patient who may suffer from cancer, such as pain, inflammation, intestinal or colon polyps, or pre-cancer when the pharmaceutical composition comprises a COX-2 inhibitor. Is done. The method includes administering to the patient a pharmaceutical composition described herein.

The pharmaceutical composition is preferably formulated for oral administration. The drug of the present invention can be produced in a form that reduces the time to onset of therapeutic effect and increases bioavailability. The pharmaceutical composition of the present invention is particularly suitable for administration to human patients.
The methods and compositions of the present invention relate to improved drug solubility, solubility and bioavailability. The present invention further relates to improving the properties of pharmaceutical compounds that initially dissolve but then precipitate or recrystallize in gastric fluid conditions.

  In a further embodiment, the invention relates to a medicament having an aminosulfonyl functional group. Here, the term “aminosulfonyl functional group” means the following structural formula (II)

(Wherein the wavy line represents a bond due to the functional group attached to the remainder of the drug molecule; R is hydrogen or an amino acid adjacent to R to form a polyethylene glycol or polyethylene glycol degradation product to form additional compounds. A substituent that protects the function to react with the group.)
The functional group which has is shown. Examples of such substituents include partially unsaturated heleocyclyl, heleoaryl, cycloalkenyl, aryl, alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, phenyl, alkoxy, aminocarbonyl , Alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, hydroxyl, alkoxyalkyloxyalkyl, haloalkylsulfonyloxy, carboxyalkoxyalkyl, cycloalkylalkyl, alkynyl, heterocyclyloxy, alkylthio, cycloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclyl Alkyl, heteroarylcarbonyl, alkylthioalkyl, arylcarbonyl, aralkyl Carbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylamino Carbonyl, alkylaminocarbonylalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl , N-aralkylamine coalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkyls Including rufinyl, alkylsulfonyl and the like.

Non-limiting examples of drugs containing aminosulfonyl include Eisai's ABT-751 (N- (2- (4-hydroxyphenyl) amino) -3-pyridyl) 4-methoxybenzenesulfonamide); alpiropride; Amosulalol; amprenavir; amsacrine; argatroban; aslacrine; azosemide, Bayer BAY-38-4766 (N- [4-[[[5- (dimethylamino) ) -1-Naphthalenyl] sulfonyl] amino] phenyl] -3-hydroxy-2,2-dimethylpropanamide); bendroflumesiazide; BMS-193884 (N- (3,4-dimethyl-5) from Bristol-Myers Squibb - isoxazolyl) -4 ¹ - (2-oxazolyl) - [1, 1 ¹ - biphenyl] -2-sulfonamide); bosentan (bosentan); Bumechido (Bumetide); celecoxib; chlorthalidone; delavirdine; de Defacoxib; dofetilide; domitroban; dorzolamide; dronedarone; Eisai's E-7070 (N- (3-chloro-1H-indol-7-yl) -1,4-benzene-disulfonamide) EF-7412 (N-3- [4- [4- (Tetrahydro-1,3-dioxo-1H-pyrrolo [1,2-c] imidazol-2 (3H) -yl) butyl] -1 from Schwarz Pharma -Piperazinyl] phenyl] ethanesulfonamide); fenquizone; furosemide; glibenclamide; gliclazide; glimepiride; glipizide; glipizide; glipizide; gliquidone; ); GlaxoSmithKline GW-8510 (4-[[6,7-Dihydro-7-oxo-8H-pyrrolo [2,3-g] benzothiazol-8-ylidene) methyl] amino] -N-2- Pyridinylbenzenesulfonamide), a Ivac GYKI-16638 (N- [4- [2-[[2- (2,6-dimethoxyphenoxy) -1-methylethyl] methylamino] ethyl] phenyl] methanesulfonamide); Aventis HMR-1098 ( 5-chloro-2-methoxy-N- [2- [4-methoxy-3 [[[(methylamino) thioxomethyl] amino] sulfonyl] phenyl] ethyl] benzamide); hydrochlorothiazide; ibutilide; indapamide; IS-741 (N- [2-[(ethylsulfonyl) amino] -5- (trifluoromethyl) -3-pyridinyl] cyclohexanecarboxamide); Nippon Tobacco JTE-522 (4- (4-cyclohexyl) 2- Methyl-5-oxazolyl) -2-fluorobenzenesulfonamide); Chugai KCB-328 (N- [3-amino-4- [2-[[2-3, 4-dimethoxyphenyl) ethyl] methylamino] ethoxy ] Phenyl] methanesulfonamide); Kotobuki KT2-962 (3- [4-[[(4-chlorophenyl) sulfonyl] amino] buty ] -6- (1-Methylethyl) -1-sulfonic acid azulene); Levosulpiride; Eli Lilly's LY-295501 (N-[[((3, 4-dichlorophenyl) amino] carbonyl] -2, 3 -Dihydro-5-benzofuransulfonamide) and LY-404187 (N-2- (4- (4-cyanophenyl) phenyl) propyl-2-propanesulfonamide); metrazone; naratriptan; nimesulide; Nippon NS-49 ((R) -N- [3- (2-amino-1-hydroxyethyl) -4-fluorophenyl] methanesulfonamide); ONO-8711 ((5Z) -6-[(2R, 3S)- 3-[[[[(4-Chloro-2-methylphenyl) sulfonyl] amino] methyl] bicyclo [2.2.2] oct-2-yl] -5-hexenoic acid); Piretanide; Pharmacia PNU-103657 (1- [5-methanesulfonamidoindol-2-ylcarbonyl] -4- (N-methyl-N- (3- (2-methylpropyl) -2-pyridinyl) amino) piperidine); polythiazide; ramatroban ; Hoffman Laroche RO-61-1790 (N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- [2- (1H-tetrazol-5-yl) -4-pyridinyl] -4-pyrimidinyl] -5-methyl-2-pyridinesulfonamide); Aventis RPR-130737 (4-hydroxy-3- [2-oxo-3 (S)-[5- (3-pyridyl) thiophene-2 -Ylsulfonamido] pyrrolidin-1-ylmethyl] benzamide) and RPR-208707; server S-18886 (3-[(6- (4-chlorophenylsulfonylamino) -2-methyl-5, 6,7,8- Tetrahydronaphth] -1-yl) propionic acid) and S-32080 (3- [6- (4-chlorophenylsulfonylamido) -2-propyl-3- (3pyridyl-methyl) -5, 6,7,8- Tetrahydronaphthalen-1-yl] propionic acid); Kaken S-36496 (2-sulfonyl- [N- (4-chlorophenyl) sulfonylamino-butyl-N-[(4-cyclobutylthiazol-2-yl) ethenyl) Phenyl-3-yl-methyl]] amino Benzoic acid); sampatrirat; GlaxoSmithKline SB-203208 (L-phenylalanine, b-methyl-, (4aR, 6S, 7R, 7aS) -4- (aminocarbonyl) -7-[[[[[[ (2S, 3S) -2-Amino-3-methyl-1-oxopentyl] amino] sulfonyl] acetyl] amino] -7-carboxy-2, 4a, 5,6, 7, 7a-hexahydro-2-methyl- 1H-cyclopenta [c] pyridin-6yl ester, (bS)-); Dipone SE-170 (2- (5-amidino-1H-indol-3-yl) N- [2 '-(aminosulfonyl)- 3-bromo (1,1'biphenyl) -4-yl] acetamide); Sivelestat; Senju SJA-6017 (N- (4-fluorophenylsulfonyl) -L-valyl-L-leucinal); Sumitomo SM- 19712 (4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) amino] carbonyl] benzenesulfonamide); sonepiprazole; sotalol ); Sulfadiazine; sulf Aguanol; sulfasalazine; sulpride; sulprostone; sumatriptan; Toyama T-614 (N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]- Methanesulfonamide); Tularik's T-138067 (2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide) and T-900607 (2, 3,4,5,6-pentafluoro-N-3-ureido-4-methoxyphenyl) benzenesulfonamide); Takeda TAK-661 (2,2-dimethyl-3-[[7- (1-methylethyl ) [1,2,4] triazole [1,5-b] pyridazin-6-yl] oxy] -1-propanesulfonamide); tamsulosin; tezosentan; tipranavir; tirofiban; tolasemide (Torasemide); trichloromediazide; tripamide; valdecoxib; veralipride; key Pamido (Xipamide); Zeria of Z-335 (2- [2- (4- chlorophenyl sulfonylaminomethyl) indan-5-yl] acetic acid); zafirlukast (Zafirlukast); Zonisamide (Zonisamide); and salts thereof.

  In a preferred embodiment, the aminosulfonyl-containing drug is a low water solubility selective COX-2 inhibitor. Suitable selective COX-2 inhibitors include the following formula (III):

Wherein A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated cyclic ring, preferably pyrazolyl, furanoyl, isoxazolyl, pyridinyl, cyclopentenonyl and A heterocyclyl group selected from a pyridazinonyl group;
X is O, S or CH ₂ ;
n is 0 or 1;
R ¹ is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, optionally in a substitutable position alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, Optionally substituted with one or more groups selected from haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
R ² is an NH ₂ group;
R ³ is hydride, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl , Acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, Aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-aryla Minocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-aryl Amino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio , Alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl, R ³ is optionally Replaceable One or more selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio And R ⁴ is selected from hydride and halo. )
It is this compound.

  In particular, suitable selective COX-2 inhibitors are those of formula (IV):

Wherein R ⁴ is hydrogen or a C _1-4 alkyl or alkoxy group,
X is N or CR ⁵ (R ⁵ is hydrogen or halogen);
Y and Z are carbon or nitrogen atoms that separately define 5 to 6 membered ring adjacent atoms substituted or unsubstituted at one or more positions with an oxo, halo, methyl or halomethyl group. )
It is a compound which has this. Preferred 5- to 6-membered rings are cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted at positions other than 1.

  By way of example, the composition of the present invention is suitable for celecoxib, delacoxib, valdecoxib and JTE-522, and further suitable for celecoxib, paracoxib, valdecoxib. Examples of other suitable compositions are: Acetazolamide CAS Registry Number: 59-66-5, Acetohexamide CAS Registry Number: 968-81-0, Alpyropride CAS Registry Number: 81982-32-3, Althiazide CAS Registry Number: 5588-16-9, Ambside CAS Registry Number: 3754-19-6, Amidephrin CAS Registry Number: 3354-67-4, Amos Aralol CAS Registry Number: 85320-68-9 , Amsacrine CAS Registry Number: 51264-14-3, Argatroban CAS Registry Number: 74863-84-6, Azosemide CAS Registry Number: 27589-33-9, Bendroflumethiazide CAS Registry Number: 73-48-3, Benzthiazide CAS registration number: 91-33-8, benzylhydrochlorothiazide CAS registration number: 1824-50-6, p- (benzylsulfonamide) Benzoic acid CAS registration number: 536-95-8, Bosentan CAS registration number: 147536-97- 8, brinzolamide CAS registration number: 138890-62-7, bumetanide CAS registration number: 28395-03-1, butzolamide CAS registration Issue: 16790-49-1, Butiazide CAS Registry Number: 2043-38-1, Carbutamide CAS Registry Number: 339-43-5, Celecoxib CAS Registry Number: 169590-42-5, Chloraminophenamide CAS Registry Number: 121 -30-2, Chlorothiazide CAS Registry Number: 58-94-6, Chlorpropamide CAS Registry Number: 94-20-2, Chlortalidone CAS Registry Number: 77-36-1, Clofenamide CAS Registry Number: 671-95- 4, Clopamide CAS registration number: 636-54-4,

Chlorexolone CAS Registry Number: 2127-01-7, Cyclopenthiazide CAS Registry Number: 742-20-1, Cyclothiazide CAS Registry Number: 2259-96-3, Daltroban CAS Registry Number: 79094-20-5, Delavirdine CAS Registered Number: 136817-59-9, Diazoxide CAS Registry Number: 364-98-7, Dichlorphenamide CAS Registry Number: 120-97-8, Disulfamide CAS Registry Number: 671-88-5, Dofetilide CAS Registry Number: 115256 -11-6, Dmitroban CAS Registry Number: 112966-96-8, Dorzocamide CAS Registry Number: 120279-96-1, Ethiazide CAS Registry Number: 1824-58-4, Ethoxyzolamide CAS Registry Number: 452-35-7 , Fenkizone CAS Registry Number: 20287-37-0, Flumethiazide CAS Registry Number: 148-56-1, N ² -Formylsulfizomidine CAS Registry Number: 795-13-1, Furosemide CAS Registry Number: 54-31- 9, glibornuride CAS registration number: 26944-48-9, gliclazide CAS registration number: 21187-98-4, glimepiride CAS registration number: 93479-97-1, Glipizide CAS registration number: 29094-61-9, Gliquidone CAS registration number: 33342-05-1, Glyoxidepide CAS registration number: 25046-79-1, N ⁴ -beta-D- Crucosylsulfanilamide CAS Registry Number: 53274-53-6, Glybride CAS Registry Number: 10238-21-8, Glicothiazole CAS Registry Number: 535-65-9, Glybazole CAS Registry Number: 1492-02-0, Glyhexamide CAS registration number: 451-71-8, Grimidine CAS registration number: 339-44-6, Glipinamide CAS registration number: 1228-19-9,

  Hydrochlorothiazide CAS Registry Number: 58-93-5, Hydroflumethiazide CAS Registry Number: 135-09-1, Ibutilide CAS Registry Number: 122647-31-8, Indapamide CAS Registry Number: 26807-65-8, Mefenide CAS Registry Number : 138-39-6, Mefluside CAS Registry Number: 7195-27-9, Metazolamide CAS Registry Number: 554-57-4, Meticlotiazide CAS Registry Number: 135-07-9, Metrazone CAS Registry Number: 17560-51- 9, Lanatriptan CAS Registry Number: 121679-13-8, Nimesquid CAS Registry Number: 51803-78-2, Nopril Sulfamide CAS Registry Number: 576-97-6, Paraflutizide CAS Registry Number: 1580-83-2 , Phenbutamide CAS registration number: 3149-00-6, phenosulfazole CAS registration number: 515-54-8, phthalyl sulfacetamide CAS registration number: 131-69-1, phthalyl sulfathiazole CAS registration number: 85 -73-4, sulfacetamide CAS registration number: 144-80-9, sulfachlorpyridazine CAS registration No .: 80-32-0, Sulfacrysoidine CAS Registration Number: 485-41-6, Sulfacitin CAS Registration Number: 17784-12-2, Sulfadiazin CAS Registration Number: 68-35-9, Sulfaziclamide CAS Registration Number: 115-68-4, Sulfadimethoxine CAS Registry Number: 122-11-2, Sulfadoxine CAS Registry Number: 2447-57-6, Piretanide CAS Registry Number: 55837-27-9, Polythiazide CAS Registry Number: 346- 18-9, Kinetazone CAS Registry Number: 73-49-4, Ramatroban CAS Registry Number: 116649-85-5, Salazosulfadimidine CAS Registry Number: 2315-08-4, Sampatrirat CAS Registry Number: 129981-36 -8,

Sematilide CAS Registry Number: 101526-83-4, Cibelestat CAS Registry Number: 127373-66-4, Sotalol CAS Registry Number: 3930-20-9, Soterenol CAS Registry Number: 13642-52-9, Succinyl Sulfathiazole CAS Registration number: 116-43-8, Scrofenide CAS registration number: 30279-49-3, Sulfabenzamide CAS registration number: 127-71-9, Sulfaethidol CAS registration number: 94-19-9, Sulfaguanol CAS registration number: 27031-08-9, sulfarene CAS registration number: 152-47-6, sulfaroxy acid CAS registration number: 14376-16-0, sulfamerazine CAS registration number: 127-79-7, sulfamethel CAS registration number : 651-06-9, Sulfamethazine CAS Registry Number: 57-68-1, Sulfamethizol CAS Registry Number: 144-82-1, Sulfamethomidine CAS Registry Number: 3772-76-7, Sulfamethoxa Zole CAS Registry Number: 723-46-6, Sulfamethoxypyridazine CAS Registry Number: 80-35-3, Sul Ametrol CAS Registration Number: 32909-92-5, Sulfamide Chrysoidine CAS Registration Number: 103-12-8, Sulfamoxol CAS Registration Number: 729-99-7, Sulfanilamide CAS Registration Number: 63-74-1 , 4-sulfanilamide salicylic acid CAS registration number: 62-221-7, N ⁴ -sulfanilylsulfanilamide CAS registration number: 547-52-4,

  Sulfanilyl urea CAS Registry Number: 547-44-4, N-Sulfanilyl-3, 4-Xylamide CAS Registry Number: 120-34-3, Sulfaperine CAS Registry Number: 599-88-2, Sulfaphenazole CAS Registry Number Number: 526-08-9, Sulfaproxyrin CAS Registry Number: 116-42-7, Sulfapyrazine CAS Registry Number: 116-44-9, Sulfapyridine CAS Registry Number: 144-83-2, Sulfaside CAS Registration Number: 1134-98-1, Sulfasalazine CAS Registration Number: 599-79-1, Sulfasomizol CAS Registration Number: 632-00-8, Sulfasimazine CAS Registration Number: 1984-94-7, Sulfathiazole CAS registration number: 72-14-0, sulfathiourea CAS registration number: 515-49-1, sulfisomidine CAS registration number: 515-64-0, sulfisoxazole CAS registration number: 127-69-5, sulfilide CAS registration number: 15676-16-1, Sulprostone CAS registration number: 60325-46-4, Sultiame CAS registration number: 61-56-3,

  Sumatriptan CAS Registry Number: 103628-46-2, Tamsulosin CAS Registry Number: 106133-20-4, Taurolidine CAS Registry Number: 19388-87-5, Teclothiazide CAS Registry Number: 4267-05-4, Tevenel (registered trademark) CAS Registry Number: 4302-95-8, Tirofiban CAS Registry Number: 144494-65-5, Tolazamide CAS Registry Number: 1156-19-0, Tolbutamide CAS Registry Number: 64-77-7, Torcyclamide CAS Registry Number: 664- 95-9, Torsemide CAS Registry Number: 56 211-40-6, Trichlormethiazide CAS Registry Number: 133-67-5, Trypamide CAS Registry Number: 73803-48-2, Vera Reply CAS Registry Number: 66644-81-3, It includes xipamide CAS Registry Number: 14293-44-8, zafirlukast CAS Registry Number: 107753-78-6, zonisamide CAS Registry Number: 68291-97-4.

  In particularly preferred embodiments, the pharmaceutical composition of the invention comprises a salt of celecoxib (eg, a sodium, lithium, potassium, magnesium or calcium salt). The salt may be much more water soluble than the neutral celecoxib currently on the market. Due to the high pKa (about 11) of celecoxib, the salt is formed only under strongly basic conditions. Generally, about 1 equivalent or more of base is required to convert celecoxib to its salt form. Suitable aqueous solutions for converting celecoxib to salt have a pH of about 11.0 or higher, about 11.5 or higher, about 12 or higher, about 13 or higher. Generally, the pH of such a solution is from about 12 to about 13. Although celecoxib is a preferred embodiment, the present invention includes other medicaments having a pKa greater than 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5 or 13. The drug is usually in neutralized form or may already exist in salt form.

  Pharmaceutical salts such as celecoxib are formed by reaction of the pharmaceutical with an acceptable base. Acceptable bases include but are not limited to metal hydroxides and alkoxides. Metals include alkali metals (sodium, potassium, lithium, cesium), alkaline earth metals (magnesium, calcium), zinc, aluminum, and bismuth. Alkoxides include methoxide, ethoxide, n-propoxide, isopropoxide and t-butoxide. Additional bases are arginine, procaine, and compounds with carbon-alkali metal bonds (eg, t-butyllithium), along with sufficiently high pKa (eg, pKa greater than about 11, pKa greater than about 11.5 or pKa greater than about 12). Other molecules with amino or guanidinine moieties having are included. Sodium hydroxide and ethoxide hydroxide are preferred bases. The amount of base used to form the salt is generally about 1 equivalent or more, about 2 equivalents or more, about 3 equivalents or more, about 4 equivalents or more, about 5 equivalents or more, about 10 equivalents or more relative to the pharmaceutical. It is. Preferably, about 3 to about 5 equivalents of one or more bases react with the drug to form a salt.

The pharmaceutical salt can be converted to the second pharmaceutical salt by a metal exchange reaction or other method of replacing the cation of the first pharmaceutical salt. In one example, a sodium salt of a medicament is prepared, followed by alkaline earth halide (eg, MgBr ₂ , MgCl ₂ , CaCl ₂ , CaBr ₂ ), alkaline earth sulfate or nitrate (Mg (N0 ₃ ) ₂ , Mg (SO ₄ ) ₂ , Ca (N0 ₃ ) ₂ , Ca (SO ₄ ) ₂ ), or alkaline metal salts of organic acids (eg, calcium formate, magnesium formate, calcium acetate, magnesium acetate, calcium propionate, propion) To react with a second salt such as magnesium acid) to form an alkaline earth metal salt of the drug.

  In a preferred embodiment of the invention, the pharmaceutical salt is substantially pure. A substantially pure salt is about 80% pure, about 85% pure, about 90% pure, about 95% pure, about 98% pure, or about 99% pure. can do. The purity of the salt can be judged on the basis of the amount of salt (in contrast, unreacted neutral drug or base), or a specific polymorph, co-crystal, solvate, desolvation of the salt. , Hydrate, dehydrate, and anhydride forms.

  The pharmaceutical salts described herein may have significantly more water solubility than existing neutral forms such as the free acid alone or neutral celecoxib currently on the market (CELEBREX). Generally, at least about 2 times, at least about 3 times, at least about 5 times, at least about 10 times, than the neutral form of CELEBREX marketed by Pfizer Inc. and GDSearle & Co. At least about 20 times, at least about 50 times or at least about 100 times or more, easily dissolved in water or simulated gastric fluid. This is described in the 2002 edition of the Physicians Desk Reference (p2676-2680 and 2780-2784) (also shown here as celecoxib currently on the market). Here, reference compounds for the present invention may include crystalline or amorphous free acid neutral celecoxib, or CELEBREX. Solubility depends on whether the salt has been tested alone or as a form further comprising the precipitation inhibitor and enhancer of the present invention.

  In general, after dissolving in a solution that is aqueous or partially aqueous (eg, such that one or more polar organic solvents are co-solvents), the salt is dissolved in by an acid or by an oil-soluble gas such as carbon dioxide. Can be summed. Generally, the pH of such a solution is 11 or less, 10 or less, 9 or less. Salt neutralization results in the precipitation of a neutral celecoxib amorphous or metastable crystalline form. In general, neutralization of pharmaceutical salts involves protonating the majority of negatively charged anions. With respect to celecoxib, protonation forms amorphous and / or metastable crystalline celecoxib, which is “neutralized” (ie, largely unchanged). Preferably, neutral pharmaceuticals (including amorphous and / or metastable crystalline forms such as celecoxib) contain no more than 10 mol% charged molecules. For example, at about pH 2 (eg, approximately the pH in the stomach), a sodium salt solution of celecoxib precipitates immediately as an amorphous form of neutral celecoxib. The amorphous form converts to a neutral metastable crystalline form, which then becomes a stable, needle-like insoluble form of neutral celecoxib. For example, amorphous neutral celecoxib formed from a salt of the present invention (eg, the sodium salt of Example 1) converts to metastable crystalline neutral celecoxib over about 5 to about 10 minutes. Amorphous neutral celecoxib converts to the same faster. Amorphous neutral celecoxib can be characterized by a lack of regular crystal structure, while metastable neutral celecoxib can generally be distinguished from crystalline neutral celecoxib by the PXRD pattern of the isolated material it can.

  The amorphous and metastable crystalline forms of neutral celecoxib are more soluble and tend to be more easily absorbed by patients than the stable crystalline form of neutral celecoxib. This is because the energy required for a drug molecule to leave a stable crystal is greater than the energy required for the same drug molecule to leave an amorphous, amorphous or metastable form. Because. However, the unstable state of neutral amorphous and neutral metastable crystalline forms makes them difficult to formulate as pharmaceutical compositions. As described in U.S. Publication No. 2002/0006951 (incorporated herein by reference in its entirety), like polymers, amorphous neutral celecoxib without being stabilized by crystallization inhibitors Convert back to a stable, insoluble crystalline form of free neutral celecoxib. Although these contents are incomplete and a bit far from the present invention, we have shown that we can make very good formulations by combining salts or co-crystals, precipitation inhibitors and optionally enhancers. I found it unexpectedly. While others focus on the initial solubilization of celecoxib, the present invention equally considers drug solubility and precipitation (see, eg, WO02 / 10237 6 and WO 01/78724) ). Furthermore, to date, no celecoxib salt and its role in organisms in solubility and precipitation have been disclosed. Furthermore, the addition of enhancers to precipitation inhibitors has never been mentioned.

A further aspect of the invention relates to a liquid formulation (eg celecoxib) of a compound of the invention. In these respects, the drug is solubilized directly with the precipitation inhibitor or with the solubilizer or solvent. A preferred solubilizer is polyethylene oxide. More preferably, polyethylene oxide is the surfactant. Preferred ethylene oxide contains the functional group — (C ₂ H ₄ O) _n — (where n ≧ 2). Other preferred polyethylene oxides have the general formula HO (C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) _a H
(Where a ≧ 2, a ≧ 3, a ≧ 2 and b ≧ 30, a ≧ 2 and b ≧ 4, a ≧ 2 and b ≧ 50 Or a ≧ 2 and b ≧ 60.)
It is.

The aminosulfonyl group containing the active pharmaceutical ingredient (celecoxib), together with a molecule containing at least two oxygen atoms (eg, an ether group), is crystallized to test the physical interactions associated with precipitation inhibitors by precipitation inhibitors. It became. From these results, in one aspect of the present invention, the precipitation inhibitor compound, preferably a surfactant, has the following physical properties or characteristics: at least one, preferably two, ten, inhibitor molecules. 25, 40, 50, 60, 80, 100 or more functional interaction groups (wherein the functional interaction group includes two oxygen atoms, each of which interacts with an active pharmaceutical ingredient ( For example, hydrogen bonding). Preferably, two oxygen atoms are interacting with the aminosulfonyl group of the active pharmaceutical ingredient. Preferably, the aminosulfonyl group is —SO ₂ NH ₂ . The two interacting oxygen atoms are preferably separated from about 3.6 angstroms to about 5.8 angstroms, from about 3.9 angstroms to about 5.5 angstroms, from 4.3 to about 5.2 angstroms, from 4.6 to about 5.0 angstroms, or from about 4.7 to about 4.9 angstroms. In one embodiment, two oxygen atoms are separated by at least three atoms. In other embodiments, two oxygen atoms are separated by five atoms. In one embodiment for segregation by five atoms, two oxygen atoms are segregated by four carbons and one oxygen atom. For segregation by five atoms, in a more detailed embodiment, the order of the five atoms is —C—C—O—C—C—. Here, one unit of the functional interaction group (including two interaction oxygen atoms) is —O—C—C—O—C—C—O—.

Glycol ethers can also be used as neutral solubilizers, or other forms of celecoxib can be represented by the formula:
R ¹ —O — ((CH ₂ ) _m O) _n —R ² (V)
Wherein R ¹ and R ² are independently hydrogen or C _1-6 alkyl, C _1-6 alkenyl, phenyl or benzyl group, but one or more of R ¹ and R ² is hydrogen;
m is an integer from 2 to about 5;
n is an integer from 1 to about 20. )
Including those corresponding to. Preferably one of R ¹ and R ² is a C _1-4 alkyl group and the other is hydrogen or a C _1-4 alkyl group, more preferably at least ^one of R ¹ and R ² is a methyl or ethyl group. is there. m is preferably 2. n is preferably an integer from 1 to about 4, more preferably 2. Also, non-surfactant glycol ethers, specifically formula (V) and the glycol ethers described above, can be specifically excluded from the present invention. Preferably, the glycol ether is a surfactant.

  The compositions of the present invention may optionally include one or more pharmaceutically acceptable co-solvents. Non-limiting examples of suitable co-solvents for use in the compositions of the present invention include any of the glycol ethers described above; alcohols such as ethanol and n-butanol; glycols not described above such as propylene glycol, 1 , 3-butanediol and polyethylene glycols such as PEG-400; oleic acid and linoleic acid triglycerides, such as soybean oil; caprin / caprylic acid, such as Halus Miglyol ™ 812; caprin / caprylic mono and diglycerides, such as Avitech ™ Capmul MCM; polyoxyethylene caprin / capryl mono and diglycerides such as polyoxyethylene caprin / capryglycerides, eg Bettaforth Labrasol ™; propylene glycol fatty acid esters, eg For example, propylene glycol laurate, polyoxyethylene castor oil, such as Cremophor ™ EL from BASF; polyoxyethylene glyceryl trioleic acid, eg, Goldschmidt target ™ TO; and lower alkyl esters of fatty acids, such as Contains ethyl butyrate, ethyl caprylate and ethyl oleate.

  Celecoxib is preferably a salt because of their stability. Therefore, it can be formulated as a pharmaceutical composition and can be stored until administration to a patient. Only after dissolution and subsequent neutralization, the celecoxib salt precipitates or is converted to a substantially amorphous and neutral form and then converted to a neutral form of substantially metastable crystals. Preferably, dissolution and neutralization of the celecoxib salt occurs in situ in the patient's gastrointestinal tract (eg, stomach, duodenum, ileum), so that the maximum amount of amorphous and / or metastable crystalline neutral celecoxib is present. Present at the maximum amount of celecoxib in aqueous solution after administration, rather than before administration (eg, in vivo).

  The salts, hydrates and solvates of the present invention are not limited to specific examples that can be more effectively dissolved in water, SFG and / or SIF than their respective free forms. For example, celecoxib sodium is more soluble in water than the free acid of celecoxib. “Spring” is defined as a very high energy species that supersaturates the active pharmaceutical ingredient. Such high energy species are less stable and are therefore more soluble than analogs in relatively more stable forms (eg, free forms, polymorphs, etc.). The intrinsic solubility of high-energy species may be 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 25, 50, 75, 100 times greater than the more stable form of the analog Absent. The spring can be in the form of, for example, free acid, free base, salt, liquid, hydrate, solvate, co-crystal, and the like. In this example, the sodium salt acts as a “spring” to supersaturate the active pharmaceutical ingredient. One embodiment of the present invention provides an active pharmaceutical ingredient in a form having improved water solubility. Once dissolved, inhibition of precipitation becomes important. Precipitation inhibition acts as a “parachute” to slow down the rate of precipitation of the active pharmaceutical ingredient from solution. Other embodiments of the invention provide active pharmaceutical ingredients in formulations that inhibit precipitation upon initial dissolution. Both aspects are very important in pharmaceutical compositions. The ability to dissolve the active pharmaceutical ingredient in the pharmaceutical composition and to maintain the active pharmaceutical ingredient in solution for a long enough time to provide the desired therapeutic effect is essential.

Modulation of solubility In another aspect of the present invention, the dissolution profile of the active pharmaceutical ingredient is adjusted and thus the aqueous dissolution rate or dissolution rate in simulated gastric or simulated intestinal fluid, or in a single solvent or multiple solvents. To increase. The dissolution rate is the rate at which the active pharmaceutical ingredient solid dissolves in the dissolution medium. For active pharmaceutical ingredients (eg, steroids) whose absorption rate is faster than the dissolution rate, the rate limiting step in the absorption process is often dissolution rate. Due to the limited residence time at the site of absorption, active pharmaceutical ingredients that do not dissolve before being transferred from the site of intestinal absorption are considered useless. Thus, dissolution rate has a significant impact on the behavior of active pharmaceutical ingredients with poor solubility. Because of this factor, the dissolution rate of the active pharmaceutical ingredient in the solid dosage form becomes an important, conventional, quality control factor used in the manufacturing process of the active pharmaceutical ingredient.

Dissolution rate = KS (Cs-C)
(Wherein K is the dissolution rate constant, S is the surface area, Cs is the apparent solubility (saturated concentration), and C is the concentration of the active pharmaceutical ingredient in the dissolution medium). C is approximately equal to Cs. The dissolution rate of the active pharmaceutical ingredient can be measured by methods known in the art.

  The increase in dissolution rate of the composition of the present invention is 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% over the free form in the same solution compared to neutral free base, Or 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400 , 500, 1000, 10,000, or 100,000 times larger. The conditions for measuring the dissolution rate are as described above. The increase in dissolution may further be defined by the time that the composition remains supersaturated.

  In the above embodiment, at 37 ° C. and pH 7.0, the composition increased at least 5 times compared to the neutral free form, and the dissolution rate in SGF increased at least 5 times relative to the neutral free form. A composition having an increased dissolution rate with SIF at least 5-fold over the neutral free form.

  The present invention provides for the length of time that remains in solution of celecoxib or other active pharmaceutical ingredients, as described herein, precipitation inhibitors, usually surfactants (eg, poloxamers, TPGS, SDS, etc.) and any Shows that it can be increased to a surprisingly high degree by using a salt or co-crystal form with the presence of an enhancer (eg hydroxypropylcellulose). The presence of these agents can form a supersaturated solution of the active pharmaceutical ingredient, leaving a relatively high concentration of the active pharmaceutical ingredient in the solution for an extended period of time (compared to the neutral free acid). I will. The presence of these components does not exclude the presence of other additional agents, including additional surfactants such as polyethylene glycol and polyoxyethylene sorbitan esters. Other suitable surfactants may also be present and are listed here. Furthermore, it does not exclude additional agents that would moderate the precipitation rate such as polyvinylpyrrolidone. For example, neutral free celecoxib is soluble in less than 1 μg / ml water and cannot be maintained as a supersaturated solution for a considerable time. In the present invention, a predetermined time (for example, 15, 30, 45, 60 minutes or more), 2, 3, 5, 7, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% concentration 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 than the solubility of the neutral free form in the same solution (eg water or SGF) , 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 times or more. .

  The amount of precipitation inhibitor or enhancer is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45 for each or both of the formulated pharmaceuticals. , 50, 55, 60, 70, 80 or less than 90 w / w%. In addition, w / w% of either the precipitation inhibitor or the enhancer or both is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35 , 40, 45, 50, 55, 60, 70, 80, or 90 may be the range represented by two integers.

  Celecoxib salts of the present invention generally have a moisture content of at least about 1 week, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 2 years, Is stable at room temperature (ie, more than 90% of the celecoxib salt does not change in composition or crystal structure). Room temperature is generally in the range of about 15 ° C to about 30 ° C. As defined herein, absence of moisture refers to celecoxib salts rather than contact amounts of liquids, particularly water or alcohol. For purposes of the present invention, gas such as water vapor is not considered moisture.

  The compositions of the present invention include an active pharmaceutical ingredient and a formulation comprising the active pharmaceutical ingredient and exhibit adequate stability for pharmaceutical use. Preferably, the active pharmaceutical ingredients or their formulations of the present invention are stable so that degradation products form less than 0.2% when stored at 30 ° C. for 2 years. The term “degradation product” here refers to the product of a single type of chemical reaction. For example, if a hydrolysis event occurs that splits a molecule into two, it will be considered a single degradation product for purposes of this application. More preferably, degradation products are formed in less than 0.2% when stored at 40 ° C. for 2 years. Alternatively, when stored at 30 ° C. for 3 months, 0.2% or 0.15% or less than 0.1%, any one degradation product is formed, or when stored at 40 ° C. for 3 months, 0.2% or 0.15 % Or less than 0.1%, any one degradation product is formed. Alternatively, when stored for an additional 4 weeks at 60 ° C., any one degradation product is formed at less than 0.2% or 0.15% or less than 0.1%. Relative humidity (RH) can be specified by air (RH), 75% (RH) or any single integer between 1 and 99% (RH).

Bioavailability Modulation The method of the present invention provides higher solubility, solubility, bioavailability, AUC, time to small T _max , mean time from administration to reach peak serum levels compared to the natural free form, Formulation of a pharmaceutically active pharmaceutical ingredient having a higher C _max , mean maximum serum concentration of the active pharmaceutical ingredient after administration and a longer T _1/2 , mean final half life of the serum concentration of the active pharmaceutical ingredient after T _max Used to form.

  AUC is the area under the plasma concentration curve (not concentration logarithm) of the active pharmaceutical ingredient over time after administration of the active pharmaceutical ingredient. The area is measured appropriately by the “trapezoidal law”, the data points are connected by a straight line segment, a vertical line is drawn from each abscissa, and the total area of the triangle and trapezoid so constructed is Calculated. If the final measured concentration (at Cn, tn) is not zero, the AUC from tn to infinity is estimated by Cn / kel.

AUC is used to estimate the bioavailability of the active pharmaceutical ingredient and to estimate the total clearance (Cl _T ) of the active pharmaceutical ingredient. In the following single intravenous administration, AUC = D / Cl _T or AUC = C ₀ / _kel in a single compartment system following primary elimination kinetics. For routes other than veins, in such a system, AUC = F · D / Cl _T , where F is the absolute bioavailability of the active pharmaceutical ingredient.

Thus, in a further aspect, the present invention provides a method of modulating the bioavailability of an active pharmaceutical ingredient when administered in a normal and effective dose range, thus increasing AUC and time to T _max Decrease or increase C _max . This method
(1) forming a salt or co-crystal of the active pharmaceutical ingredient,
(2) including combining the salt or co-crystal with a precipitation inhibitor and optionally an enhancer.

In the above embodiment examples, a composition that reduces the time to T _max by at least 10% compared to the natural free form, a composition that reduces the time to T _max by at least 20% compared to the free form, A composition in which the time to T _max is reduced by at least 40% compared to the free form, a composition in which the time to T _max is reduced by at least 50% compared to the free form, a composition to T _max compared to the free form A composition in which time is reduced by at least 60%, a composition in which time to T _max is reduced by at least 70% compared to free form, a composition in which time to T _max is reduced by at least 80% compared to free form, composition C _max as compared to the free form is increased by at least 20%, a composition C _max as compared to the free form is increased by at least 30%, a composition C _max as compared to the free form increases at least 40% , composition C _max as compared to the free form is increased by at least 50%, C _max is small compared to the free form Composition increases Kutomo 60%, composition C _max as compared to the free form is increased by at least 70%, a composition C _max as compared to the free form is increased by at least 80%, as compared to the free form AUC A composition that increases AUC by at least 10% compared to the free form, a composition that increases AUC by at least 20% compared to the free form, and a composition that increases AUC by at least 20% compared to the free form. Composition with 30% increase, composition with at least 40% increase in AUC compared to free form, composition with at least 50% increase in AUC compared to free form, composition with at least 60% AUC compared to free form Compositions that increase, compositions that increase AUC by at least 70% compared to free form, or compositions that increase AUC by at least 80% compared to free form.

In addition, the maximum serum concentration and the time to reach the maximum serum concentration can be estimated by the patient's drug intake. Pharmaceutical compositions having an even faster onset of treatment generally achieve higher maximum serum concentrations (C _max ) in a shorter time (T _max ) after oral administration. Preferably, the compositions of the present invention (preferably containing salts) have a higher C _max and / or a shorter T _max than currently available celecoxib. The T _max of the composition of the present invention is about 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes after administration (eg, oral administration). Within minutes or about 5 minutes. More preferably, the therapeutic effect of the composition of the present invention is about 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, within 30 minutes, within about 25 minutes of administration (eg, oral administration), Within about 20 minutes, within about 15 minutes, within about 10 minutes or within about 5 minutes. US Pat. No. 6,598,895, Karim et al. Reported that the suspension of neutral free celecoxib particles in aqueous solution increased approximately 2.5-fold at Cmax over that of the currently available celecoxib (CELEBREX). ing. The present invention results in an increase in Cmax of about 4 times that of currently marketed drugs. Furthermore, the present invention provides an increase in AUC of at least about 12 times that of currently marketed drugs.

  The composition of the present invention has greater bioavailability than natural celecoxib, and CEREBREX is currently marketed. In some embodiments, the composition of the present invention comprises at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, more than that of neutral celecoxib and currently commercially available CEREBREX. Has 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% greater bioavailability.

  Administration to a patient of the present invention may be effective for pain relief. The desired therapeutic effect requires inter alia an appropriate serum concentration of the active pharmaceutical ingredient. Effective serum concentrations of celecoxib may vary based on a number of factors (eg, age, weight, etc.), but are generally from about 10 ng / mL to about 500 ng / mL or from about 25 ng / mL to 400 ng / mL or about 50 ng / mL to about 300 ng / mL. In particular, about 250 ng / mL may be suitable for effective pain relief. In general, an effective dose of celecoxib will be found in the range of about 1 mg / kg to about 6 mg / kg body weight. For an average 75 kg patient, this range is from about 75 mg to about 450 mg of celecoxib. This is particularly due to the extensive binding of celecoxib to plasma albumin known to occur after oral administration (Davies et al., Clin. Pharmacokinet. 38: 225-242,2000 and US Pat. No. 6,579). , 895, incorporated herein by reference in its entirety). Thus, it cannot be predicted that a particular serum concentration will result in analgesia.

  As used herein, “effective pain relieving concentration” or “effective pain relieving serum concentration” is the average of patients who reach an average score indicating pain relief when tested in a standard test that includes patients who score pain severity. Intended for serum concentration. In a study such as that shown below, patients scored pain on a scale from 0 (no reduction in pain severity) to 4 (pain completely relieved) and an average equal to or greater than the value obtained. The score is considered to be effective pain relief. As an example here, an average score of 0.5 or more, preferably 1.0 or more in such a test, is considered to be effective pain relief. However, one of ordinary skill in the art will appreciate that other approaches may be used to assess the severity of pain and to relieve such pain.

  Thus, one aspect of the present invention is a treatment for analgesia by orally administering to a patient a composition comprising a celecoxib salt or co-crystal in a formulation that provides detectable pain relief within about 30 minutes after oral administration. Includes methods. “Detectable pain relief” means that the formulation provides effective pain relief that can be measured by standard methods as described above. For example, a formulation that achieves an average score of 0.5 or greater, preferably 1.0 or greater, on a scale of 0 to 4 in a test system as described above is considered to provide detectable pain relief. The present invention is not limited to the use of any particular formulation type as long as it exhibits the pharmacokinetic profile described herein. Examples of suitable formulation types are shown below.

Human pharmacokinetic study protocols are known in the art, and any standard protocol should be used to determine if a particular celecoxib formulation meets the pharmacokinetic criteria set here. Can do. An example of a suitable protocol is shown below.
The advantages of the present invention are that pain, for example, extreme pain relief as may occur after oral, general or orthopedic surgery, is achieved fairly quickly, i.e., with a standard formulation of celecoxib. To achieve in a very short time after administration.
Any standard pharmacokinetic protocol can be used to measure serum concentration profiles in humans after oral administration of celecoxib preparations, and therefore whether the preparations meet the pharmacokinetic criteria set here Can prove.

By way of illustration, a random single dose crossover study can be performed using a group of healthy adult subjects. A small number of subjects may be sufficient for a purpose, but a sufficient number of subjects, typically about 10 or more, to provide an appropriate subject of variation in statistical analysis. Each subject will receive a single dose (eg, 200 mg) of a celecoxib test formulation by oral administration, usually at around 8:00 and after midnight, after an overnight fast. The subject continues to fast after administration of the celecoxib preparation and maintains standing for about 4 hours. Blood samples are taken from the subject before administration (eg, 15 minutes before administration) and at several intervals after administration. For this purpose, it is preferable to take some within the first hour and then less frequently after that. By way of example, blood samples may be taken at 15, 30, 45, 60 and 90 minutes after administration and then every 2 to 10 hours after administration. Optionally, blood samples may also be collected thereafter, for example at 12 and 24 hours after administration. If the same subject is used for the study of the second test formulation, there will be at least 7 days before administration of the second formulation. Plasma is separated from the blood sample by centrifugation, and celecoxib is analyzed in the separated plasma by effective high performance liquid chromatography (HPCL) with a detection limit as low as 10 ng / mL (eg, Paulson et al., Drug Metab. Dispos. 27: 1133-1142, 1999; Paulson et al., Drug Metab. Dispos. 28: 308-314, 2000; see Davies et al.). The serum concentration of celecoxib referred to herein is the average total celecoxib collected from plasma samples and includes both free and bound celecoxib as measured by HPCL detection according to methods known in the art as described above. Refers to concentration.
The diseases that can be treated with celecoxib and salts thereof of the present invention are described below. Treatment of chronic pain is a preferred embodiment of the present invention.

Dose Response Modulation In a further aspect, by producing the composition of the present invention, the present invention provides a method for improving the dose response of an active pharmaceutical ingredient.
A dose response is the quantitative relationship between the magnitude of a response and the dose that causes the response and can be measured by methods known in the art. The dose (independent variable) versus effect (dependent variable) curve for the active pharmaceutical ingredient-cell system is the “dose response curve”. In general, dose response curves are determined in response to a plot of active pharmaceutical ingredient against a given dose of active pharmaceutical ingredient (mg / kg). A dose response curve is also the curve of AUC for a given dose of active pharmaceutical ingredient.

  The dose response curve of celecoxib currently on the market is non-linear. Preferably, the dose curve of a celecoxib salt or co-crystal composition of the invention is linear or comprises a broader range of linearity than currently available celecoxib. Also, the absorption or ingestion of celecoxib currently on the market depends in part on the food action, and the intake of celecoxib salt increases when taken with food, especially fat food. Preferably, the intake of celecoxib salt of the present invention is less dependent on food, and thus the difference in intake between taking and not taking food is greater than in taking celecoxib currently on the market. Also make it smaller.

Hygroscopic reduction In a further aspect, the present invention provides an active pharmaceutical ingredient that is less hygroscopic and further provides a method for reducing the hygroscopicity of an active pharmaceutical ingredient by making it.
In an aspect of the present invention, a pharmaceutical composition is provided comprising a composition of an active pharmaceutical ingredient that is less hygroscopic than an amorphous or crystalline free form. Hygroscopicity can be assessed by dynamic gas phase sorption analysis, in which 5-50 mg of compound is suspended on a Cahn microbalance. The analyzed compound is placed in a non-hygroscopic pan and is weighed relative to an empty pan composed of the same material, approximately the same size, form and weight. Ideally, platinum bread should be used. The pan should be suspended in a chamber that is controlled and flushed with a gas such as air or nitrogen with a known relative humidity (% RH) until an equilibrium standard is reached. A common equilibrium criterion is a weight change of less than 0.01% over 3 minutes at a constant humidity and temperature. Relative humidity is constant weight at 40 ° C (<0.01% change over 3 minutes) for samples dried under dry nitrogen unless desolvated or otherwise convert material to amorphous compound Should be adjusted. In one aspect, the hygroscopicity of the dry compound is such that 5% RH changes from 5% to 95%, then 5% changes to 95% RH to form a moisture sorption isotherm. RH can be assessed by reducing from 5 to 5%. The sample weight can be balanced between each change in% RH. If the compound deliquesces or becomes amorphous between 75% RH and below 95% RH, the experiment should be repeated with a new sample, and the relative humidity cycle range is 5 to 95% RH. Instead, it should be narrowed to 5-75% RH or 10-75% RH. If the sample cannot be dried prior to testing due to lack of form stability, the sample is tested using two full humidity cycles, either 10-75% RH or 5-95% RH If there is significant weight loss at the end of the first cycle, the result of the second cycle should be used.

  Hygroscopicity can be defined using various parameters. For purposes of the present invention, when repeated between 10-75% RH (relative humidity at 25 ° C.), non-hygroscopic molecules are 1.0 wt% or less at 25 ° C., more preferably 0.5%. Will increase or decrease below weight percent. More preferred non-hygroscopic molecules are less than 1.0% by weight, more preferably less than 0.5% by weight, more preferably between 10% and 75% RH when repeated between 5 and 95% RH at 25 ° C. It will increase or decrease below 0.25 wt% of its weight. Most preferably, the non-hygroscopic molecule will increase or decrease by 0.25% or less of its weight when repeated between 5 and 95% RH.

  Alternatively, for the purposes of the present invention, hygroscopicity is defined using the parameters of Callaghan et al., Equilibrium moisture content of pharmaceutical constituents, in API Dev. Ind. Pharm., Vol. 8, pp. 335-369 (1982). be able to. Callaghan et al. Classified the degree of hygroscopicity into four classes.

Class 1: Non-hygroscopic (essentially no increase in moisture at relative humidity below 90%),
Class 2: Slightly hygroscopic (essentially no increase in moisture at relative humidity below 80%),
Class 3: moderate hygroscopicity (moisture content does not increase more than 5% after 1 week storage at 60% or less relative humidity),
Class 4: Very hygroscopic (increased moisture content may occur even at relative humidity as low as 40-50%),

Alternatively, for the purposes of the present invention, the parameters of the European Pharmacopoeia Technical Guide (1999, p. 86) where hygroscopicity is defined based on static methods after storage at 25 ° C. and 80% RH for 24 hours are used. The hygroscopicity can be defined.
Slightly hygroscopic: mass increase is less than 2% m / m and 0.2% m / m or more.
Hygroscopicity: Mass increase is less than 15% m / m and 0.2% m / m or more.
Very hygroscopic: increase in mass is 15% m / m or more.
Deliquescent: Sufficient moisture is absorbed to form a liquid.

  The compositions of the invention can be class 1, class 2 or class 3 as indicated above, or can be slightly hygroscopic, hygroscopic or very hygroscopic. Moreover, the composition of this invention can be based on those hygroscopic decreasing ability. Thus, preferred compositions of the invention are less hygroscopic than the natural free form. Furthermore, the composition included in the present invention is a composition that increases and decreases by less than 1.0% by weight at 25 ° C. when it is repeated between 10 and 75% RH, where the reference compound is under the same conditions. Below, it increases or decreases by over 1.0% by weight. Further, the composition included in the present invention is a composition that increases and decreases by less than 0.5% by weight at 25 ° C. when it is repeated between 10 and 75% RH, where the reference compound is under the same conditions. Below, increase or decrease by more than 0.5 wt% or more than 1.0 wt%. Furthermore, the composition included in the present invention is a composition that increases and decreases by less than 1.0% by weight at 25 ° C. when it is repeated between 5 and 95% RH, where the reference compound is under the same conditions. Below, it increases or decreases by over 1.0% by weight. Furthermore, the composition included in the present invention is a composition that increases and decreases by less than 0.5% by weight at 25 ° C. when it is repeated between 5 and 95% RH, where the reference compound is under the same conditions. Below, increase or decrease by more than 0.5 wt% or more than 1.0 wt%. Further, the composition included in the present invention is a composition that increases and decreases by less than 0.25 wt% at 25 ° C. when it is repeated between 5 and 95% RH, where the reference compound is under the same conditions. Below, increase or decrease by more than 0.5 wt% or more than 1.0 wt%.

  Further, the compositions included in the present invention have a hygroscopicity (according to Callaghan et al.) That is at least one class lower than the reference compound or at least two classes lower than the reference compound. Class 2 composition if it is a Class 2 reference compound, Class 2 composition if it is a Class 3 reference compound, Class 3 composition if it is a Class 4 reference compound, and Class 3 composition if it is a Class 3 reference compound Class 1 compositions, Class 4 reference compounds include Class 1 compositions, and Class 4 reference compounds include Class 2 compositions.

  Furthermore, the compositions included in the present invention have a hygroscopicity (according to the European Pharmacopoeia Technical Guide) that is at least one class lower than the reference compound or at least two classes lower than the reference compound. Examples are not limited, and a slightly hygroscopic composition if it is a hygroscopic reference compound, a hygroscopic composition if it is a very hygroscopic reference compound, or a very deliquescent reference compound. Hygroscopic composition, slightly hygroscopic composition if very hygroscopic reference compound, slightly hygroscopic composition if deliquescent reference compound, hygroscopic if deliquescent reference compound Of the composition.

  In another aspect of the invention, a correlation exists between in vivo solubility and in vitro solubility. For example, the solubility of a celecoxib sodium hydrate formulation in SFG at 37 ° C. is comparable to the pharmacokinetic data obtained with the dog of Example 7. For example, the magnitude of Cmax in pharmacokinetic studies correlates with the Cmax obtained in in vitro studies conducted with PLURONIC127 and HPC at an equivalent weight ratio of celecoxib to free acid. Also, other pharmacokinetic parameters such as Tmax and AUC may be closely related between both types of experiments.

  Celecoxib salts can be characterized by differential scanning calorimetry (DSC). The sodium salt of celecoxib formed in Example 1 is characterized by at least three overlapping endothermic transitions between 50 ° C. and 110 ° C. (FIG. 1). The DSC conditions are clarified in the examples.

  Celecoxib salts can be characterized by thermogravimetric analysis (TGA). The sodium salt formed according to Example 1 is characterized by TGA, three loosely coupled equivalents of water evaporated between about 30 ° C. and about 40 ° C., water evaporated between about 40 ° C. and about 100 ° C. It was determined to have one tighter bond corresponding to and one stronger close bond corresponding to water evaporated between about 140 ° C. and about 160 ° C. (FIG. 2). However, as detailed herein, the sodium salt can exist in various hydrated states depending on moisture, temperature and other conditions. The TGA conditions are clarified in the examples.

  The celecoxib salts of the present invention can also be characterized by powder X-ray diffraction (PXRD). The sodium salt of celecoxib formed according to Example 1 has strong reflections or peaks at 6.36 ° 2θ angles and other reflections or peaks at 7.01 °, 16.72 ° and 20.93 ° (FIG. 3). The conditions for PXRD are clarified in the examples.

In one embodiment of the invention, the solid form of celecoxib exhibits characteristics that lack a Raman scattering peak at 906 cm ⁻¹ (eg, salt, solvate, etc.). The Raman scattering spectrum of celecoxib free acid has a peak at this position.
Celecoxib salts may contain solvate molecules and can exist in various solvate states, also known as solvates. Thus, celecoxib salts can exist as crystalline polymorphs. Polymorphs are different crystalline forms of the same drug substance, and the use herein for that term includes solvates and hydrates. For example, different polymorphs of celecoxib salts can be obtained by changing the production method (comparative example). Crystal polymorphs, generally polymorphs with different solubilities and more thermodynamically stable, are less soluble than polymorphs that are less thermodynamically stable. Pharmaceutical polymorphs may also differ in properties such as shelf life, bioavailability, morphology, vapor pressure, density, color and compressibility.

  Suitable solvate molecules include water, alcohols, other polar organic solvents, and mixtures thereof. Alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, propylene glycol and t-butanol. Propylene glycol solvates are particularly preferred because they are more stable and less hygroscopic than other forms. The alcohol includes a polymerized alcohol such as polyalkylene glycol (for example, polyethylene glycol or polypropylene glycol). In the embodiment, water is used as a solvent. In embodiments of the invention, the celecoxib salt is about 0.0%, less than 0.5%, 0.5, 1.0, less than 1.0%, less than 1.5, 1.5%, 2.0, 2.0%, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, less than 5.5%, or about 6.0 equivalents of water per equivalent of salt, about 1.0 to about 6.0, about 2.0 to about 5.0, about 3.0 to about 6.0, about 3.0 to about 5.0, about 1.0 to about 4.0, about 2.0 to About 4.0, about 1.0 to about 3.0, about 2.0 to about 3.0, 0.0 to about 3.0, 0.5 to about 3.0, 0.0 to about 2.0, 0.5 to about 2.0, 0.0 to about 1.5, 0.5 to about 1.5, 1.0 to about 1.5 or Contains about 1.0 equivalent. The amount of water equivalent in the hydrate is initially affected by experimental conditions (eg, temperature). Since the solvate molecule can be removed from the crystalline salt, the salt is partially or completely desolvated. If the solvate molecule is water (forms a hydrate), the desolvated salt will be referred to as the dehydrate. The salt from which all water has been removed is anhydrous. Solvate molecules can be removed from the salt by methods such as heating, treatment under vacuum or reduced pressure, blowing dry air over the salt, or combinations thereof. Desolvation is generally about 1 to about 5 equivalents, about 1 to about 4 equivalents, about 1 to about 3 equivalents, or about 1 to about 2 equivalents per equivalent of crystalline salt.

  A medicament comprising celecoxib can be co-crystallized with one or more other substances. As used herein, the term “co-crystal” means a crystalline material consisting of two or more single solids at room temperature, each having unique physical properties such as structure, melting point and heat of fusion. Yes. Solvates of active pharmaceutical ingredient compounds that do not further comprise a co-crystal forming compound are not co-crystals of the present invention. However, the co-crystal may contain one or more solvents in the crystal lattice. That is, a co-crystal solvate, or a co-crystal further comprising a solvent or compound that is liquid at room temperature, is included in the present invention, but a crystal material composed of only one solid and one or more liquids (at room temperature). ) Is not included in the term “co-crystal”. The co-crystal may comprise a co-crystal former and a salt of the active pharmaceutical ingredient, but the active pharmaceutical ingredient and the co-crystal former of the present invention are configured or bound together through hydrogen bonds. Other methods of molecular recognition may also exist including Π-stacking, guest-host complexes and van der Waals interactions. In the interaction described above, hydrogen bonding is the main interaction in the formation of a co-crystal, and thus a non-covalent bond is formed between one hydrogen bond donor and the other hydrogen bond acceptor of the molecule. . In another embodiment, the co-crystal former provides a co-crystal that is the second active pharmaceutical ingredient. In another embodiment, the co-crystal former is not an active pharmaceutical ingredient.

  In some embodiments of the invention, the composition is a co-crystal. In another embodiment, the co-crystal former is selected from 1 or 2 (for ternary co-crystals): saccharin, nicotinamide, pyridoxine (4-pyridoxic acid), acesulfame, glycine, arginine, asparagine , Cysteine, glutamine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, threonine, tyrosine, valine, aspartic acid, glutamic acid, tryptophan, adenine, acetohydroxamic acid, alanine, allopurinol, 4-aminobenzoic acid, cyclamic acid, 4 -Ethoxyphenylurea, 4-aminopyridine, leucine, nicotinic acid, serine, tris, vitamin k5, xylitol, succinic acid, tartaric acid, pyridoxamine, ascorbic acid, hydroquinone, salicylic acid, benzoic acid, cafe , Benzenesulfonic acid, 4-chlorobenzene-sulfonic acid, citric acid, fumaric acid, gluconic acid, glutaric acid, glycolic acid, hippuric acid, maleic acid, malic acid, mandelic acid, malonic acid, 1,5-naphthalene-disulfone Acid (armstrong acid), clemizole, imidazole, glucosamine, piperazine, procaine or urea.

  In other embodiments of the invention, a PXRD diffractogram of the solid form of celecoxib can be obtained. This may be caused by polymorphism, variable hydrates, various environmental conditions, etc. In one embodiment, a propylene glycol solvate of celecoxib sodium salt may result in a PXRD pattern with or without a peak at 2θ of 8.21 °. In other embodiments, a propylene glycol solvate of celecoxib sodium salt may result in a PXRD pattern with or without a peak at 8.79 ° of 2θ.

  In other embodiments, propylene glycol solvate trihydrate of celecoxib sodium salt is observed at 10 to 60% relative humidity (RH). In other embodiments, propylene glycol solvate anhydride of celecoxib sodium salt is observed at 0% relative humidity (RH). In other embodiments, the propylene glycol solvate dihydrate of celecoxib sodium salt is observed at 40-60% relative humidity (RH). In other embodiments, celecoxib sodium salt monohydrate is observed at 10-20% relative humidity (RH). In other embodiments, celecoxib sodium salt trihydrate is observed at 40 to 70% relative humidity (RH). In other embodiments, propylene glycol solvate anhydride of celecoxib potassium salt is observed at 0 to 40% relative humidity (RH).

  Celecoxib salts can be formed by contacting celecoxib with a solvent. Suitable solvents include water, alcohols, other polar organic solvents and combinations thereof. Water and isopropanol are preferred solvents. Since celecoxib reacts with a base (suitable bases are as described above), celecoxib forms a salt and preferably dissolves. Since the base can be added to the celecoxib with the solvent (ie, dissolved in the solvent), the celecoxib solvates and deprotonates substantially simultaneously. Alternatively, the base may be added after the celecoxib has come into contact with the solvent (see, eg, Examples). In the latter scenario, the base may be dissolved in a solvent (it may be a solvent that is already in contact with celecoxib or a different solvent), or the base may be a pure solid or You may add as a liquid or those combination. Sodium hydroxide and sodium ethoxide are preferred bases. The amount of base required is as described above. The solvent may be evaporated to obtain celecoxib salt crystals, or, independent of evaporation, the celecoxib salt may be precipitated and / or crystallized. Celecoxib salt crystals can be filtered to remove large amounts of solvent. The method for removing the solvated solvent molecules is as described above.

  The excipients used in the pharmaceutical composition of the present invention can be solid, semi-solid, liquid or combinations thereof. Preferably the excipient is a solid. Compositions of the invention comprising excipients can be made by any known technique including mixing excipients with drugs or therapeutic agents. The pharmaceutical composition of the present invention contains the desired amount of celecoxib per dosage unit, and when intended for oral administration, for example, tablets, capsules, pills, hard or soft capsules, troches, cachets, sachets , Granules, suspensions, elixirs, dispersions, liquids, or any other form reasonably suitable for such administration. When intended for parenteral administration, it can be in the form of, for example, a suspension or transdermal patch. When intended for rectal administration, it can be in the form of, for example, a suppository. Currently, oral dosage units, each containing a predetermined amount of drug, such as tablets or capsules, are preferred.

Non-limiting examples of excipients that can be used to produce the pharmaceutical compositions of the present invention are as follows.
The pharmaceutical composition of the present invention optionally comprises one or more pharmaceutically acceptable carriers or diluents as excipients. Suitable carriers or diluents include, but are not limited to, lactose including anhydrous lactose and lactose monohydrate, by way of example or in combination; starch that is directly compressible and hydrolyzed starch (eg, Celutab and Emdex ™) Mannitol; sorbitol; xylitol; dextrose (for example, Cerelose ™ 2000) and dextrose monohydrate; calcium hydrogen phosphate dihydrate; sucrose diluent; powdered sugar; monobasic sulfate Calcium monohydrate; calcium sulfate dihydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; microcrystalline cellulose, α and Edible grade sources of amorphous cellulose (eg Rexce1J), powdered cellulose and hydro Calcium carbonate; cellulose containing shea methylcellulose (HPMC) and the like; glycine; bentonite; block copolymers; polyvinyl pyrrolidone. Such carriers or diluents, if used, total about 5% to about 99%, preferably about 10% to about 85%, more preferably about 20% to about 80% of the total weight of the composition. Configure. The selected carrier, the plurality of carriers, the diluent or the plurality of diluents preferably exhibit suitable fluidity, and preferably exhibit compressibility when a tablet is desired.

  Lactose, mannitol, sodium hydrogen phosphate and microcrystalline cellulose (eg, Avicel ™ PH (FMC)) are preferred diluents, either alone or in combination. These diluents are chemically compatible with celecoxib. Very granular microcrystalline cellulose (ie microcrystalline cellulose added to the granule composition) can be used to improve hardness (tablets) and / or disintegration time. Lactose, especially lactose monohydrate, is particularly preferred. Lactose generally provides a composition with adequate release rate, stability, preload flowability and / or drying properties of celecoxib at a relatively low dilution cost. This is because it provides a high density substrate that promotes densification in granulation (when wet granulation is used), thus improving mixing flowability and tablet properties.

The pharmaceutical composition of the present invention may optionally contain one or more pharmaceutically acceptable disintegrants as excipients, particularly for tablet formation. Suitable disintegrants include, but are not limited to, sodium starch glycolate (eg, PenWest Explotab ™) and α-corn starch (eg National Starch and Chemical Company National ™ 1551, National (Including trademark 1550 and Colocorn ™ 1500); clay (eg RT V and erbilt Veegum ™) HV); purified cellulose, microcrystalline cellulose, cellulose including methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose; croscarmellose sodium (eg FMC Ac-Di-Sol ™); alginate, crospovidone and agar, Including rubber such as guarana, locust bean gum, Indian rubber, pectin rubber and tragacanth rubber.

  The disintegrant can be added in a suitable step during the purification of the composition, in particular in the step of applying a lubricant before granulation or before compression. Such disintegrants, if added, constitute a total of about 0.2% to about 30%, preferably about 0.2% to about 10%, more preferably about 0.2% to about 5% of the total weight of the composition. To do.

  Croscarmellose sodium is preferred as a disintegrant for tablet or capsule disintegration. If added, it preferably constitutes from about 0.2% to about 10%, preferably from about 0.2% to about 7%, more preferably from about 0.2% to about 5% of the total weight of the composition. Croscarmellose sodium imparts intergranular disintegration ability to the granular pharmaceutical composition of the present invention.

  The pharmaceutical composition of the present invention optionally comprises one or more pharmaceutically acceptable binders or binders as excipients, especially for tablet form. Such binders and binders preferably give the tableted powder sufficient tack to allow normal manufacturing operations such as sizing, lubrication, compression and packaging, but still Allows tablet disintegration and allows absorption of the composition upon ingestion. Such binders may also prevent or inhibit further crystallization or recrystallization / precipitation of celecoxib salts of the present invention once the salt is dissolved in solution. Suitable binders and binders include, but are not limited to, gum arabic; tragacanth; sucrose; gelatin; glucose; but not limited to α-starch (eg, National ™ 1511 and National ™ ) 1500), etc .; celluloses such as, but not limited to, methylcellulose and carmellose sodium (eg, Tylose ™); alginic acid and salts of alginic acid; aluminum magnesium silicate; PEG; guar gum; polysaccharide acid; bentonite; Polymethacrylate; HPMC; Hydroxypropylcellulose (eg, Aqualon's Klucel ™); and Ethylcellulose (eg, Dow Chemical Company's Ethocel ™, eg, Povidone K-15, K-30 and K-29 / 32; ))including. Such binders and / or binders, if added, preferably total about 0.5% to about 25%, preferably about 0.75% to about 15%, and more preferably about total weight of the composition. Make up 1% to about 10%.

  Many binders are polymers containing amide, ester, ether, alcohol or ketone groups, which are preferably included in the pharmaceutical composition of the present invention. Polyvinyl pyrrolidone such as povidone K-30 is particularly preferred. Polymeric binders can vary molecular weight, degree of crosslinking and polymer grade. The polymer binder may be a copolymer such as a block copolymer containing a mixture of ethylene oxide and propylene oxide units. Changes in the proportion of these units in the resulting polymer affect properties and performance. Examples of block copolymers that involve block unit composition changes include Poloxamer 188 and Poloxamer 237 (BASF Corporation).

  The pharmaceutical composition of the present invention may optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Such humectants are preferably selected to maintain celecoxib in close association with water at conditions that are believed to improve the bioavailability of the composition. Such wetting agents can also be used to solubilize and increase solubility of the metal salt of celecoxib.

  Surfactants that can be used as wetting agents (not necessarily as precipitation inhibitors) in the pharmaceutical compositions of the present invention are not limited and are quaternary ammonium compounds (eg, benzalkonium chloride, benzethonium chloride and cetyl chloride). Pyridinium), dioctyl sodium sulfosuccinate, polyoxyethylene alkyl phenyl ethers (eg, nonoxynol 9, nonoxynol 10 and octoxynol 9), poloxamers (polyoxyethylene and polyoxypropylene block copolymers), poly Oxyethylene fatty acid glycerides and oils (eg, polyoxyethylene (8) capryl / caprin mono and diglycerides (eg, Gattefosse Labrasol ™), polyoxyethylene (35) castor oil and polyoxyethylene (40 Hardened castor oil); polyoxyethylene alkyl ether (eg, polyoxyethylene (20) cetostearyl ether), polyoxyethylene fatty acid ester (eg, polyoxyethylene (40) stearate), polyoxyethylene sorbitan ester (eg, , Polysorbate 20 and polysorbate 80 (eg ICI's Tween ™ 80)), propylene glycol fatty acid esters (eg propylene glycol laurate (eg Lauroglycol ™ from Gattefosse)), sodium lauryl sulfate, fatty acids And salts thereof (for example, oleic acid, sodium oleate, triethanolamine oleate), glyceryl fatty acid esters (for example, glyceryl monostearate), sorbitan esters (for example, sol monolaurate) And sorbitan monopalinate, sorbitan monopalmitate and sorbitan monostearate), tyloxapol, and mixtures thereof, such wetting agents, if added, total about 0.25% of the total weight of the composition. About 15%, preferably about 0.4% to about 10% and more preferably about 0.5% to about 5%.

  The wetting agent is preferably an anionic surfactant. Sodium lauryl sulfate is a particularly preferred wetting agent. Sodium lauryl sulfate, if added, constitutes about 0.25% to about 7%, preferably about 0.4% to about 4%, and more preferably about 0.5% to about 2% of the total weight of the composition.

  The pharmaceutical composition of the present invention optionally comprises one or more pharmaceutically acceptable lubricants (including anti-adhesives and / or lubricants) as excipients. Suitable lubricants include, but are not limited to, glycerin behapate (eg, Gattefosse Compritol ™ 888); stearic acid and their salts (including magnesium, calcium and sodium stearate), alone or in combination ); Hydrogenated vegetable oil (eg, Avitech's Sterotex ™); colloidal silica; talc; wax; boric acid; sodium benzoate; sodium acetate; sodium fumarate; Company Carbowax ™ 4000 and Carbowax ™ 6000), sodium oleate, sodium lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if added, constitute a total of about 0.1% to about 10%, preferably about 0.2% to about 8% and more preferably about 0.25% to about 5% of the total weight of the composition. To do.

Magnesium stearate is a preferred lubricant used, for example, to reduce friction between the device and the granular mixture when compressing tablet formulations.
Suitable anti-adhesive agents include, but are not limited to, talc, corn starch, DL-leucine, sodium laurate sulfate and metal stearate. Talc is a preferred anti-adhesive or lubricant that is also used, for example, to reduce the formulation that adheres to the surface of the device and to reduce static in the mixture. Talc, if added, constitutes from about 0.1% to about 10%, more preferably from about 0.25% to about 5%, and even more preferably from about 0.5% to about 2% of the total weight of the composition.

  Lubricants can be used to promote powder flow of solid formulations. Suitable lubricants include, but are not limited to, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, magnesium trisilicate. Colloidal silicon dioxide is particularly preferred. Other excipients such as colorants, flavors, sweeteners and the like are known in the pharmaceutical field and can also be used in the pharmaceutical compositions of the present invention. The tablets may or may not be coated with an enteric coating, for example. The composition of the present invention may further contain a buffer.

  Optionally, one or more foaming agents may be used as a disintegrant and may be used to enhance the sensory acceptance of the pharmaceutical composition of the present invention. When added to the pharmaceutical composition of the present invention to promote the disintegration of the dosage form, one or more effervescent agents may comprise a total of about 30% to about 75%, preferably about 45% to the total weight of the composition. Preferably it is present at about 70%, for example about 60%.

  A particularly preferred embodiment of the present invention improves the dispersion of celecoxib in an aqueous medium by allowing the blowing agent to be present in the solid dosage form in an amount less than that effective to promote the disintegration of the dosage form. Without being bound by theory, effervescent agents are believed to be effective in promoting the dispersion of celecoxib from the dosage form in the gastrointestinal tract, thus further enhancing absorption and rapidly developing therapeutic effects. Can do. When added to the pharmaceutical composition of the present invention to facilitate gastrointestinal dispersion without increasing disintegration, the blowing agent is preferably about 1% to about 20% of the total weight of the composition, More preferably from about 2.5% to about 15%, more preferably from about 5% to 10%.

  As used herein, a “foaming agent” is an agent that includes one or more compounds that act together or alone to produce a gas upon contact with water. The generated gas is generally oxygen, more commonly carbon dioxide. Preferred blowing agents include acids and bases that react in the presence of water to generate carbon dioxide gas. Preferably, the base is an alkali metal or alkaline earth metal carbonate or bicarbonate and the acid comprises an aliphatic carboxylic acid.

  Suitable bases as blowing agent components useful in the present invention include, but are not limited to, carbonate (eg, calcium carbonate), bicarbonate (eg, sodium bicarbonate), sesquicarbonate and mixtures thereof. Calcium carbonate is a preferred base.

  Acids suitable as components of blowing agents and / or solid organic acids useful in the present invention are not limited and are citric acid, tartaric acid (D-, L- or D / L-tartaric acid), malic acid, maleic acid, fumaric acid. Acids, adipic acid, succinic acid, acid anhydrides of these acids, acid salts of those acids and mixtures thereof. Citric acid is the preferred acid.

  In a preferred embodiment of the present invention, when the blowing agent comprises an acid and a base, the acid: base weight ratio is about 1: 100 to about 100: 1, more preferably about 1:50 to about 50: 1, Preferably from about 1:10 to about 10: 1. In a further preferred embodiment of the invention, when the blowing agent comprises an acid and a base, the acid: base ratio is approximately stoichiometric.

  Excipients that solubilize the metal salt of celecoxib generally have both hydrophilic and hydrophobic sites, preferably are amphiphilic or have amphiphilic sites. One excipient that is amphiphilic or partially amphiphilic includes or is an amphiphilic polymer. A particular amphiphilic polymer is polyalkylene glycol, which is usually composed of ethylene glycol and / or propylene glycol subunits. Such polyalkylene glycols may be esterified at their ends with carboxylic acids, esters, acid anhydrides or other suitable molecules. Examples of such excipients include poloxamers (symmetric block copolymers of ethylene glycol and propylene glycol, such as poloxamer 237), polyalkylene glycolated esters of tocopherol (formed from di- or multi-functionalized carboxylic acids). Esters, such as d-α-tocopherol polyethylene glycol-1000 succinate) and macrogol glycerides (mono-, di- and triglycerides and mono- and diester mixtures) Including those formed by esterification, such as stearoyl macrogol-32 glycerides). Such pharmaceutical compositions are advantageous for oral administration.

  The pharmaceutical composition of the present invention comprises a metal salt of celecoxib by weight from about 10% to about 50%, from about 25% to about 50%, from about 30% to about 45%, or from about 30% to about 35%; Inhibiting excipients from about 10% to about 50% by weight, from about 25% to about 50%, from about 30% to about 45%, from about 30% to about 35%; To about 50%, about 10% to about 40%, about 15% to about 35%, or about 30% to about 35%. In one embodiment, the weight ratio of the metal salt of celecoxib, the excipient that inhibits precipitation, and the binder is about 1: 1: 1.

  The resulting formulation described above is both physically and chemically stable. The present invention can be prepared in solid dosage form with sufficient margin for oral administration without the risk of premature neutralization or precipitation of the active pharmaceutical ingredient. Liquid suspensions of celecoxib particles experience oral particle aggregation and / or increase in size by crystal growth after a few minutes of standing. This crystal growth can significantly reduce the bioavailability and therapeutic effects of the drug.

The solid dosage forms of the present invention are not limited to the methods described herein, but can be made by any suitable method.
Exemplary methods include: (i) mixing the celecoxib salt of the present invention with one or more excipients to obtain a mixture; and (ii) tableting or encapsulating the mixture to form a tablet or capsule, respectively. The process of carrying out is included.

  In a preferred method, the solid dosage form comprises (a) mixing the celecoxib salt to form a mixture, (b) granulating the mixture to form granules, (c) compressing or encapsulating the mixture. Or a tablet or a capsule, respectively. Step (b) can be performed by other dry or wet granulation methods known in the art. Celecoxib salts are conveniently granulated to form particles of about 10 micrometers to about 1000 micrometers, about 25 micrometers to about 500 micrometers, or about 50 micrometers to about 300 micrometers. More particularly, particles with a diameter of about 100 micrometers are very suitable for providing the desired therapeutic effect. One or more diluents, one or more disintegrants and one or more binders may be added, for example, in the mixing step, and a wetting agent may optionally be added, for example, in the granulating step, and one or more Disintegrants may be added after granulation and before tableting or encapsulation. The lubricant may be added before tableting. Mixing or granulation may be performed separately under low or high shear. A method in which the content of the drug forms uniform granules so that weight variation can be easily controlled during capsule filling or tableting; a method in which easily disintegrating granules are formed; A method of forming; and a method of forming a granule that is sufficiently dense in bulk so that the batch can be processed in a selected apparatus and each dose fits a particular capsule or tablet mold. It is preferable to select.

  In another embodiment, the solid dosage form is produced by a method that includes a spray drying step. That is, the celecoxib salt is suspended with one or more excipients in one or more sprayable liquids, preferably in an aprotic (eg, non-aqueous or non-alcoholic) sprayable liquid, It is then spray dried quickly with a stream of warm air.

  Granules or spray-dried powders produced from any of the above exemplary methods can be compressed or molded to produce tablets, or encapsulated to produce capsules. Conventional tableting or encapsulation techniques known in the art can be used. If a coated tablet is desired, conventional coating techniques are appropriate.

  Excipients for the tablet compositions of the present invention provide disintegration times in a standard disintegration test of less than about 30 minutes, preferably less than about 25 minutes, more preferably less than about 20 minutes, more preferably less than about 15 minutes. It is preferable to be selected as follows.

  The celecoxib dosage form of the present invention is about 10 mg to about 1000 mg, more preferably about 50 mg to about 100 mg, about 100 mg to about 150 mg, 150 mg to about 200 mg, 200 mg to about 250 mg, 250 mg About 300 mg, 300 mg to about 350 mg, 350 mg to about 400 mg, 400 mg to about 450 mg, 450 mg to about 500 mg, 500 mg to about 550 mg, 550 mg to about 600 mg, 600 mg to about 700 mg and Preferably, a daily dose of 700 mg to about 800 mg of celecoxib is included.

  The pharmaceutical composition of the present invention comprises one or more orally administrable dosage units. Each dosage unit preferably contains a therapeutically effective amount of celecoxib as listed herein. As used herein, the term “dose unit” means a single dose of a pharmaceutical composition containing an amount of a therapeutic or prophylactic agent suitable for single oral administration in order to provide a medical effect in the subject celecoxib. In general, a single dosage unit or several (up to about 4) dosage units provide a dosage that contains a sufficient amount of the agent to produce the desired effect in a single administration. Administration of such doses can be repeated as needed, generally at a dosing frequency of 1, 2, 3 or 4 times per day.

  It is understood that for patients, the effective amount of celecoxib treatment depends in particular on the patient's weight. A “patient” to which celecoxib salt or a pharmaceutical composition thereof is administered includes a human patient of both sexes and any age, and also includes any non-human animal, particularly a homeothermic animal, as well as domestic animals or pets (eg, cats, Dog or horse). If the patient is a child or small animal (eg, dog), for example, a relatively low amount of celecoxib in the preferred range of about 10 mg to about 1000 mg (measured as neutral celecoxib, ie, the counter ion of the salt in the hydrate or It does not contain water in the hydrate), but is likely to provide a serum consistent with therapeutic effects. If the patient is an adult or a large animal (eg, a horse), achieving such a serum concentration of celecoxib tends to require a dosage unit containing a relatively large amount of celecoxib.

  Typical dosage units in the pharmaceutical composition of the invention comprise about 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400 mg of celecoxib. In adults, the therapeutically effective amount of celecoxib per dosage unit in the compositions of the invention is generally from about 50 mg to about 400 mg. In particular, a preferred amount of celecoxib per unit dose is from about 100 mg to about 200 mg, such as about 100 mg or about 200 mg. A dose other than the current use of CELEBREX may be selected if the bioavailability is changed with the new formulation. For example, 300 mg may be a preferred dose for a particular condition.

  The dosage unit containing a particular amount of celecoxib can be selected in view of the desired frequency of administration used to reach the desired daily dosage. The daily dose and frequency of administration and the selection of the appropriate dosage unit therefor will depend on various factors including age, weight, gender and the patient's condition, its symptoms or the nature and severity of the disorder and thus vary widely. You may let them.

  For pain management, the pharmaceutical composition of the present invention is about 50 mg to about 1000 mg, preferably about 100 mg to about 600 mg, more preferably about 150 mg to about 500 mg, more preferably about 175 mg to about 400 mg, such as about 200 mg. Can be used to provide a daily dose of celecoxib. About 0.7 to about 13 mg / kg body weight, preferably about 1.3 to about 8 mg / kg body weight, more preferably about 2 to about 6.7 mg / kg body weight, and more preferably about 2.3 to about 5.3 mg / kg body weight, for example A daily dose of about 2.7 mg / kg body weight of celecoxib is generally appropriate when administered to a pharmaceutical composition of the invention. The daily dose can be administered from 1 to about 4 doses per day. Four times daily, one 50 mg dose unit; twice daily, one 100 mg dose unit; or two 50 mg dose units; once a day, two 100 mg dose units; or four 50 mg doses Administration in units is preferred.

  As used herein, the term “oral administration” is each an embodiment of the present invention, but the therapeutic agent or composition is placed in the patient's mouth, regardless of whether the agent or composition is swallowed immediately. Any form of distribution of those therapeutic agents or compositions to a patient. Thus, “oral administration” includes buccal and sublingual as well as esophageal administration. Absorption of the drug occurs in some or part of the digestive tract, including the mouth, esophagus, gastrointestinal tract, duodenum, ileum and colon. As used herein, the term “can be given orally” means suitable for oral administration.

  In certain embodiments of the invention, multiple pellets can be incorporated into the formulation, each having a different coating thickness. This will allow each pellet to be dissolved at a limited, desired time interval after administration. As a result, the duration of the desired therapeutic effect is increased. Such controlled release (CR) formulations can reduce the frequency with which medications must be administered to patients and can reduce the total amount of drug uptake. Reduced side effects, reduced drug accumulation, and improved serum concentration variability are some of the advantages of controlled release formulations. Further embodiments allow one or more therapeutic agents to be included in the formulation. Two or more active pharmaceutical ingredient pellets can be incorporated, each having a different coating thickness, which can result in two, three or more drugs (Chemg-ju Kim, Controlled Release Dosage Form Design).

  An important aspect of drug administration in the conventional form is the variation in high and low serum concentrations of the drug between the administration of two consecutive doses. In fact, if the drug is absorbed too early, excessive plasma concentrations are reached, causing unwanted toxic side effects. On the other hand, the disappearance of drugs with a short half-life is too early and therefore requires frequent administration. In either case, the patient must be careful during the treatment because of the special attention and continuity of administration required, and such conditions are not always readily available. To formulate pharmaceutical formulations that can prolong the time of drug activity in the body at optimal plasma levels in order to reduce the number of doses and thus improve the patient's response to treatment Attempts have been made.

  Formulations of pharmaceutical compositions intended to provide a controlled release over time of the active ingredient and are well known in the pharmaceutical art. The system is known to include tablets, capsules, microcapsules, microspheres and general formulations, where the active ingredient is released gradually by various means including: The particles containing the active pharmaceutical ingredient may be individually coated with a specific surface coating so that the release of the active agent from the inner core is divided at successive intervals. The prescribed number of pulses of drug release by the formulation can range from about 1 to about 10, in particular from about 1 to about 5. Where applicable, the time delay of drug release can be set before the first dose release of the active agent. This delay in drug release is achieved by a delay in the initial pulse release.

  The dosage forms of the present invention may optionally be coated with one or more materials suitable to regulate release or protect the formulation. In one embodiment, the coating is provided to allow either pH dependence or pH independence, for example when exposed to gastrointestinal fluid. The pH dependent coating serves to release the active pharmaceutical ingredient in the desired region of the gastrointestinal (GI) tract, eg, the stomach or small intestine, so that the absorption profile is at least about 8 hours, preferably from about 12 hours to about Provided to allow the patient to feel painless for up to 24 hours. A pH-independent coating is desirable, and the coating is designed to achieve optimal release regardless of pH changes in, for example, the surrounding liquid in the GI tract. It is also possible to formulate a composition that releases a portion of the dose in the desired area of the GI tract, eg, the stomach, and releases the remaining dose in other areas of the IG tract, eg, the small intestine. .

  Also, the formulations of the present invention that utilize a pH-dependent coating to obtain a formulation may give repeated effects, so that unprotected drugs are coated with an enteric coating and released in the stomach. While the remainder is coated with an enteric coating and released further downstream of the gastrointestinal tract. A pH dependent coating may be used in accordance with the present invention and includes shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate and methacrylate copolymers, zein, and the like.

  In certain preferred embodiments, the substance containing the active pharmaceutical ingredient (eg, tablet core beads, matrix particles) is coated with a hydrophobic material selected from (i) alkylcellulose, (ii) acrylic polymers or (iii) mixtures thereof. Has been. The coating can be applied in the form of an organic or aqueous solution or dispersant. The coating may be applied with an increase of about 2 to about 25% of the substrate to obtain the desired sustained release profile. Coatings derived from aqueous dispersants are described in detail in US Pat. Nos. 5,273,760 and 5,286,493, which are incorporated herein by reference in their entirety. Other examples of sustained release formulations and coatings used in accordance with the present invention include US Pat. Nos. 5,324,351, 5,356,467 and 5,472,712, which are incorporated herein by reference in their entirety.

  Cellulosic materials and polymers include alkylcelluloses, giving hydrophobic materials that are very suitable for coating the beads of the present invention. By way of example only, preferably the alkyl cellulose polymer is ethyl cellulose, but those skilled in the art will recognize other celluloses and / or alkyl cellulose polymers, alone or in any combination, all or part of the hydrophobic coating of the present invention. Fully understand that it can be used easily.

  One commercially available aqueous dispersant with ethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pa., U. S. A.). Aquacoat® is made by dissolving ethyl cellulose in a water miscible organic solvent and then emulsifying it in water in the presence of a surfactant and stabilizer. After homogenization to produce submicron droplets, the organic solvent is evaporated under vacuum to form a simulated emulsion. The plasticizer is not incorporated into the simulated emulsion during the manufacturing stage. Thus, before using it as a coating, it is necessary to thoroughly mix Aquacoat® and a suitable plasticizer prior to use.

  Another aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pa., U.S. A.). This product is manufactured by incorporating a plasticizer into the dispersant during the manufacturing stage. Hot-melt polymer, plasticizer (dibutyl sebacate), stabilizer (oleic acid) are produced as a homogeneous mixture and then diluted with an alkaline solution to obtain an aqueous dispersion that can be applied directly to a substrate .

  In other preferred embodiments of the present invention, the hydrophobic material comprising the controlled release coating includes, but is not limited to, acrylic acid and methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, polyacrylic acid, Pharmaceuticals containing polymethacrylic acid, methacrylic acid alkylamide copolymer, polymethyl methacrylate, polymethacrylate, polymethyl methacrylate copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, polymethacrylic anhydride and glycidyl methacrylate copolymer Is an acceptable acrylic polymer.

In certain preferred embodiments, the acrylic polymer comprises one or more amino methacrylate copolymers. Amino methacrylate copolymers are known in the art and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic esters having a low content of quaternary ammonium groups.
In order to obtain the desired solubility profile, it may be necessary to incorporate two or more aminomethacrylate copolymers having different physical properties, such as different molar ratios of quaternary ammonium groups and neutral methacrylic esters.

  Certain methacrylate-based polymers are useful for producing pH dependent coatings that can be used in accordance with the present invention. For example, there is a family of copolymers synthesized from diethylaminoethyl methacrylate and other neutral methacrylic esters, known as methacrylic acid copolymers or polymeric methacrylates, Eudragit® (from Rohm Tech, Inc) Is commercially available. There are several different types of Eudragit®. For example, Eudragit® E is an example of a methacrylic acid copolymer that swells and dissolves in an acidic medium. Eudragit® L is a methacrylic acid copolymer that does not swell at a pH of less than about 5.7 and dissolves at a pH greater than pH 6. Eudragit® S does not swell at a pH of less than about 6.5 and dissolves at a pH greater than pH 7. Eudragit (R) RL and Eudragit (R) RS are water swellable and the amount of water absorbed by these polymers is pH dependent, but covered with Eudragit (R) RL and RS The dosage form achieved is pH independent.

  In one preferred embodiment, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit (registered trademark) RL30D and Eudragit (registered trademark) RS30D are copolymers of acrylic acid and methacrylic acid ester having a low content of quaternary ammonium groups. The ammonium group and the remaining neutral methacrylic acid ester are It is 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. The average molecular weight is about 150,000. The code designations RL (high permeability) and RS (low permeability) indicate the penetration properties of these agents. Eudragit® RL / RS mixture is insoluble in water and digestive fluids. However, the film formed therefrom is swellable and permeable to aqueous and digestive fluids.

  The Eudragit® RL / RS dispersant of the present invention may be mixed in any desired ratio to ultimately obtain a sustained release formulation with the desired dissolution profile. Desired sustained release formulations are, for example, 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS and 10% Eudragit® RL: Eudragit® It may be obtained from a delayed coating derived from 90% RS. Of course, those skilled in the art will recognize that other acrylic polymers such as, for example, Eudragit® L can be used.

  In embodiments of the invention in which the coating comprises an aqueous dispersion of a hydrophobic material, inclusion of an effective amount of plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties of the sustained release coating. Let's go. For example, since ethyl cellulose has a relatively high glass transition temperature and does not form a plastic film under normal coating conditions, it incorporates a plasticizer into an ethyl cellulose coating, including a sustained release coating, before using it as a coating material. It is preferable. Generally, the amount of plasticizer included in the coating solution is based on the concentration of the film formation, for example, from about 1 to about 50% by weight of the film formation is most often used. However, the concentration of plasticizer can be appropriately determined after careful experimentation with a particular coating solution and application method.

  Examples of suitable plasticizers for ethyl cellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin, but other water insoluble plasticizers (acetyl monoglycerides, phthalates) It is also possible to use (such as castor oil). Triethyl citrate is a particularly preferred plasticizer for the aqueous dispersion of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to, citrate esters such as triethyl citrate, tributyl citrate, dibutyl phthalate and possibly 1,2-propylene glycol. Other plasticizers that have proven to be suitable for enhancing the elasticity of films formed from acrylic films such as Eudragit® RL / RS lacquer solutions are polyethylene glycol, propylene glycol, diethyl phthalate, castor oil And triacetin. Triethyl citrate is a particularly preferred plasticizer for the aqueous dispersion of ethyl cellulose of the present invention.
Furthermore, it has been found that the addition of a small amount of talc reduces the tendency of aqueous dispersion to tack during manufacture and functions as an abrasive.

  When a hydrophobic material is used to coat the inert pharmaceutical beads, a plurality of resulting solid controlled release beads are then ingested and contacted with surrounding fluids such as gastric juice or dissolution media, for example. May be placed in gelatin capsules in an amount sufficient to provide an effective controlled release dose.

  The controlled release bead formulation of the present invention slowly releases the therapeutically active agent when ingested and exposed to, for example, gastric fluid and then intestinal fluid. The controlled release profile of the formulation of the present invention shows the relative plasticity relative to the hydrophobic material by changing the amount of protective film in the hydrophobic material and by changing the way the plasticizer is added to the hydrophobic material. By changing the amount of the agent, it can be changed by adding a further component or excipient, by changing the production method, or the like. The final product dissolution profile may also be altered, for example, by increasing or decreasing the thickness of the retarding coating.

  A sphere or bead coated with a therapeutically active agent can be produced, for example, by dissolving the therapeutically active agent in water and then spraying the solution onto the substrate using, for example, a Wuster insert. Also, optionally further components may be added prior to coating the beads to help bind the active pharmaceutical ingredient to the beads and / or to color the solution. For example, a product containing hydroxypropyl methylcellulose and the like may be added to the solution with or without a colorant (eg, commercially available from Opadry®, Colorcon, Inc.) and the solution is applied to the beads. May be mixed (eg, about 1 hour). The resulting coated substrate, such as the beads in this example, may then optionally be protected with a barrier agent to separate the therapeutically active agent from the hydrophobic controlled release coating. An example of a suitable barrier agent is one comprising hydroxypropyl methylcellulose. However, any film formation known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product.

  An example of a suitable barrier agent includes hydroxypropyl methylcellulose. However, any film formation known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product.

  The beads may then be protected with an aqueous dispersion of hydrophobic material. The aqueous dispersion of hydrophobic material preferably further includes an effective amount of a plasticizer such as, for example, triethyl citrate. A pre-formulated aqueous dispersion of ethylcellulose such as Aquacoat® or Surelease® may be used. When using Surelease®, it is not necessary to add a separate plasticizer. Alternatively, an acrylic polymer pre-formulated aqueous dispersant such as Eudragit® may be used.

  In addition to film formers, plasticizers and solvent systems (eg, water), the coating solutions of the present invention preferably include a colorant to provide aesthetics and product distinction. The colorant may be added in place of the therapeutically active agent solution, or may be added in addition to the aqueous dispersion of the hydrophobic material. For example, a colorant can be added in an alcohol or propylene glycol based colorant dispersant, mill, by shearing the colorant into a water-soluble polymer liquid and then adding to the plasticized Aquacoat® using low shear. It may be added to Aquacoat® through the use of opacifiers such as processed aluminum lakes and titanium oxide. Alternatively, any suitable method of coloring the formulation of the present invention may be used. When aqueous acrylic polymer dispersants are used, suitable ingredients for imparting color to the formulation include colored pigments such as titanium oxide and iron oxide pigments. However, pigment incorporation may increase the retarding action of the coating.

  The plasticized hydrophobic material may be applied by spraying onto a substrate containing the therapeutically active agent using a suitable sprayer known in the art. In a preferred method, a Wurster fluidized bed system is used, and an air jet injected from below flows the core material and functions for drying while an acrylic polymer coating is sprayed thereon. When the coated substrate is exposed to an aqueous solution such as gastric juice, in order to obtain a predetermined controlled release of the therapeutically active ingredient, the hydrophobic material, taking into account the physical characteristics of the therapeutically active agent, the method of incorporating the plasticizer, etc. It is preferable to apply a sufficient amount of After coating with a hydrophobic material, an additional film former (Opadry® coating is optionally applied to the beads. This coating, if present, substantially reduces the agglomeration of the beads. Provided.

  The release of the therapeutically active agent from the controlled release formulation of the present invention can be further controlled by adding one or more release modifiers or by providing one or more passages through the coating, ie The desired speed may be adjusted. The ratio of the water-soluble material to the hydrophobic material is determined from other factors, i.e. the required release rate and the solubility characteristics of the selected material.

Release modifiers that function as pore formers may be organic or inorganic substances including materials that can be dissolved, extracted or leached from the coating in the environment of use. The pore former may include one or more hydrophobic materials such as hydroxypropylmethylcellulose.
The sustained release coating of the present invention may also contain an erosion promoter such as starch and gum. The sustained release coatings of the present invention may include materials useful for forming microporous thin films in the environment of use, such as polycarbonates composed of linear polyesters of carboxylic acids in which carbonate groups repeat in the polymer chain. The modified release agent may comprise a semi-permeable polymer.

In certain preferred embodiments, the release modifier is selected from hydroxypolymethylcellulose, lactose, metal stearic acid, and mixtures of any of these.
The sustained release coating of the present invention may also include outlet means including at least one passage, orifice or the like. The passages may be formed by methods such as those disclosed in U.S. Pat. Nos. 3,845,770, 3,916,889, 4,063,064 and 4,088,864 (incorporated herein by reference in their entirety). it can. The passage may have any shape such as a circle, a triangle, a square, an ellipse, and an indefinite shape.

  The present invention may include a dual release composition, wherein the salt of celecoxib is formulated to include both a fast acting drug delivery component and a sustained release component. This formulation minimizes the frequency of administration while allowing both relatively fast and long therapeutic effects. Dual release compositions are further described in International Patent Publication No. WO 01/45706, incorporated herein by reference in its entirety.

  A variety of known controlled-or sustained-release dosage forms, formulations and devices can be employed for use with celecoxib salts and compositions of the present invention. US Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548 No. 5,073, 543, 5,639, 476, 5,354, 556, 5,733, 566 and 6,365, 185 (incorporated herein by reference in their entirety). These dosage forms may be modified, for example, by hydroxypropylmethylcellulose, other polymer matrices, gels, osmotic membranes, osmotic systems (OROS® (Alza Corporation, Mountain View, Calif. USA)), multilayer coatings, microparticles, liposomes or microspheres, or combinations thereof can be used to provide delayed or controlled release of one or more active ingredients. In addition, ion exchange materials may be used to produce a fixed or adsorbed salt form of celecoxib, thereby enabling controlled transmission of the drug. Specific anion exchange materials include, but are not limited to, Duolited® A568 and Duolited® AP143 (Rohm & Haas, Spring House, PA. USA).

  One embodiment of the present invention is a pharmaceutically acceptable salt of celecoxib (eg, sodium, potassium or lithium salt) or polymorph, solvate, hydrate, dehydrate, co-crystal, anhydride or their Including a unit dosage form comprising an amorphous form and one or more pharmaceutically acceptable excipients or diluents, the pharmaceutical composition or dosage form is formulated in controlled release. Certain dosage forms utilize osmotic drug delivery systems.

  Particles and a known osmotic drug delivery system are designated as OROS® (Alza Corporation, Mountain View, Calif. USA). This technique can be readily applied for delivery of the compounds and compositions of the invention. Various aspects of the technology are described in U.S. Patent Nos. 6,375, 978 B 1, 6,368, 626 B 1, 6,342, 249 B1, 6,333, 050 B2, 6,287, 295 B1, 6,283, 953 B1, 6,270. 787 B1, 6,245,357 B1 and 6,132,420, each of which is incorporated herein by reference in its entirety. Specific applications of OROS® that can be used in the administered compounds and compositions of the present invention include, but are not limited to, OROS® Push-Pull ™, delayed Push-Pull ™, multi-layer All are known, including the Push-Pull ™ and Push-Stick ™ systems (see eg http://www.alza.Com). Additional OROS® systems that can be used for controlled oral delivery of compounds and compositions of the present invention include OROS®-CT and L-OROS® Id (Delivery Times, vol. II, issue II (Alza Corporation)).

  Conventional OROS® oral dosage forms are made by compressing a drug powder (eg, celecoxib salt) into a hard tablet, coating the cellulose derivative on the tablet to form a semi-permeable membrane, and then coating the An orifice is formed in (e.g., with a laser). Kim, Chemg-ju, Controlled Release Dosage Form Design, 231-238 (Technomic Publishing, Lancaster, Pa .: 2000). The advantage of such a dosage form is that the rate of drug delivery is not affected by physiological or experimental conditions. Even drugs with pH-dependent solubility can be delivered at a constant rate regardless of the pH of the delivery medium. However, because these benefits are provided by increased osmotic pressure in the dosage form after administration, conventional OROS® drug delivery systems are used to effectively deliver low water-soluble drugs. I can't. Because celecoxib salts and complexes of the present invention (eg, celecoxib sodium) are much more water soluble than celecoxib itself, they are more suitable for osmotic-based delivery to patients. However, the present invention encompasses the incorporation of celecoxib and their non-salt isomers and isomer mixtures in the OROS® dosage form.

  Certain dosage forms of the invention have a wall defining a cavity, the wall having an exit orifice formed or formable therein, at least a portion of the wall being permeable; remote from the exit orifice An expandable layer located within the cavity and in fluid communication with a permeable portion of the wall; a dry or positioned in the cavity adjacent to the exit orifice and in direct or indirect contact with the expandable layer A substantially dry drug layer; and a flow promoting layer sandwiched between the inner wall of the wall and at least the outer surface of the drug layer located in the cavity, the drug layer comprising a salt of celecoxib, polymorphs thereof Solvates, hydrates, dehydrates, co-crystals, anhydrides or amorphous. See US Pat. No. 6,368,626 (hereby incorporated by reference in its entirety).

  Another particular dosage form of the present invention has a wall defining a cavity, the wall having an exit orifice formed or formable therein, at least a portion of which is permeable; from the exit orifice An expandable layer located in a remote cavity and in fluid communication with a permeable portion of the wall; located in a cavity adjacent to the exit orifice and in direct or indirect contact with the expandable layer Including a drug layer, the drug layer comprising an active agent formulation adsorbed to a liquid, porous particle, the porous particle comprising a liquid, active agent formulation, a protocol sevo layer between the exit orifice and the drug layer. Optionally applied to counteract compressive force sufficient to form a shaped drug layer without substantial leaching of the dosage form, and the active agent formulation is a salt of celecoxib, their polymorphs, solvates Hydrate, dehydration , Co-crystal, containing anhydride or amorphous. See US Pat. No. 6,342,249 (hereby incorporated by reference in its entirety).

  Celecoxib compositions useful in the methods of the present invention can be used in combination therapy with opioids and other actions. A compound administered in combination with a celecoxib composition useful in the methods of the invention may be formulated separately from the composition or may be co-formulated with the composition. When the celecoxib composition is co-formulated with a second drug, eg, an opioid drug, the second drug can be formulated in a rapid release, rapid onset, sustained release or dual release form. In certain embodiments of the invention, celecoxib may be combined with an antiplatelet agent such as, but not limited to, tirofiban, aspirin, dipridamol, anagrelide, epoprostenol, epitifibatide, clopidogrel, cilostazol, abciximab or triclopsin.

  In other embodiments of the invention, the formulation comprises a celecoxib salt (eg, celecoxib sodium salt) and a free acid form. This combination allows both rapid onset and delayed response after administration to the patient. Also, in other embodiments, the combination of celecoxib salt and free acid is any one, any two, any three, any four, or any five or more excipients listed herein (For example, precipitation inhibitor, enhancer, etc.) may be included.

  The pharmaceutical compositions of the invention are useful for the treatment and prevention of a very wide range of COX-2 mediated diseases, including but not limited to disorders characterized by inflammation, pain and / or heat. Such pharmaceutical compositions have the additional effect of significantly fewer harmful side effects than compositions of conventional non-steroidal anti-inflammatory drugs (NSAIDs) that lack the selectivity of COX-2 over COX-1. And is particularly useful for anti-inflammatory agents such as the treatment of arthritis. In particular, the pharmaceutical composition of the present invention reduces gastrointestinal toxicity and gastrointestinal irritation, including ulcers and bleeding in the upper gastrointestinal tract, compared to conventional NSAIDs compositions, and reduces fluid retention and hypertension. It reduces the likelihood of kidney side effects, such as reduced renal function, leading to reduced effects on bleeding time, including inhibition of platelet function, and the potential for aspirin sensitive asthmatics to cause asthma attacks. Thus, the composition of the present invention may be used as a substitute for conventional NSAIDs that are contraindicated for such NSAIDs, such as peptic ulcer, gastritis, localized enteritis, ulcerative colitis, diverticulitis patients or gastrointestinal disorders Patients with a history of recurrence; Patients with coagulopathy or other bleeding problems including gastrointestinal bleeding, anemia such as hypoprothrombinemia, hemophilia, etc .; Kidney disease; It is particularly useful for patients taking medication.

The pharmaceutical composition of interest is useful for the treatment of various arthritic disorders including, but not limited to, rheumatoid arthritis, spondyloarthritis, gout arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.
Such pharmaceutical compositions include asthma, bronchitis, menstrual cramps, early labor, tendinitis, mucocystitis, allergic neuritis, cytomegalovirus infectivity, apoptosis including HIV-induced apoptosis, low back pain, liver including hepatitis Useful in treating post-operative inflammation, including diseases, psoriasis, eczema, acne, skin-related symptoms including ultraviolet damage including burns, dermatitis and sunburn, and those following eye surgery such as cataract or refractive surgery is there.

The pharmaceutical composition of the present invention is useful for the treatment of gastrointestinal symptoms such as, but not limited to, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.
Such a pharmaceutical composition can be used for migraine, polyarteritis, thyroiditis, aplastic anemia, Hodgkin's disease, dysphagia, rheumatic fever, type I diabetes, neuromuscular dysfunction including myasthenia gravis, multiple occurrences It is useful for the treatment of white matter diseases including sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury including cerebral edema, myocardial ischemia and the like.

Furthermore, these pharmaceutical compositions are useful for the treatment of retinitis, conjunctivitis, retinopathy, uveitis, visual phobia and acute damage of ocular tissues.
Such pharmaceutical compositions are also useful for the treatment of pneumonia such as those associated with viral infection and cystic fibrosis, and the treatment of bone resorption such as that associated with osteoporosis.
This pharmaceutical composition is useful for the treatment of certain central nervous system disorders such as Alzheimer's disease, cortical dementia including neurodegeneration, and central nervous system damage caused by stroke / ischemia and trauma. The term “treatment” in this context includes partial or complete suppression of dementia including Alzheimer's disease, vascular dementia, multiple cerebral infarct dementia, presenile dementia, alcohol dementia and senile dementia.
Such pharmaceutical compositions are useful for the treatment of allergic rhinitis, dyspnea syndrome, endotoxin shock syndrome and liver disease.

  Furthermore, the pharmaceutical composition of the present invention is useful for the treatment of pain including, but not limited to, postoperative pain, toothache, muscle pain and cancer pain. For example, such compositions may include rheumatic fever, other viral infections including influenza and common colds, back and neck pain dysmenorrhea, headache, toothache, sprains and contusions, myositis, neuralgia, synovitis, Useful in reducing arthritis including rheumatoid arthritis, osteoarthritis (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns and various pains including trauma following surgery and dental procedures, heat and inflammation It is.

  The present invention is further directed to therapeutic methods for treating conditions or disorders that require treatment with a COX-2 inhibitor. This method comprises orally administering the pharmaceutical compositions of the present invention to a patient as needed. The drug regimen that prevents, reduces or ameliorates the symptoms or disorders is preferably treatment once a day or twice a day, but can vary depending on various factors. These include the patient's body shape, age, weight, sex, diet and medical condition, personality and severity of the disorder. Thus, the drug regimen actually used can vary widely, and thus may deviate from the preferred drug regimen described above. This pharmaceutical composition can also be used in conjunction with other therapies or therapeutic agents. Without limitation, opioids and, in particular, narcotic analgesics, Mu receptor antagonists, kappa receptor inhibitors, non-narcotic (emergency) analgesics, monoamine absorption inhibitors, adenosine modulators, cannabinoid derivatives, Treatment with other analgesics, including GABA activators, norexin neuropeptide modulators, sapstans P inhibitors, neurokinin-1 receptor inhibitors and sodium channel blockers.

  Combination therapy comprises the composition of the present invention and aceclofenac, acemethacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine, alclofenac, Alfentanil, allylprozin, aluminoprofen, alloxypurine, α-prozin, aluminum bis (acetylsalicylate), ampenac, aminochlortenoxazine, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, Aminopropyrone, Aminopyrine, Amixetrine, Ammonium salicylate, Ampiroxicam, Anthol metching acyl, Anilellidine, Antipyrine, Antipyrine salicylate, Anthrafenine, Apazone,

  Vendazac, Benolylate, Benoxaprofen, Benzpiperilone, Benzylmorphine, Belmoprofen, Vezitoramide, α-Bisabolol, Bromfenac, p-Bromoacetanilide, 5-Bromosalicylate acetate, Bromosaligenin, Busetine, Bucloxy acid, Bucolome, Buffet Xamac, bumadizone, buprenorphine, butacetin, butibufen, butophanol,

  Calcium acetylsalicylate, carbamazepine, carbifen, caprophene, carsalam, chlorobutanol, chlortenoxazine, choline salicylate, cinchofene, cinmetacin, silamadol, clidanac, clometacin, clonitazen, clonixin, clopilac, clove, codeine, codeine methyl bromide, codeine phosphate Codeine sulfate, clopropamide, crotetamide,

  Desomorphin, Dexosesadrol, Dextromoramide, Dezocine, Diampromide, Diclofenac sodium, Diphenamizole, Difenpyramide, Diflunisal, Dihydrocodeine, Dihydrocodeine enol acetate, Dihydromorphine, Dihydroxyaluminum acetylsalicylic acid, Dimenoxadol dimefeptanol, Dimethylthianbutene, dioxafetil butyrate, dipipanone, diprocetyl, dipyrone, ditasol, droxicam, emorphazone, emphenamic acid, epilysole, eptazocine, ethersalate, etenzamide, etoheptazine, etoxazene, ethylmethylthianbutene, ethylmorphine, etodolac, Etofenamate, etonitazen, eugenol, felbinac, Embbufen, fenclozinic acid, fendosar, fenoprofen, fentanyl, fenthiazac, feprazinol, feprazone, ferrotaphenine, flufenamic acid, flunoxaprofen, fluoresone, flupirin, fluprocazone, flurbiprofen, phosphosal, gentisic acid, grafenine, Glucamethatin, glycolsalicylate, guaiazulene,

  Hydrocodone, hydromorphone, hydroxypetidin, ibufenac, ibuprofen, ibuproxam, imidazolic salicylate, indomethacin, indoprofen, isofezolac, isoladol, isomethadone, isonixin, isoxepak, isoxicam, ketobemidone, ketoprofen, ketorolac, p-lactophenetole, lephafenol Lofentanil, ronazolac, romoxicam, loxoprofen, lysine, acetylsalicylic acid, magnesium acetylsalicylate, meclofenamic acid, mefenamic acid, meperidine, meptazinol, mesalamine, methazocin, methadone hydrochloride, methotrimiprazine, methiazine acid, metholine, methopon, modafinil, modafinil , Mofezolac, morazon Morphine, morphine hydrochloride, morphine sulfate, salicylic acid morphine, Mirohine,

  Nabumetone, nalbuphine, 1-naphthylsalicylic acid, naproxen, narcein, nefopam, nicomorphine, nifenazone, niflumic acid, nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxa Seprol, oxamethasine, oxaprozin, oxycodone, oxymorphone, oxyphenbutazone, papaveretam, paraniline, parasanide, pentazocine, perisoxal, phenacetin, phenadoxone, phenazosin, phenazopyridine hydrochloride, phenocol, phenoperidine, phenopyrazone, phenylacetylsalicylic acid, phenyl Butazone, phenylsalicylic acid, phenylamidol,

  Piketoprofen, Piminodine, Pipepezone, Piperilone, Piperphene, Pyrazolac, Pyrtramide, Piroxicam, Planoprofen, Progouritacin, Proheptadine, Promedol, Propacetamol, Propyram, Propoxifen, Propifenazone, Procazone, Protidic acid, Lamifentanil, Ramifentanil Methyl lamazolium sulfate, salacetamide, salicin, salicylamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalto, salverine, cimetride, sodium salicylate, sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, succibzone, talniflumate , Tenidap, tenoxicam, telofenamate, tetrandrine,

  Thiazolinobutazone, thiaprofenic acid, thiaramide, thiridine, tinolidine, tolfenamic acid, tolmetine, topiramate, tramadol, tropesin, viminol, xembucin, xymoprofen, zaltoprofen and zomepilac (Merck Index 12th edition, Therapeutic Category and Biological Activity Index, ed. S. Budavari (1996), pp. Ther-2 to Ther-3 and Ther-12 (analgesics (D) ental), analgesics (anesthetics), analgesics (non-anesthesia), anti-inflammatory drugs (nonsteroids) )))). The use of a composition with one or more compounds selected from

  The pharmaceutical composition of the present invention is used for vascular disease, ischemic heart disease, aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including heart transplant atherosclerosis, myocardial infarction, embolism, stroke, vein Thrombosis including thrombosis, angina including unstable angina, coronary platelet inflammation, bacteria-induced inflammation including chlamydia-induced inflammation, virus-induced inflammation, and surgical procedures such as artificial blood vessels including aortic coronary artery bypass surgery, blood vessels It is useful for the treatment and prevention of inflammation related to cardiovascular disorders including inflammation associated with revascularization methods including formation, stenting, arterial endarterectomy or other invasive methods involving arteries, veins and capillaries.

  These pharmaceutical compositions are also useful for the treatment of diseases related to angiogenesis in patients, for example, inhibition of tumor angiogenesis. Such a pharmaceutical composition comprises neoplasia including metastasis; rejection after corneal transplantation, neovascularization of the eyeball, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, macular degeneration Ophthalmic symptoms including posterior lens lens fibroproliferation and neovascular glaucoma; ulcerative diseases such as gastric ulcers; infantile hemangioma, nasopharyngeal hemangiofibroma and hemangioma including ischemic osteonecrosis, but not malignant but abnormal Useful for treating female genital system disorders such as endometriosis.

  Furthermore, the pharmaceutical composition of the present invention comprises: colorectal cancer; brain tumor; osteosarcoma; tumor formation derived from epithelial cells such as basal cell carcinoma (epithelial malignant tumor); adenocarcinoma; lip cancer, oral cancer, esophageal cancer, small intestine Gastrointestinal cancer such as cancer, stomach cancer, colon cancer; liver cancer; bladder cancer; pancreatic cancer; ovarian cancer; cervical cancer; lung cancer; skin cancer such as breast cancer, squamous cell carcinoma and basal cell carcinoma; prostate cancer; It is useful for the prevention and treatment of benign and malignant tumors and tumorigenesis including cancers such as cell carcinomas; and other known cancers that act on epithelial cells throughout the body. Tumor formation specifically intended for use with the compositions of the present invention includes cancer of the digestive tract, Barrett's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer It is. Such pharmaceutical compositions can also be used to treat fibrosis that occurs with radiation therapy. These pharmaceutical compositions can be used to treat patients with nematodes, including patients with familial nematode polyposis (FAP). Furthermore, the pharmaceutical composition of the present invention can be used to prevent polyps from forming in patients at risk for FAP.

  The pharmaceutical composition also inhibits prostanoid-induced smooth muscle contraction by inhibiting the synthesis of contractile prostanoids and can therefore be used to treat dysmenorrhea, preterm labor, asthma and acidophilic related disorders. They can also be used to reduce osteoporosis (ie, treat osteoporosis) and treat glaucoma, especially in postmenopausal women.

  The pharmaceutical composition of the present invention is used for the treatment of rheumatoid arthritis and osteoarthritis, pain management in general (especially pain after oral surgery, pain after general surgery, pain after orthopedic surgery, and acute redness of osteoarthritis. ), Preferably used for treatment of Alzheimer's disease and chemoprevention of colorectal cancer. A particularly preferred use is rapid pain treatment, such as when celecoxib salts or pharmaceutical compositions thereof provide the effect of treating pain within about 30 minutes.

  In addition to being useful for human treatment, the pharmaceutical compositions of the present invention are also useful for the treatment of veterinarians such as pets, foreign animals, farm animals, etc., particularly mammals. More particularly, the pharmaceutical composition of the present invention is useful for the treatment of equine, dog and cat COX-2 mediated diseases.

  The following are standard procedures for obtaining Raman, PXRD, DSC and TGA data herein. These procedures follow each method for analysis herein, unless otherwise indicated.

Raman collection Collection Samples were placed in glass vials to process them or aliquots of samples were transferred to glass slides. A glass vial or glass slide was placed in the sample chamber. The measurements were performed using an Almega ™ Dispersive Raman System (Almega ™ Dispersive Raman, Thermo-Nicolet, 5225 Verona Road, Madison, Wisconsin 53711-4495) fitted with a 785 nm laser source. Samples were manually focused using the microscope portion of the instrument equipped with a 10x objective (unless otherwise noted). Spectra were obtained using the parameters outlined in Table 1. (Exposure time and number of exposures may vary. Changes to the parameters will be indicated with each acquisition.) Unless otherwise noted, all Raman scattering peaks are +/- 5 cm ^-1 .

X-ray powder diffraction (PXRD) procedure All X-ray powder diffraction patterns were measured using a D / Max Rapid X-ray diffractometer (D / Max) equipped with a copper source (Cu / Kα 1.5406), a manual xy stage and a 0.3 mm collimator. Rapid, Contact, USA, Texas, Woodland, New Trails Drive 9009, 7781-5209 Rigaku / MSC). The sample is cut at one end of the tube, the cut end is inserted into a layer of powder sample or slurried sediment sediment, and the opening is tapped to form a 0.3 mm boron-rich glass capillary tube. (For example, Charles Supper Company, 15 Tech Circle, Natick, MA 01760-1024). It should be noted that the precipitate can be amorphous or crystalline. The loaded capillary was attached to a holder fixed to the xy stage. The diffractogram is oscillated about 0-5 degrees around the omega axis at 1 degree / s and rotated around 2 degrees / s around the phi axis, and in atmospheric conditions with output settings of 40 mA and 46 kV in the reflection mode. (For example, control software: RINT Rapid control software, Rigaku Rapid / XRD, version 1.0.0, copyright 1999 Rigaku Co.). The exposure time was 15 minutes unless otherwise specified. The resulting diffractogram is obtained using the RINT Rapid Display Software cyllnt utility provided with the instrument by Rigaku, with a step size of 0.02 degrees, 2-θ and 0 to 2-60 degrees. Integrated into a 360-degree chi (one segment) (analysis software: RINT Rapid display software, version 1.18, Rigaku / MSC.). The dark coefficient value was set to 8 by system calibration (system setup and calibration by Rigaku). Standardization was set to average. The omega offset was set to 180. Chi and phi offsets were not used for integration. Analysis software JADE XRD pattern processing, versions 5.0 and 6.0 (81995-2002, Materials Data, Inc.) were also used.

  The relative intensity of the peaks in the diffractogram varies from sample to sample due to, for example, crystalline impurities, so the peak intensity is not necessarily limited to the PXRD pattern. Further, the angle of each peak may vary by about +/− 0.1 degrees, preferably +/− 0.05 degrees. Also, the entire pattern or most of the pattern peak may be shifted by about +/− 0.1 degrees due to calibration, settings, and differences between devices and workers. The above limitation results in a 2θ PXRD error of +/− 0.2 ° at each diffraction peak.

Differential Operating Calorimetry (DSC) Procedure An aliquot of the sample was loaded onto an aluminum sample pan (eg, Pan part # 900786.091; lid part # 900779.901; Germany 19720, Newcastle, 109 Luckens Drive 109 TA Instruments) ). Sample pans were sealed either by crimping for dry samples or by press fitting for wet samples (eg, hydrate or solvate samples). The sample pan was placed on the instrument (DSC: Q1000 Differential Scanning Calorimeter, Germany 19720, Newcastle, 109 Instruments, TA Instruments, 109 Instruments), and the instrument was equipped with an autosampler and its temperature Record charts by individually heating the sample from T _min (about 20 ° C.) to T _max (about 300 ° C.) at a rate of 10 ° C./min using an empty aluminum pan as a reference (eg, Control software: Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0, copyright 2001 TA instruments-Water LLC) (heating rate and time range may be changed, change of these parameters For each sample). Dry nitrogen (eg, compressed nitrogen, grade 4.8, NJ, 07974-2082, Murray Hill, Mountain Avenue 575 BOC gas) was used as the sample purge gas and set at a flow rate of 50 ml / min. Analysis software (analysis software: Universal Analysis 2000 for Windows (registered trademark) 95/95/2000 / NT, version 3.1E; Build 3.1.0.40, copyright 1991-2001TA instruments-) Water LLC) was used for observation and diffraction.

Thermogravimetric Analysis (TGA) Procedure An aliquot of the sample was transferred to an aluminum pan (Pan part &num;952019.906; TA Instruments, 109 Luckens Drive, Newcastle, Delaware 19720). Place the pan on the loading platform and then use the control software (Control Software: Advantage for QWSeries, version 1.0. 0.78, Thermal Advantage Release 2.0, 0 2001 TA instruments-Water LLC) to install the instrument (TGA: Q500 Thermal Automatically loaded with gravimetric analyzer, TA Instruments, 109 Luckens Drive, Newcastle, Delaware 19720). Self-recording temperature chart with sample purge flow rate 60ml / min, balance purge flow rate 40ml / min under dry nitrogen flow (eg compressed nitrogen, grade 4.8, NJ, 07974-2082, Murray Hill, Mountain Avenue 575 BOC gas) Obtained by individually heating the sample from 25 ° C. to 300 ° C. at 10 ° C./min (heating rate and time range may be varied, and changes in these parameters are indicated for each sample). Change in temperature (for example, change in weight) is analyzed using analysis software (analysis software: Universal Analysis 2000 for Windows (registered trademark) 95/95/2000 / NT, version 3.1E; Build 3.1.0.40, work) (Right 1991-2001 TA instruments-Water LLC).

Example 1
Celecoxib sodium salt from aqueous solution 1.0 mL of distilled water was added to 77.3 mg of commercially available celecoxib, followed by 0.220 mL of 1M NaOH (VWR). The mixture was heated to 60 ° C. with stirring, whereupon 1.0 mL of distilled water was added. Solid NaOH (22 mg) was added to dissolve the solid NaOH and celecoxib. The mixture was heated again to 60 ° C. to evaporate the water. The mixture was agitated and heated at 60 ° C. with a stream of air while simultaneously adding approximately 15 mL of reagent grade ethanol. Heating was continued until the solution was dry. The obtained substance was analyzed by a differential scanning calorimeter (DSC), thermogravimetric analysis (TGA), and powder X-ray diffraction apparatus (PXRD). The results are shown in FIGS. Most of the water was contained in NaOH co-precipitated with the salt, but the product was found to contain about 4.1 equivalents of water per equivalent of salt.

  For DSC analysis, the purge gas used was dry nitrogen, the reference material was a crimped empty aluminum pan, and the sample purge was 50 mL / min. DSC analysis of the sample was performed by placing 2.594 mg of sample in a closed aluminum crimp pan. At a heating rate of 10 ° C / min, 20 ° C was set as the starting temperature, and the ending temperature was set at 200 ° C. The reproducibility of the obtained DSC analysis is shown in FIG. The observed changes are between about 40 to about 70 ° C. dissolution / dehydration step, other transitions that may have resulted from recrystallization / precipitation events between about 70 ° C. to about 100 ° C. and about 100 ° C. And a second dissolution / dehydration change between about 110 ° C.

  The TGA sample was a 2.460 mg sample placed on a platinum dish. At a heating rate of 10 ° C./min, 20 ° C. was set as the start temperature, and the end temperature was set at 300 ° C. A copy of the resulting TGA analysis is shown in FIG. TGA exhibits a mass loss of about 12.5% between about 30 and about 50 ° C., due to a loss of about 2.8 water. A second mass loss of about 2.5% between about 71 and 85 ° C. is due to a loss of about 0.5 water. Finally, a mass loss of about 4.0% between about 148 and 170 ° C. is due to a loss of about 1 water or some degradation of the drug compound. The state of the salt hydrate may vary depending on moisture, temperature and other conditions, as described in Examples 24, 25 and 30.

  A copy of the PXRD pattern of the compound produced above is shown in FIG. In the diffractogram of FIG. 3, the background is removed. The PXRD pattern may be, for example, any one or any two, any three, any four, or any of the peaks at the 2θ angle of FIG. 3 including peaks at 2.87, 6.36, 7.01, 16.72, and 20.83 °. It has a characteristic peak that can be used to characterize a salt, including any combination of any five peaks, or any other combination.

Example 2
Celecoxib sodium salt from 2-propanol solution To 126.3 mg of celecoxib was added a 1.0 mL aliquot of isopropanol and the mixture was heated to dissolve the celecoxib. Sodium ethoxide was added as a solution in ethanol (21%) (0.124 mL solution, 3.31 × 104 mol sodium ethoxide). Furthermore, 1.0 mL of isopropanol was added. The mixture was stirred to obtain a white crystalline solid slurry that appeared as fine birefringent needle crystals by a polarizing microscope.

  The slurry was filtered by suction filtration and washed with 2 mL isopropanol. The solid was air dried before being lightly crushed to a powder. The product was analyzed by PXRD, DSC and TGA as in Example 1, but in the PXRD experiment a 0.5 mm capillary was used to hold the sample. The compound lost 17.37% weight between room temperature and 120 ° C. (see FIG. 101). The DSC thermogram shows a wide endothermic range, which is consistent with the loss of volatile components with increasing temperature (see Figure 102). The endotherm peaked at 66 ° C. The PXRD pattern peaks used to characterize the salt are 4.09, 4.99, 6.51, 7.07, 9.99, 11.59, 16.53, 17.69, 18.47, 19.13, 20.11, 20.95, 22.67. 1 or any 2, 2, 3, 4, 5, 6, 7, 8, 9, 9, 10, 11, 12 of the 2θ angle of °. Or all 13 combinations, or any one or combination of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 peaks in FIG.

Example 3
Celecoxib sodium salt from aqueous solution Synthesis 1: Celecoxib 29.64 mg and 1M sodium hydroxide 3.00 mL were added to a vial. Celecoxib dissolved immediately. After some time, celecoxib sodium salt precipitated from the solution.

  Synthesis 2: Celecoxib 7.10 mg and 1M sodium hydroxide 3.00 mL were added to the vial. Celecoxib dissolved. Overnight, celecoxib sodium salt precipitated and formed white needles.

  Synthesis 3: Celecoxib 17.6 mg and 1M sodium hydroxide 10 mL were added to the vial. Celecoxib dissolved. The vial was placed in a beaker covered with aluminum foil and filled with a large thin fabric for thermal insulation. When the beaker was allowed to stand, celecoxib sodium salt crystals formed within about 12-36 hours.

  Analysis: The resulting solids from synthesis 1 and 2 were combined and analyzed by PXRD, DSC and TGA as in FIG. 1, but in the PXRD experiment a 0.5 mm capillary was used to hold the sample. As noted herein, the hydrated state of the salt may vary with humidity, temperature and other conditions, but the salt produced was found to contain about 4 equivalents of water in 1 equivalent of salt. . The TGA showed a weight loss of 14.9% at 10 ° C / min with a 100 ° C increase from room temperature. DSC analysis showed a large endothermic change at 74 +/- 1.0 °, and a wide noisy second endothermic change at about 130 +/- 5.0 °. The PXRD pattern includes a combination of peaks of any 1 or any of 2, 3.6, 8.9, 9.6, 10.8, 11.4 and 20.0 °, any 3, any 4, any 5, 5 or 6 2θ angles. Has a peak that can be used to characterize.

Example 4
Pharmacokinetic studies in rats The sodium salt form (from Example 6) was compared with CELEBREX powder for absorption in rats (FIGS. 4A and 4B).
A pharmacokinetic study after oral administration of 5 mg / kg orally to male Sprague-Dawley rats with a crystalline form of celecoxib used in the commercial formulation and sodium salt form is shown in FIGS. 4A and 4B. The solid was filled into size 9 gelatin capsules (Torpac) and administered through a gavage needle, followed by oral gavage with 1 mL of water. CELEBREX granules were transferred from a commercially available 200 mg capsule. The sodium salt was mixed with polyvinylpyrrolidone (eg povidone K30) (weight ratio of celecoxib sodium salt 4: 1). From the plasma of 5 rats, the mean plasma concentration at each time point was plotted.
The pharmacokinetics of celecoxib sodium salt at a 5 mg / kg dose indicate earlier peak levels of drug in plasma. From an early time point, celecoxib levels in the sodium salt plasma have been shown to be higher than for CELEBREX (see FIG. 4A).

Example 5
Solubility of celecoxib sodium salt in the presence of polyvinylpyrrolidone Water was added to a 1: 4 mixture of celecoxib sodium salt and polyvinylpyrrolidone (PVP) to give a clear solution. The solution was stable for at least 15 minutes before neutral celecoxib crystals began to form.
Crystalline neutral celecoxib did not dissolve when added to aqueous polyvinylpyrrolidone or when water was added to the dry mixture of neutral crystalline celecoxib and polyvinylpyrrolidone.

Example 6
Preparation of Celecoxib Sodium Salt Celecoxib free acid (5.027 g, 13.16 mmol) was suspended in an aqueous solution of 1M NaOH (13.18 mL, 13.18 mmol). The suspension was gently heated at 60 ° C. for 1 minute to dissolve the residual solids. The mixture was cooled to room temperature but no solid was produced. Further, cooling with an ice bath for 1 hour gave product crystals. The resulting suspension was filtered and air dried.

  Product characteristics were measured by TGA, DSC, PXRD and Raman spectroscopy. TGA exhibits a weight loss of 6.67 wt% from 25 ° C to 105 ° C. This weight loss indicates some hydration or residual water. DSC shows a large endotherm centered at 100 °. The PXRD pattern has a peak characteristic as shown in FIG. 13A. Intensity peaks are found at 19.85 and other peaks at 2θ angles including, but not limited to, 3.57, 10.69, 13.69, 20.43, 21.53 and 22.39. The crystal is characterized by any one, any two, any three, any four, any five or all six of the above peaks, or any of the 2θ angles in FIG. 13A Any one or a combination of values can be characterized.

Raman spectroscopy is shown in FIG. 13B. The Raman shift (cm ⁻¹ ) peak is not limited to any one of 1617, 1446, 1374, 975 and 800 cm ⁻¹ , any two, any three, any four, all five Or it occurs at a location that includes any combination of 2, 3, 4, 5 or more peaks in FIG. 13B.

Example 7
Administration of celecoxib composition to dogs The celecoxib salt of Example 6 was administered to dogs and compared to the administration of commercially available celecoxib. Six male beagle dogs 2-4 years old, weighing 8-12 kg, were fasted overnight and given water. Each dog received 3 test doses as indicated below. There was a one week washout period between doses. The test doses were (1) commercially available celecoxib mixed with 1 milligram per kilogram (mpk) of CELEBREX and 70:30 PEG400: water (intravenous administration), and (2) body weight of each dog. Oral dose of commercially available celecoxib in the form of CELEBREX adjusted to 5 mpk in 4 gelatin capsules and (3) the invention produced in Example 6 adjusted to 5 mpk in size 4 gelatin capsules at the weight of each dog The sodium salt was orally administered. Details regarding intravenous and oral dosage formulations can be seen in FIG. 5A. Approximately 2 ml blood samples containing sodium heparin were obtained by cervical venipuncture at 0.25, 0.5, 1, 3, 4, 6, 8, 12 and 24 hours after administration. In addition, samples were obtained before administration and at 0.08 hours for intravenous administration studies. Blood samples were immediately placed on ice and centrifuged within 30 minutes of collection. Plasma samples (˜1.0 ml) were collected and stored in 4 aliquots of 0.25 ml at −20 ° C. Plasma samples were analyzed for celecoxib using a low quantitation limit LC-MS / MS assay of 5 ng / ml. The pharmacokinetic profile of celecoxib in plasma was analyzed using the PhAST software program (version 2.3, Pheonix Life Sciences, Inc.). Absolute bioavailability (F) is reported as an oral dose relative to an intravenous dose.

  FIG. 5B shows the average pharmacokinetic parameters (and their standard deviation) of celecoxib in plasma in male dogs that received a single oral or single intravenous dose of celecoxib or celecoxib sodium salt. The maximum serum concentration and bioavailability of celecoxib sodium administered orally is about 3 and 2 times greater than the approximately equal dose of celecoxib administered orally, respectively, and the maximum serum concentration of celecoxib sodium is greater than that of celecoxib Reached 40% faster. FIG. 6 shows the solubility of celecoxib in plasma in male dogs that received a single oral or single intravenous dose of celecoxib or celecoxib sodium salt.

  All new combinations of form and formulation performed much better than the commercial product, Celebrex. The resulting support data is shown in FIG. 5B and summarized below. (1) The formulation was fully bioavailable, compared to only 40% bioavailable with Celebrex. (2) As shown in FIG. 5C, the preparation showed linear pharmacokinetics with respect to the dose, unlike the case of Celebrex. (3) The half dose of the formulation (ie 2.5 mg / kg) showed an average celecoxib plasma concentration 5 times greater than the total dose of celeblex (5 mg / kg) in the first 15 minutes after administration . The latest observations are shown in FIG. 5B and show an improved therapeutic onset rate with the formulations of the present invention.

  FIG. 5B shows the average pharmacokinetic parameters of celecoxib after administration of intravenous and oral doses. The parameter definition is as follows. (a) Cmax: peak concentration; observed value, (b) Tmax: time to reach Cmax; observed value, (c) AUC (I): area endurance curve under plasma concentration (from 0 hour to infinity), (d) t: terminal half-life, (e) F: relative oral bioavailability, and (f) plasma clearance of absorption. The number of beagle dogs used per formulation is defined by the superscript next to the formulation name, (i) a is n = 6, (ii) b is n = 3 and (iii) c is n = 2 is shown.

Example 8
Production method of celecoxib lithium salt: MO-116-49B
To celecoxib (101.4 mg, 0.2656 mmol) was added an aqueous solution of LiOH (0.35 M, 1.05 ml, 0.37 mmol). The mixture was heated gently with occasional rotation until the solid dissolved. Water was evaporated by blowing a stream of nitrogen to give a white crystalline solid. Raman spectroscopy (FIG. 16) and PXRD (FIG. 17) indicated the presence of celecoxib lithium salt. In addition, the drug can be purified by recrystallization to remove excess base.

  The DSC thermogram results (FIG. 14) showed an endotherm at 111.84 ° C. and a second endotherm at 237.11 ° C. TGA results (Figure 15) showed a 14% weight loss between about 25 ° C and about 190 ° C. Raman spectroscopy results show multiple spectral peaks that can be used to characterize the salt. These are the peaks in FIG. 16, for example, any one of 1617, 1597, 1450, 1374, 1115, 1063, 976, 801, 741 and 634, any 2, any 3, any 4, any Including 5, any 6, any 7, any 8, any 9, any 10, or any other combination. The PXRD pattern has a characteristic peak as shown in FIG. The PXRD peak that can be used to characterize the salt is the peak of FIG. 17, eg any one or any of 4.14, 9.04, 10.705, 12.47, 15.08, 15.75, 18.71, 19.64, 20.52, 21.55 and 23.00. 2, any 3, any 4, any 5, any 6, any 7, any 8, any 9, any 10, any 11, or any combination. A 0.8 mm collimator was used during diffractogram acquisition.

Example 9
Production Method of Celecoxib Potassium Salt (MO-116-49A) An aqueous solution of KOH (0.35 M, 1.15 ml, 0.40 mmol) was added to celecoxib (100.7 mg, 0.2637 mmol). The mixture was gently heated while dissolving with occasional rotation until the solid dissolved. Thereafter, water was evaporated while blowing nitrogen to obtain a white crystalline solid. The resulting mixture was characterized by DSC (Figure 18), TGA (Figure 19), Raman spectroscopy (Figure 20) and PXRD (Figure 21) to confirm the presence of celecoxib potassium salt. In addition, the drug can be purified by recrystallization to remove excess base.

The results of DSC analysis are shown in the graph of FIG. It indicates that the mixture has an endotherm at 87.4 ° C. The result of TGA is shown in FIG. It showed a weight loss of 5.8% by weight between 25 and 200 ° C. The shoulder in the data is seen at 80 ° C. The Raman spectrum is shown in FIG. A position including, but not limited to, any one of 1618, 1448, 1374, 976 and 801 cm ⁻¹ , or any 2, any 3, 3 or any combination thereof, or two or three of FIG. The characteristic Raman shift (cm ⁻¹ ) peak containing a combination of 4, 5 or more peaks. The PXRD pattern has a characteristic peak as shown in FIG. The peaks can be viewed at 2θ angles including but not limited to 4.03, 9.11, 12.23, 15.35, 18.87, 19.79, 20.97 and 22.81 °. The crystal is any one or any one of the above angles, any two, any three, any four, any five, any six, any seven, all eight, or the 2θ angle of FIG. Can be characterized by a combination of numbers. A 0.8 mm collimator was used during diffractogram acquisition.

Example 10
Method for Producing Celecoxib Potassium Salt (MO-116-55D) A suspension of celecoxib (100.2 mg, 0.2627 mmol) (in toluene (2.2 mL) and methanol (0.1 mL)) was gently warmed to obtain a solution. To the solution was added 3M KOH (0.090 ml, 0.027 mmol) aqueous solution. After layer separation was obtained, the aqueous phase was removed and dried by blowing nitrogen. The resulting crystalline solid was characterized by TGA (FIG. 22), Raman spectroscopy (FIG. 23) and PXRD (FIG. 24).

The TGA sample was heated to 90 ° C. at 10 ° C./min, held for 10 minutes, heated to 300 ° C. at 10 ° C./min, and held for 10 minutes with nitrogen purge gas 40 ml / min. The result is shown in FIG. The weight loss was about 4.9 wt% between 25 and 200 ° C, and about 2.9 wt% on the shoulder between 70 and 200 ° C. This weight loss indicates some level of solvation or residual solvent. A solid Raman spectrum is shown in FIG. Without limitation, any one or any one of 1616, 1446, 1374, 1233, 1197, 1109, 1061, 973, 799, 740 or 633, any 3, any 4, any 5, any 6, any 7, any 8, any 9, any 10 or all combinations of 11, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 in FIG. , A characteristic Raman shift (cm ⁻¹ ) peak at a position containing a combination of 14 or more peaks. The PXRD pattern is shown in FIG. 3. Characteristic peaks at 2θ of 93, 10.83, 12.11, 15.07, 17.79, 18.57, 19.95, 24.77 and 26.97 ° are shown. Any 1, any 2, any 3, any 4, any 5, any 6, any 7, any 8, any 9 or more, or those listed in FIG. 24, celecoxib potassium Can be used for salt characterization.

Example 11
Method for producing celecoxib calcium salt (MO-116-62A) To celecoxib (100 mg, 0.262 mmol) was added a solution of 1 M NaOH (in methanol (0.29 mL, 0.29 mmol)). The mixture was heated gently with occasional rotation until all solids were dissolved, resulting in a colorless solution. To the solution was added a 3MCaCl ₂ (0.131 mL, 0.393 mmol) solution in methanol. The precipitate was filtered and the powder was dried overnight by blowing nitrogen.
Analysis was carried out. The product mixture was characterized by TGA (FIG. 25), Raman spectroscopy (FIG. 26) and PXRD (FIG. 27), which showed the presence of celecoxib Ca circles and NaCl.

TGA results (Figure 25) showed a total weight loss of about 4.2% between 25 and 200 ° C. In the Raman data spectrum, the characteristic Raman shift (cm ⁻¹ ) peak is not limited, but any one of 1617, 1598, 1450, 1377, 973, 801, 642, any 2, any 3, any 4, any 5, and any 6 or all 7 combinations, or positions containing 2, 3, 4, 5, 6, 7 or more peak combinations in FIG. The PXRD pattern shows 2θ angles at 3.91, 7.82, 9.27, 11.66, 20.56 and 23.08 °. 2θ at 27.35 and 31.67 ° is due to NaCl.

Example 12
Comparative analysis of neutral celecoxib For the purpose of some analysis of the data obtained, commercially available celecoxib was subjected to the same analytical techniques as powder X-ray diffraction (PXRD) and Raman spectroscopy. The results were used as a comparison to the salts of the present invention.

Comparison data: Celecoxib (PXRD)
A small amount of the collected sample was filled into a 0.3 mm glass PXRD tube. Place tube on Rigaku D / Max RAPId PXRD, Cu; 46kV / 40mA, squeeze 0.5mm, Omega axis vibration; Pos (°) 0-5, speed 1, phi axis rotation, Pos 360, speed 2, collection The time was set at 15 minutes. The result is shown in FIG.
Some of the free acid peaks are observed in the compositions of the present invention. As a further method of characterizing the composition of the present invention, the free acid peak feature can be specifically excluded from the composition of the present invention, as shown in FIG.

Comparison data: Celecoxib (Raman)
A small amount of the collected sample was placed on a slide glass and mounted on a Thermo Nicolet Almega Dispersive Raman spectrometer. Sample capture was set for 6 background scans and 12 sample collection scans. The result is shown in FIG.
An important feature in the Raman spectrum of celecoxib free acid is a peak around 906 cm ⁻¹ . This peak is not seen in the Raman spectra of the sodium, potassium, lithium and calcium salts of the present invention.

Example 13
Solid State Formulation of Rececoxib Sodium Salt Hydrate Selected PLURONIC excipient based solid formulation combining hydroxypropylcellulose (HPC) and crystalline celecoxib sodium salt hydrate, conventional mortar and pestle technology And showed increased solubility of celecoxib salt in simulated gastric fluid.
This example shows that solid formulations increase solubility and celecoxib salts inhibit precipitation compared to neutral free acid compounds of celecoxib. The method used to identify and test the preferred excipients in these examples consists of two parts. (1) “Precipitation delay analysis” is used to identify excipients that supersaturate celecoxib in solution, and (2) in vitro dissolution tests are selected to change the “precipitation delay analysis” results. For the excipients.

Example 14
Precipitation Inhibition Analysis Precipitation Inhibition Analysis—Method 58 excipients in Table 2 were prepared in simulated gastric fluid (SGF) containing 200 mM hydrochloric acid at a concentration of 1.8 mg / ml (0.18 wt%), and the same was added to a 96-well plate with a volume of 150 μl. Distributed. SGF lacking excipients was used as a negative control. The composition of SGF was 2 g / L sodium chloride, 1 g / L Triton X-100 and 200 mM hydrochloric acid in deionized water.

2. The 96-well plate was sealed and incubated for 20 minutes at a temperature of 40 ° C. After incubation, the plate seal was removed.

3. Celecoxib at a concentration of 5.5 mg / ml pre-dissolved in potassium hydroxide was dispensed into each well in 15 μl aliquots and mixed immediately. This gave a final celecoxib concentration of 0.5 mg / ml to each well. The final excipient concentration was 1.8 mg / ml. The assay plate was sealed using an optically clear seal.

4). Nephelometer (Neplelostar Galaxy, BMG Technologies, Durham, NC) equipped with a sambar preheated to 37 ° C to analyze the ability of excipients to suppress crystallization and precipitation of supersaturated celecoxib with a scattered light instrument Used for.

Precipitation inhibition analysis-results:
FIG. 30 shows the precipitation inhibition time of celecoxib as a function of the excipient in simulated gastric fluid (SGF). The final concentration of celecoxib was 0.5 mg / ml. Black bars indicate precipitation inhibition time over 60 minutes. The excipients listed in Table 8 were excluded from FIG. 30, but did not show any measurable precipitation inhibition time (ie, greater than 1.5 minutes). Of the 58 excipients, 19 were found to inhibit celecoxib recrystallization / precipitation.

  The presence of six PLURONIC (poloxamer) excipients among successful precipitation inhibitors prompted further study of these compounds. PLURONIC is an ethylene oxide-propylene oxide block copolymer whose properties can be significantly altered by adjusting the ratio of copolymer blocks (eg, melting point, cloud point, molecular weight, HLB number, critical micelle concentration, surface tension) , Interfacial tension, etc.). Further testing for these properties showed that the surface tension of these copolymers at a concentration of 0.1% in water correlates with their ability to suppress celecoxib crystallization / precipitation. PLURONIC excipients with low interfacial tension (ie less than about 10 dyne / cm) or surface tension less than about 42 dyne / cm retain celecoxib in solution than PLURONIC excipients with higher surface or interfacial tension It was more effective. This observation is shown in FIG. 31A, along with PLURONIC interface data that was not tested.

  FIG. 31A shows the interfacial tension values of selected PLURONIC excipients in water. PLURONIC excipients with low interfacial tension correlate with excipients that inhibit celecoxib crystallization / precipitation in simulated gastric fluid. The threshold for interfacial tension for precipitation inhibition was broadly defined as less than about 9 or 10 dyne / cm. The excipient concentration in the analysis was 0.18% and the celecoxib concentration was 0.5 mg / ml. Interface data was obtained by BASF at a concentration of 0.1% in water to mineral oil at 25 ° C. (PLURONIC is a trademark of BASF). It is important to emphasize that PLURONIC was used at a concentration of 1.8 mg / mL in this analysis. It is suggested that higher interface and surface tension thresholds may correlate with the ability to prevent celecoxib precipitation when PLURONIC is used at higher concentrations. The precipitation inhibition data obtained using PLURONIC excipient is also correlated with critical micelle concentration (CMC) as a function of temperature. In this analysis, the dependence of the CMC value as a function of propylene oxide content (ie, PPO units) at both 25 ° C. and 37 ° C. is shown in FIG. 31B. Here, the PLURONIC excipient concentration values used in this screen cover a comparative example. As shown in FIG. 31, because the inhibitor was used at a higher concentration than CMC, the effectiveness of the inhibitor at 37 ° C. has a propylene oxide content greater than 40 PPO. At 25 ° C., the concentration of PLURONIC compound used decreased below the CMC value at this temperature, so the value of effective inhibitor was reduced. Thus, a concentration of PLURONIC excipient greater than CMC is preferred to prevent immediate precipitation of celecoxib. Reported CMC data was obtained from V. M. Nace, in Nonionic Surfactants (V. M. Nace, Ed.), Marcel Dekker, New York, 1996, pp78-80.

Example 15
In vitro dissolution studies of PLURONIC excipients
In vitro dissolution studies of PLURONIC excipients-Method 1. Preparation of celecoxib
a. Fresh celecoxib sodium hydrate was prepared and analyzed as about 90% free acid relative to sodium content.
b. Celecoxib salt was ground using a mortar and pestle until a fine powder was formed. The fine powder was sieved using a 105 μm pore size sieve and stored at room temperature in a 20 ml scintillation vial.

2. Formulation manufacture
a. Fresh PLURONIC excipients were formulated in a mortar. First, if the solid was at room temperature, PLURONIC was ground until a slick powder was formed.
b. If hydroxypropylcellulose (HPC) is added, blend after PLURONIC excipient. HPC is mixed with PLURONIC and the two are ground together using a pestle and mixed with a spatula for 1 minute.
c. Add 105 μm sieved celecoxib salt to the mortar, grind the mixture and mix for a few minutes.
d. If necessary, a liquid excipient such as poloxamer 124, PEG 200 or PEG 400 is added to the mortar as a granulating liquid-like liquid to form complete contact between the drug and excipient. To do. The mixture is ground and mixed until a uniform density is observed in the solid mixture.

3. Solubility analysis
a. The water bath was set to 37 ° C.
b. Fasted simulated gastric fluid (SGF) was adjusted to pH 1.7 and diluted 5-fold with deionized water. The final pH was about 2.4. Simulated gastric juice was diluted 5 times to mimic the effect of taking the drug with a glass of water. SGF was preheated to 37 ° C.
c. The formulation was placed in a 20 ml scintillation vial.
d. A 10 mm × 3 mm stir bar was added.
e. Diluted SGF was added to the formulation. The volume added was set to meet the 2 mg / ml dose of free acid of celecoxib.
f. The vial was placed in a water bath and stirred.
g. At each time point, 0.9 ml of solution was extracted and filtered through a 0.2 μm polyvinyl phlorizin filter. The first 2/3 of the filtrate was discarded as waste and the last 1/3 was collected in an Eppendorf tube. 0.1 ml of the collected filtrate was immediately transferred to an autosampler vial and diluted 10-fold with 0.9 ml of methanol. The autosampler vial was caulked and sealed, and subjected to content analysis using high performance liquid chromatography with UV detection.

In vitro solubility studies of PLURONIC excipients-Results 1. Solubility of two PLURONIC excipients with low interfacial tension: PLURONIC P123 and F127. PLURONIC P123 was a paste at room temperature, resulting in a viscous formulation of celecoxib salt. PLURONIC F127 was a solid at room temperature and formed a flowable powdered solid mixture with celecoxib salt. The solubility results of these mixtures at equal weight concentrations of excipients against celecoxib free acid content are shown in FIG. 32 (the weight ratio of the dissolution test is based on the molar mass of celecoxib free acid). PLURONIC P123 improved the solubility of celecoxib salt, whereas PLURONIC F127 did not. The insufficient ability of PLURONIC F127 in improving celecoxib solubility is due to slow dissolution of excipients. In contrast, PLURONIC P123 binds completely with the celecoxib salt within the “sticky” wax mass, thereby slowing the dissolution of celecoxib. This allowed the excipients to dissolve to a considerable extent prior to sufficient dissolution of the celecoxib salt form.

2. Celecoxib sodium hydrate dissolution was performed in the presence of HPC using PLURONIC P123, PLURONIC F127 and PLURONIC F87. PLURONIC F87 has a high interfacial tension value. For the celecoxib free acid content, PLURONIC and HPC were used in the formulation at equal weight concentrations. The PLURONIC P123 formulation is viscous due to the pasty properties of the excipients. The PLURONIC F127 and F87 formulations were flowable because these excipients were solid at room temperature. The dissolution data for these formulations is shown in FIG. The data showed that the addition of HPC in the PLURONIC P123 formulation resulted in a broadening of the dissolution profile. In the PLURONIC F127 formulation, HPC increased the initial dissolved component of the profile (ie, <10 minutes). In contrast, no dissolution profile was observed with the PLURONIC F87 formulation. Since PLURONIC 87 has a high interfacial tension (17.4 dyne / cm), the data obtained support the correlation between interfacial tension and precipitation inhibitors. PLURONIC P123 formulation (ie, viscous) showed that the dissolution profile was significantly improved over PLURONIC F127 formulation (ie, loose powder) with respect to time to recrystallization / precipitation. It was hypothesized that the addition of excipients that physically bind the components of the F 127 formulation resulted in further dissolution enhancement.

3. Celecoxib sodium hydrate using PLURONIC F127 and HPC was dissolved to be combined with the solid mixture using granule fluid-like liquid. Three granule fluid-like liquids, PEG 200, PEG 400, and poloxamer 124 were selected. Celecoxib free acid content, PLURONIC F127 and HPC were formulated in equal weight ratios at 40-45% of the celecoxib free acid weight of the granule fluid. The effect of these formulations on dissolution is shown in FIG. The granule fluid-like liquid increased the dissolution of celecoxib, possibly by delaying contact between the celecoxib salt and the dissolution medium until PLURONIC F127 was dissolved to a significant extent.

  The dissolution of celecoxib sodium hydrate was then measured with a molded formulation containing PLURONIC F127 and HPC excipients. Formulations containing equal weight ratios of celecoxib free acid content, PLURONIC F127 and HPC were mixed and molded into 6 mm discs at 4900 psi. In the dissolution results, as shown in FIG. 35A, it was shown that suppression started in about 15 to 20 minutes and dissolution was enhanced. The molding method produced a similar dissolution effect and additional delayed release mechanism as observed by the addition of granule fluid (see FIG. 34). The delayed release characteristics of the profile can be adjusted by selecting HPC or HPMC that changes the degree of viscosity and adding a disintegrant to the shaped body. Molded articles are attractive formulations due to their relatively low production costs and fewer manufacturing processes. FIG. 31B shows the concentration of PLURONIC excipients as a function of polypropylene oxide (PPO) units. This figure shows that a PLURONIC concentration higher than CMC is preferred to effectively inhibit precipitation.

  The data obtained so far assumes that both initial solubilization and precipitation inhibition were necessary to increase the solubility of celecoxib. To confirm this assumption, the free acid celecoxib was tested with selected precipitation inhibiting excipients, Pluronic F127 and HPC. As shown in FIG. 35B, the solubility of celecoxib showed no supersaturated component. A small but measurable increase in solubility relative to the commercial formulation (ie Celebrex) indicates an increase in the thermodynamic solubility of celecoxib free in the excipient solution. These data highlight the importance of the new form acting as a “spring” and provide a good driving force to cause oversaturation. For precipitation inhibition screening, the driving force is celecoxib free acid pre-dissolved in 1M potassium hydroxide.

  FIG. 35B shows that the dose of celecoxib free acid in the dissolution medium was 2 mg / ml. The parachute component includes surfactant, Pluronic F127 and enhancer, 100,000 MW hydroxypropylcellulose (HPC) in equal mass ratios of celecoxib free acid. “Spring” refers to celecoxib free acid dissolved in either 2: 1 PEG400: DI water or Transcutol P. “No spring” is the net resecoxib free acid. DI was deionized, Transcutol P was diethylene glycol monoether, and dissolution was performed at 37 ° C.

  To test whether the “parachute” concept (ie surfactant or surfactant + enhancer) enhances the dissolution of these springs, we decided to formulate various species with Pluronic F127 and HPC did. The solubility data obtained with these “springs” strongly suggests that “parachute” (surfactant or surfactant + enhancing agent) is required for any appropriate dissolution, as in FIG. 35B. Show. Addition of “parachutes” such as Pluronic F127 and HPC makes dissolution effective.

  In order to generally deal with the notion that “parachute” functions independently of the “spring” type, dissolution was performed by selecting celecoxib “spring”. In these experiments, it is speculated that the selected “spring” was “sufficiently strong” to promote the compound of interest into solution. Once in solution, the “spring” component is theoretically exhausted and the “parachute” component plays an active role in inhibiting precipitation. The following celecoxib "spring" was compared. (i) free acid, (ii) sodium hydroxide, (iii) sodium propylene glycol solvate, (iv) n-methylpyrrolidone (NMP) solvate and (v) celecoxib: nicotinamide co-crystal. The parachute used in this comparison was a combination of surfactant and enhancer, Pluronic F127 and HPC at the same celecoxib free acid mass concentration. A granulating agent such as Pluronic L44 or PEG400 was added to some samples in order to measure its effect on the dissolution profile. The results shown in FIG. 35C confirm that “parachute” maintained the supersaturation level of celecoxib when “spring” was used. Free acid samples showed springs at zero strength and showed concentration levels below those obtained with the other springs.

  FIG. 35C shows a spring with enhanced celecoxib dissolution in the presence of parachute. The dose of celecoxib free acid in the dissolution medium was 2 mg / ml. The implied parachute in all samples was a combination of surfactant and enhancer, Pluronic F127 and 100,000 MW HPC in the same amount of celecoxib free acid by weight. PG is propylene glycol, NMP is n-methylpyrrolidone, and PEG400 is propylene glycol having an average molecular weight of 400 Da. Dissolution was performed at 37 ° C.

Example 16
General Methods for Precipitation Inhibition Analysis The method described above inhibits nucleation from solutions where solid active pharmaceutical ingredients, their derivatives and other non-pharmaceutical compositions of interest in the market are supersaturated with active pharmaceutical ingredients. It is a specific example of the general method of the present invention aimed at identifying the excipients to be used. The method is outlined in FIG. 36 and detailed below.

1. Excipients are dissolved in deionized (DI) water or other media (ie, simulated gastric fluid or intestinal fluid) at the desired concentration.
2. The active pharmaceutical ingredient is dissolved in a suitable solvent that exhibits high solubility (ie, an acidic pH environment for the free base type active pharmaceutical ingredient and a basic pH environment for the free acid type active pharmaceutical ingredient).

3. Excipient solutions are dispensed into assay plates (ie 96 or 384 well optically clear plates) using manual or automated liquid handling equipment. Excipients may be added to each well alone, as a binary, ternary or higher order excipient combination. An example of a liquid processing apparatus is Tecan Gnesis (Tecan US Inc, Research Triangle Park, NC).
4). Distribute the solution of the active pharmaceutical ingredient to the assay plate. The solution of the active pharmaceutical ingredient may be dispensed into all wells at one time using a Tecan Genesis device, one well, column by row, or simultaneously using a Tecan Genesis device. The volume of the active pharmaceutical ingredient solution added is limited to a small amount to prevent any variation in the properties of the excipient solution.

5. The solution is mixed with an excipient solution such that the active pharmaceutical ingredient is uniformly dispersed. The plate is sealed and incubated at the desired temperature.
6). The onset of solid nucleation is measured using a device capable of measuring scattered light. Examples of devices capable of measuring scattered light include the NepheloStar nephelometer (BMG Technologies, Durham, NC) and the SPECTRAmax PLUS plate reader (Molecular Devices Corp, Sunnyvale, CA). The temperature is maintained by the incubation mechanism of the device at a constant predefined set temperature.
7). Birefringence screening, PXRD, etc. may be performed to measure when the precipitated active pharmaceutical ingredient is amorphous or crystalline. If the active pharmaceutical ingredient is crystalline, crystal habit and particle size may be recorded.

8). Data is analyzed and excipients are ranked by their respective inhibition times.
9. Information science may be used to elucidate the correlation between physical properties and excipients that have successfully suppressed nucleation.

Example 17
Explanation of the resulting precipitation inhibition data:
Target: Identify excipients that inhibit solid nucleation of Compound A in liquid F at a temperature of 37 ° C.

Method:
1.24 excipient solution was prepared with deionized water to a concentration of 16 mg / ml.
2. Liquid F was prepared with deionized water by mixing the ingredients twice to achieve the desired final concentration.
3. A solution of the active pharmaceutical ingredient was prepared in liquid C at a concentration of 5.5 mg / ml.
4). Using a Tecan Genesis apparatus, dispense 75 μl of liquid F, 18.75 μl of excipient solution and 56.25 μl of deionized water to each well of a 96-well plate. The final excipient concentration in each well was 2 mg / ml in liquid F. The total liquid volume per well was 150 μl. Four duplicate measurement wells were used for each single excipient solution. The arrangement is illustrated in FIG.

5. The plate was sealed using a clear seal and incubated for 20 minutes at 40 ° C.
6). The seal was removed and 15 μl of active pharmaceutical ingredient was dispensed simultaneously into all 96-wells. The final concentration of active pharmaceutical ingredient in each well was 0.5 mg / ml (Note: the time dependence on solid nucleation began immediately upon addition of the active pharmaceutical ingredient solution).
7). The contents of the well were mixed and sealed using a clear seal.
8). Plates were placed on a Nephelostar apparatus to collect light scattering data for over 1 hour. Nephelostar incubated the plates at 37 ° C. as defined by the goals of the analysis.

9. At the end of the analysis, the data was analyzed using Microsoft Excel format and the suppression time was calculated. The collected light scattering data is illustrated in FIG. The onset of solid nucleation is defined by the time when the light scatter signal increases above the baseline signal. The threshold threshold for the increase in light scatter signal used to define the precipitation / crystal event is usually set to three times the standard deviation of the baseline signal taking into account background noise. However, the threshold can be set to various values depending on the sensitivity of the analysis and the desired limitation of precipitation / crystallization.
10. The inhibition time (if any) of the excipient solution was ranked. FIG. 30 is a graph showing the ranking.

Another non-limiting example of this general method includes:
1. Inhibition time may be measured as a function of excipient concentration.
2. Inhibition time may be measured as a function of the concentration of the active pharmaceutical ingredient salt or co-crystal.
3. The active pharmaceutical ingredient may be concentrated in a non-aqueous medium before analysis.
4). The temperature may be varied and controlled according to desired criteria.

Example 18
Propylene glycol solvate of celecoxib sodium salt A propylene glycol solvate of celecoxib sodium salt was prepared. To a solution of celecoxib (312 mg, 0.818 mmol) in diethyl ether (6 mL) was added propylene glycol (0.127 ml, 1.73 mmol). To this clear solution was added sodium ethoxide in ethanol (21%, 0.275 1 L, 0.817 mmol). After 1 minute, crystals began to form. After 5 minutes, the solid had completely crystallized. The solid was collected by filtration and washed with additional diethyl ether (10 mL). The off-white solid was then air dried and collected. The crystalline salt form was confirmed as a 1: 1 solvate of propylene glycol. The solid was characterized by TGA and PXRD. The results are shown in FIGS. 39 and 40A.

  FIG. 39 shows the TGA results. A weight loss of about 15.6% was observed between about 65 ° C. and 200 ° C. (it represents 1 molar equivalent of propylene glycol relative to celecoxib sodium salt). FIG. 40A shows the result of PXRD. The peaks that can be used to characterize the solvate at the 2θ angle are any one of 3.77, 7.57, 8.21, 11.33, 14.23, 16.13, 18.69, 20.65, 22.69 and 24.77 °, 1, 2, 3, 4, 5 , 6, 7, 8, 9 or 10 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of FIG. 40A, or any combination thereof including. TGA thermograms or powder X-ray diffraction data may also be used alone or in several combinations to characterize solvates. A 0.8 mm collimator was used during diffractogram acquisition.

  Several closely related and more distinguishable PXRD diffractograms have been obtained by performing the above synthesis several times. FIGS. 40B, 40C and 40D are further diffractograms of the propylene glycol solvate of celecoxib sodium salt. Comparison of these diffractograms gives many notable differences. For example, the peak at 2θ of 8.21 ° in FIG. 40A does not exist in FIG. 40B or 40C. The other peak at 27.9 at 8.79 ° is present in FIGS. 40B and 40D, but not seen in FIGS. 40A or 40C. Other differences can also be observed between the four diffractograms. Such differences in similar diffractograms suggest the presence of polymorphs or possibly various hydrates.

Example 19
Propylene glycol solvate of celecoxib potassium salt Propylene glycol solvate of celecoxib potassium salt was prepared. To a solution of celecoxib in diethyl ether (6 Ml) (253 mg, 0.664 mmol) was added propylene glycol (0.075 ml, 1.02 mmol). To the clear solution was added potassium t-butoxide in tetrahydrofuran (THF) (1 M, 0.66 mL, 0.66 mmol). Crystals began to form immediately. After 5 minutes, the solid had completely crystallized. The solid was collected by filtration and further washed with diethyl ether (10 mL). The white solid was then air dried and collected. This crystalline salt form was a 1: 1 propylene glycol solvate of celecoxib potassium salt. The solid was characterized by TGA and PXRD. The results are shown in FIGS.

  FIG. 41 shows the TGA results. A weight loss of 14.94% was observed between about 65 and 250 ° C. (which corresponds to 1 molar equivalent of propylene glycol to celecoxib potassium). FIG. 42 shows the result of PXRD. The peaks that can be used to characterize the solvate are 1.75, 7.47, 11.33, 14.89, 15.65, 18.31, 20.49, 21.73, 22.51 and 24.97 at 2θ angles, 1, 2, 3, 4 , 5, 6, 7, 8, 9 or 10 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more peaks in FIG. 42, or any Including a combination of

Example 20
A propylene glycol solvate of a lithium salt of celecoxib A propylene glycol solvate of a lithium salt of celecoxib was prepared. Diethyl ether, celecoxib solution (264 mg, 0.693 mmol) in Et ₂ 0 (8 mL) propylene glycol (0.075 ml, 1.02 mmol) was added. To this clear solution was added t-butyllithium in pentane (1.7 M, 0.40 mL, 0.68 mmol). A brown solid formed immediately but dissolved within 1 minute, resulting in a white fluffy solid. The white solid crystallized completely after 10 minutes. The solid was collected by filtration and washed with additional diethyl ether (10 mL). The white solid was then air dried and collected. The crystalline salt form was found to be a 1: 1 propylene glycol solvate of celecoxib lithium. The solid was characterized by TGA and PXRD.

  The result of TGA is shown in FIG. It shows a weight loss of about 16.3% between 50 ° C. and 210 ° C. (which corresponds to one equivalent of propylene glycol to celecoxib lithium). The result of PXRD is shown in FIG. The characteristic peak of 2θ angle that can be used to characterize the salt is any one or any of 3.79, 7.51, 8.19, 9.83, 11.41, 15.93, 18.29, 19.19, 19.87, 20.63, 22.01 or 25.09 °. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, or any one or any combination of the peaks in FIG.

Example 21
Propylene glycol solvate preparation of celecoxib sodium trihydrate:
Celecoxib sodium salt propylene glycol solvate was left for 3 days at 20 ° C., 60% RH to form celecoxib sodium propylene glycol trihydrate (note: 75% at 40 ° C. similarly) Hydrate formation). Trihydrate begins to form at any of 31-41% at room temperature.

The solids were characterized by TGA and PXRD, which are shown in FIGS. 44 and 45, respectively. FIG. 44 shows the TGA results, where 9.64% weight loss was observed between room temperature and 60 ° C., and 13.6% weight loss was observed between 60 ° C. and 175 ° C. .
The PXRD pattern has a characteristic peak at the 2θ angle shown in FIG. For example, any one, two, three, four, five, six, seven, eight, nine, ten or more peaks including 3.47, 6.97, 10.37, 13.97, 16.41, 19.45, 21.29, 22.69, 23.87 and 25.75 ° Can be used to characterize solvates.

  Trihydrates can also be formed by crystallization of celecoxib sodium propylene glycol in the presence of water. A solution of celecoxib (136.2 mg, 0.357 mmol) in diethyl ether (6 mL), water (0.025 mL, 1.39 mmol) and propylene glycol (0.030 ml, 0.408 mmol) in ethanol (21 wt.%, 0.135 mL, 0.362 mmol). Sodium ethoxide in) was added. A solid formed within 1 minute and was separated by filtration. The solid was then washed with additional diethyl ether (2.0 mL) and air dried. This process substantially gives the same PXRD pattern, but there is a slight excess of water, which is probably surface water.

  The solids are characterized by TGA and PXRD, which are shown in FIGS. 46 and 47, respectively. FIG. 46 shows the TGA results, indicating that 10.92% weight loss between room temperature and 50 ° C. and 12.95% weight loss between 50 ° C. and 195 ° C. were observed.

  The PXRD pattern has a characteristic peak at the 2θ angle shown in FIG. For example, any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, including 3.43, 6.95, 10.25, 13.95, 16.39, 17.39, 17.75, 19.43, 21.21, 22.61 and 25.71 ° Twelve or more peaks can be used to characterize the solvate. A 0.8 mm collimator was used during diffractogram acquisition.

Example 22
Isopropyl alcohol (0.070 mL) was added to a solution (204.2 mg, 0.5354 mmol) of celecoxib in diethyl ether (6.0 mL). To this colorless solution was added a solution of sodium methoxide in methanol (0.5 M, 2.52 mL, 6.75 mmol) followed by hexane (3.0 mL). Volatiles were reduced under a stream of nitrogen gas. A white solid was formed and collected by filtration. After drying, the solid was found to be an isopropanol solvate (1.5: 1 isopropanol: celecoxib) by TGA and PXRD.

  The results of DSC, TGA and PXRD analysis are shown in FIGS. FIG. 48 shows the results of DSC analysis in which the peak endotherm was observed at 67.69 ° C. The TGA results show a weight loss of about 18.23% from about room temperature to about 120 ° C., as shown in FIG. 49, which represents 1.5 equivalents of isopropanol to celecoxib sodium. The PXRD pattern has a characteristic peak at the 2θ angle shown in FIG. For example, any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 including 3.43, 7.03, 10.13, 11.75, 14.11, 16.61, 17.61, 18.49, 19.51, 20.97, 22.33, 22.81 and 25.93 , 11, 12, 13 or more peaks can be used to characterize solvates.

Example 23
Celecoxib: nicotinamide (1: 1) co-crystal Celecoxib (100 mg, 0.26 mmol) and nicotinamide (32.0 mg, 0.26 mmol) were dissolved in acetone (2 mL), respectively. The two solutions were mixed and the resulting mixture was slowly evaporated overnight. The precipitated solid was collected and characterized. Detailed characterization of the co-crystal was performed using DXC, TGA and PXRD. DSC results showed a two-step phase transition at 117.2 and 118.8 ° C and a sharp endotherm at 129.7 ° C. TGA results show degradation starting at about 150 ° C. The result of PXRD is shown in FIG. Characteristic peaks that can be used to characterize the co-crystal are 3.77, 7.56, 9.63, 14.76, 16.01, 17.78, 18.68, 19.31, 20.435, 21.19, 22.10, 23.80, 24.70, 25.295 and 26.73. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, or any combination of the peaks in FIG. Including.

Example 24
Celecoxib sodium salt hydrate and celecoxib sodium propylene glycol solvate Celecoxib sodium is a changing hydrate. To analyze the hydration effects in the crystal structure, celecoxib sodium salt and celecoxib sodium salt propylene glycol solvate were subjected to PXRD under constant relative humidity (RH) of 17%, 31%, 59% and 74% at room temperature. Was analyzed. Analysis of celecoxib sodium salt hydrate and celecoxib sodium propylene glycol solvate was performed by incubating the samples at room temperature for 48 hours at room temperature. The following table shows the PXRD 2θ angle (°) peak at different relative humidity.

The composition is any one or any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, listed in Table 3. 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or a combination of peaks, or any one of FIGS. 53 to 60, or 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 Or characterized by a combination of more peaks.
Figures 53 to 56 are PXRD diffractograms of celecoxib sodium hydrate at 17%, 31%, 59% and 74% RH, respectively. Figures 57 to 60 are PXRD diffractograms of celecoxib sodium propylene glycol hydrate at 17%, 31%, 59% and 74% RH, respectively.
PXRD analysis of celecoxib sodium hydrate shows that the crystal packing changes as water is adsorbed (see dynamic moisture absorption data in FIG. 69 and Example 30). PXRD analysis of celecoxib sodium propylene glycol solvate shows that there are two distinct crystalline forms when exposed to various humidity (see dynamic moisture absorption data in FIG. 70 and Example 30). Form I was present at 31% RH, while Form II was present at 59% RH and above.

Example 25
Various hydrates hydration celecoxib sodium salt is changed (1 are thought to be in the range of about 0.5 to 4 equivalents of per equivalent H ₂ 0 celecoxib), a plurality of celecoxib sodium salt samples, all form M1 was analyzed by PXRD. PXRD patterns were then classified based on common peaks. Several groups were identified in four of these groups shown in FIG. Group D was consistent with a mixture of amorphous and crystalline celecoxib salts. Table 4 lists the characteristics of PXRD peaks common to groups A, B and C and the peaks specific to each group.

Example 26
Celecoxib potassium salt hydrate Celecoxib potassium salt hydrate was prepared. To a solution of celecoxib (233.4 mg, 0.6120 mmol) in methanolic potassium hydroxide solution (1.008 M, 0.606 0.611 mL) was added wet methanol (methanol 1.0 mL, water 0.100 mL). The solution was then reduced to almost dryness (0.5 ml) by evaporation with a stream of nitrogen gas. Diethyl ether (6.0 mL) was added to the remaining solution, and the mixture was stirred. Within 1 minute, crystals began to form and the solid crystallized completely within 10 minutes. The solid was then filtered and air dried. The solid was characterized by TGA and PXRD.

  The results of TGA and PXRD are shown in FIGS. FIG. 63 shows the result of TGA, where a weight loss of 8.36% was observed between room temperature and 140 ° C. The PXRD pattern has a characteristic peak at the 2θ angle shown in FIG. For example, including any peaks at 2.69, 3.69, 8.99, 10.65, 11.11, 13.35, 20.05, 21.45, 22.39, 24.77 and 26.71 °, any 1, 2, 3, 4, 5, 6, 7, 8, 9, Ten or more peaks can be used to characterize celecoxib potassium hydrate.

Example 27
Production of celecoxib sodium salt using sodium chloride
To a solution of celecoxib (1.787 g, 4.686 mmol) in 1M sodium hydroxide (5.0 mL, 5.0 mmol) was added a solution of 1M sodium chloride (5 ml). The mixture was stirred and cooled until crystals of celecoxib sodium salt were slowly obtained. The solid was collected by filtration and washed with additional 1M sodium chloride (10 ml). The solid was dried with a stream of nitrogen gas.

  The results of TGA and PXRD are shown in FIGS. FIG. 65 is a TGA result in which a weight loss of 4.06% was observed between 50 ° C. and 140 ° C. and a weight loss of 8.98% between room temperature and 140 ° C. was observed. The PXRD pattern has a characteristic peak at the 2θ angle shown in FIG. For example, including peaks at 2.65, 3.65, 8.95, 9.61, 10.77, 11.43, 14.01, 17.19, 18.33, 19.47, 19.99, 20.61, 21.71, 22.57 and 25.81 °, any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more peaks can be used to characterize celecoxib potassium hydrate.

Example 28
In Vitro Dissolution Test of Incubated Celecoxib Sodium Hydrate Salt Formulation In vitro dissolution was performed with celecoxib preparation pre- and post-incubated for 18 weeks at 40 ° C. The composition of the test formulation is
(i) Celecoxib sodium hydrate salt, hydroxypropylcellulose (HPC) and poloxamer 407,
(ii) Celecoxib sodium hydrate salt, hydroxypropyl cellulose (HPC), poloxamer 407 and PEG 400 and
(iii) Celecoxib sodium propylene glycol solvate, hydroxypropyl cellulose (HPC) and poloxamer 407.
Dissolved in a 20 ml scintillation vial equipped with a magnetic stirrer at 37 ° C. using simulated gastric juice diluted 0.3 fold (0.3 mM Triton X-100).

  As shown in FIG. 67, the dissolution profile of the dissolution profiles of formulations (ii) and (iii) after incubation at 40 ° C. showed a small loss at the peak of the dissolution size relative to the fresh formulation. It was. However, as this loss was observed in the canine pharmacokinetics section (where the in vitro dissolution profile of various peak sizes correlates with the canine pharmacokinetic profile. Shown (ie, in vivo-in vitro correlation)) does not adversely affect the in vivo bioavailability and dose-response characteristics of celecoxib. In contrast to the dissolution tendency of formulations (ii) and (iii), formulation (i) showed improved dissolution that may result in slight dissolution of Pluronic F127 at 40 ° C. Dissolved Pluronic F127 may provide a dissolution benefit similar to that provided by Pluronic L44 and PEG400.

Example 29
Controlled release formulation of celecoxib sodium propylene glycol solvate A membrane coating system was selected to achieve controlled release of celecoxib. The membrane is a polymer that corrodes with low water permeability and controlled the release of celecoxib through the corrosion process. The membrane is used to promote corrosion of the coating in water without allowing water to enter the interior of the pellet. The rate of celecoxib release is controlled by applying the polymer in increasing film thickness to a subpopulation of pellets within the final formulation dose. Pellets with a thin polymer coating release celecoxib faster than pellets with a thicker polymer coating. Changing the film thickness across many pellets results in a distribution of the drug release profile. Factors affecting the rate of polymer corrosion include polymer type, plasticizer content, temperature, solvent, cure and film thickness. The formulation used in this example contains celecoxib sodium propylene glycol solvate, Pluronic F127 and hydroxypropyl cellulose (100,000 MW), equal to the weight equivalent of celecoxib free acid. The formulation was supplemented with magnesium stearate at a concentration of 0.05% by weight to help compress and eject the pellets. This formulation contains 30.4% by weight of celecoxib free acid.

The pellet was compressed at 10.3 Mpa into a cylindrical pellet with a diameter of 2 mm. The cylindrical pellet had an average height of 1 mm and an average weight of 3.8 mg. A polymer coating (eg, cellulose acetate phthalate (CAP), polyvinyl acetate crotonic acid copolymer) was applied using a spray coater. The film thickness value ranged from 15 to 70 μm.
Application of the polymer coating was designed to delay the release of celecoxib and prevent its rapid conversion to the free acid form prior to absorption. To determine how the coating affects delayed release and affects dissolution during passage through the stomach, analysis was performed using both SGF and SIF. This analysis was performed in a two-step process in which dissolution was performed with SGF in the first step and SG media was replaced with SIF media to complete the solubility analysis in the second step. Two assumptions were made. (1) The typical transit time of small food particles in the stomach is 30 minutes, and (2) dissolved celecoxib is rapidly absorbed, thus adjusting the exchange of celecoxib dissolved SGF for complete SIF.

  In vitro, dissolution was tested in both fasted simulated stomach and intestinal fluid. As a specific example, celecoxib sodium propylene glycol pellets (approx. 64 μm film thickness) coated with cellulose acetate phthalate (containing 10 wt% triethyl citrate plasticizer) were dissolved in simulated gastric juice. It was. After about 30 minutes, the dissolution medium was replaced with simulated intestinal fluid. The dissolution profile shows no celecoxib release in the first 30 minutes, which is consistent with the trend of enteric coatings in low pH solutions. Once in the simulated intestinal fluid, the coating began to corrode and celecoxib sodium was released. A maximum concentration of 0.64 mg / ml was obtained after about 90 minutes of analysis (see FIG. 68). This example shows that controlled release can be achieved by applying varying film thicknesses in separate populations of pellets in drug capsules. Controlled release of celecoxib can be achieved by a combination of coated formulation pellets and / or a combination of coated formulation pellets and formulation powder.

Example 30
Dynamic hygroscopic analysis of celecoxib salts, hydrates, solvates and co-crystals DVS-1 instrument (surface measuring system, Monarch Beach , CA). Each sample was placed in a clear glass crucible and allowed to equilibrate in the apparatus at a specific relative humidity (RH) level. Initial equilibration was performed in a DVS apparatus unless otherwise noted. After initial equilibration, RH was changed and mass change was recorded over time as an indicator of moisture absorption. RH was controlled by varying the flow rate of the dry and water saturated nitrogen flow at 25 ° C., maintaining the combined combined flow rate of both streams at a constant 200 standard cm ³ / min. Full humidity cycles were generally increased from 0 to 95% RH at a constant rate and returned to 0% RH unless otherwise noted. Mass balance at each humidity level was obtained when the mass change value (ie, dm / dt) at a given time was less than 2 μg / min. After analysis, the mass change due to moisture absorption was mathematically converted to water molar equivalent / dry compound molar equivalent. Form analysis was performed at the end of the analysis on selected samples using a powder X-ray diffraction pattern (PXRD, D / Max Rapid, Rigaku, Danvers, Mass.). Samples were packed into 3 mm diameter borosilicate capillary tubes for analysis.

Celecoxib sodium hydrate Celecoxib sodium hydrate (dry weight: 9.2593 mg, dry molecular weight: 404.36, temperature: 25.4 ° C.) was first equilibrated at 25 ° C. and 20% RH. RH was increased at a constant rate from 20 to 95% RH and then decreased at a constant rate to 0% RH. Two complete humidity cycles were performed as shown in FIG. The hygroscopic isotherms of both cycles overlap, indicating the lack of irreversible morphological changes. In the change from 0 to 10 RH%, the compound absorbed 1 water molar equivalent / dry compound. Moisture absorption steadily increased from 20 to 40 RH% until about 3 water equivalents were obtained at 40% RH. The trihydrate was kinetically stable in the range of 40 to 70% RH. At RH values above 70%, moisture absorption continued to increase until deliquescence occurred at 95% RH. The main observation in this analysis is the formation of morphologies consistent with the trihydrate designation in the range of 40 to 70% RH and the monohydrate designation in the range of 10 to 20% RH.

Celecoxib potassium Celecoxib potassium (dry mass: 15.8563 mg, dry molecular weight: 419.48 temperature: 25.5 ° C.) was first equilibrated at 25 ° C. and 20% RH. Next, two cycles of increasing or decreasing RH from 0 to 95% RH at a constant rate were performed as shown in FIG. 72A. Moisture absorption was strongly dependent on RH, with immediate adsorption occurring at very low RH levels and deliquescence occurring at 95% RH. The analysis was characterized by very low hysteresis and large amounts of water uptake. A PXRD pattern was taken at the end of the analysis and FIG. 72B showed that the compound was in the crystalline state. Small changes in morphology appeared in PXRD, which showed any crystal rearrangement (ie, polymorphism) with moisture absorption compared to preincubation. Preincubation PXRD is typical of celecoxib potassium that reaches equilibrium at room temperature and ambient humidity.

Celecoxib sodium propylene glycol solvate Celecoxib sodium propylene glycol solvate (dry mass: 19.4851 mg, dry molecular weight: 480.45, temperature: 25.8 ° C.) was first equilibrated at 25 ° C. and 0% RH. Three cycles of increasing or decreasing RH from 0 to 75% RH at a constant rate were performed as shown in FIG. No change in mass is observed from 0 to 34% RH, indicating the presence of an anhydrous form stable to this range. At 40% RH, the compound gained 1 water molar equivalent and increased the water content monotonically to 75% RH.

  The desorption cycle was characterized by significant hysteresis consistent with the hydration process. During dehumidification, water was released very slowly until dihydrate was formed below 40% RH. The dihydrate was stable from 33 to 17% RH, and when further dried to 0% RH, the sample continued to lose water until it equilibrated at a weight less than the original dry weight (ie, 1 cycle slope). It was. Further loss of mass suggests that propylene glycol was released during RH transfer. Assuming that the compound was dry at 0% RH (ie, no water), the calculated loss of propylene glycol was 0.16 equivalents. Two more humidity cycles were performed to confirm these observations. Further cycles showed a similar trend as the first cycle, but the y-axis scale was lower due to propylene glycol mass loss. In addition, further mass loss was observed at the end of each cycle. The total propylene glycol loss calculated was 0.25 and 0.32 propylene glycol equivalents at the second and third ends, respectively.

A second dynamic moisture absorption analysis was performed with celecoxib sodium propylene glycol solvate. In this attempt, the sample was incubated at 55% RH at room temperature for 72 hours in a salt bath solution. For moisture absorption analysis, samples were removed from the 55% RH chamber and equilibrated at 25 ° C. and 20% RH in a dynamic moisture absorber. Then, in the first cycle, RH was increased from 20 to 60% RH at a constant rate and decreased to 0% RH. As shown in FIG. 74, stable trihydrate was observed at 10-60% RH. At 0% RH, it was removed from moisture absorption to give the anhydrous form.
In the second moisture absorption cycle, it began to absorb moisture at an RH value greater than 20% RH, and at 40 RH%, 2 water equivalents were adsorbed consistent with the dihydrate form indication. This dihydrate was stable at 40-60% RH. At higher RH, the water content increased exponentially and disequilibrium was observed at 95% RH. The desorption cycle is characterized by significant hysteresis below 70% RH. From 30 to 10% RH, the dihydrate form was reconstituted. By further drying to 0% RH, the sample reached equilibrium at a weight lower than the original dry weight of the compound. Assuming the sample was completely dried, the calculated loss of propylene glycol was estimated to be 0.16 molar equivalents.

A third humidity analysis was begun but stopped immediately after reaching 30% RH before reaching equilibrium. As shown in FIG. 75, when morphological changes were shown, a PXRD pattern was taken for the raw material, suggesting that moisture absorption involves rearrangement of the crystal structure.
The main difference observed in this test for the initial celecoxib sodium propylene glycol solvate analysis is the presence of a stable trihydrate form region from 10 to 60% RH and then an equilibrium at 55% RH for 72 hours. Met. The observations made in the second humidity cycle are in good agreement with those made in the previous analysis, confirming the reproducibility of the analysis. These observations suggest that the dihydrate form is dynamically stable over a long period of time (ie, time) before converting to the thermodynamically stable trihydrate form.

Celecoxib potassium propylene glycol solvate Celecoxib potassium propylene glycol solvate (dry mass: 17.2584 mg, dry molecular weight: 496.57, temperature 25.1 ° C.) was first equilibrated at 25 ° C. and 0% RH. One cycle of increasing or decreasing RH from 0 to 95% RH at a constant rate was performed as shown in FIG. No change in mass is observed from 0 to 43% RH, indicating the presence of an anhydrous form stable to this range. Above 43% RH, moisture absorption increased exponentially with increasing% RH. Deliquescent was observed at 95% RH.

  The desorption cycle was characterized by a negative hysteresis consistent with that observed in the sodium propylene glycol solvate form. At 30% RH, the sample reached equilibrium at a mass below that of the dry weight of the first sample. This mass loss is attributed to the removal of propylene glycol and is calculated to be 0.27 equivalents at 0% RH. A PXRD pattern (see FIG. 77) is taken at the end of the analysis, which indicates that the sample has been converted to an amorphous form.

Celecoxibutylium propylene glycol solvate Celecoxib lithium propylene glycol solvate (dry mass: 5.5916 mg, dry molecular weight: 387.32, temperature: 25.5 ° C.) was first equilibrated at 25 ° C. and 20% RH. RH was increased from 20 to 95% RH at a constant rate and decreased to 0% RH. Two complete humidity cycles were performed as shown in FIG. For the first 20 to 50% RH conversion, the data show that 1 molar water equivalent was desorbed, indicating that PG was not lost at this stage. Above 60% RH, moisture absorption increased exponentially with increasing% RH until deliquescence was observed at 95% RH.

  In the desorption cycle, the decrease in dry weight at 0% RH is consistent with the characteristics of other propylene glycol forms, suggesting loss of propylene glycol during the RH increase / decrease cycle. The calculated loss of propylene glycol was 0.11 molar equivalent. As shown in FIG. 79, the PXRD pattern is taken at the end of the analysis and shows a change to the crystal form during the analysis.

Celecoxib: nicotinamide co-crystal Celecoxib: nicotinamide co-crystal (dry mass: 3.129 mg, dry molecular weight: 1044.8, temperature: 25.3 ° C.) was first equilibrated at 25 ° C. and 0% RH. In two cycle experiments, RH was increased at a constant rate from 0 to 95% RH as shown in FIG. The co-crystal was hygroscopic at 70% RH or less. The small amount of water content observed in the figure is due to surface adsorption. Above 70% RH, the water content increased gradually, reaching a peak concentration of 2 molar equivalents of water per mole of co-crystal at 95% RH. The desorption cycle was characterized by minimal hysteresis.

Example 31
Amorphous celecoxib potassium salt: Manufacturing method MO-116-55B
A 3M KOH (0.090 mL, 0.27 mmol) aqueous solution was added to celecoxib (105.3 mg, 0.2761 mmol) to obtain a suspension. The suspension was heated gently and methanol (0.3 ml) was added to give a colorless solution. The solution was cooled to room temperature and then the volatiles were evaporated by blowing nitrogen. The resulting amorphous solid was characterized by DSC, Raman spectroscopy and PXRD.

The DSC is shown in FIG. A Raman spectrum is shown in FIG. Characteristic Raman shift (cm ^-1) peaks, but are not limited to, 1616,1450,1376,1236,1198,1112,1063,976,800,742 or any one or any two of 634cm ^-1, Any three, any four, any five and any six or any combination of 7, 8, 9, 10, 11 or 2, 3, 4, 5, 6, 7, 8, 9, 10, Observed at positions containing 11, 13, 14 or more peak combinations. The PXRD pattern is shown in FIG. 83, and one peak was observed at 2.87 ° of 2θ angle.

Example 32
Crystallization of celecoxib and valdecoxib with various ethers Celecoxib: 18-crown-6 co-crystal Solid 18-crown-6 (118.1 mg, 0 ,. 447 mmol) was converted to celecoxib (157.8) in diethyl ether (10.0 ml). mg, 0.4138 mmol). The opaque solid dissolved immediately, after which the white solid began to crystallize very quickly. The solid was collected by filtration and washed with additional diethyl ether (5 ml).
The solid was air dried and characterized by TGA, DSC and PXRD. Unit cell measurements by single crystal X-ray diffraction were consistent with a 2: 1 adduct (celecoxib: 18-crown-6). This co-crystal has a higher melting point (189 ° C.) than celecoxib (156-159 ° C.).

  FIG. 84 shows a TGA thermogram of celecoxib: 18-crown-6 co-crystal. TGA analysis results show a weight loss of about 25% from 125 ° C to 220 ° C. FIG. 85 shows a DSC thermogram of celecoxib: 18-crown-6 co-crystal. The results of DSC analysis show an endotherm at 189.6 ° C. FIG. 86 shows a PXRD diffractogram of celecoxib: 18-crown-6 co-crystal. Peaks are 2θ angles and include, but are not limited to, 8.73, 11.89, 13.13, 16.37, 17.75, 18.45, 20.75, 22.37 and 23.11 °. The crystal may be characterized by one or a combination of the above two or more of the above angles of 2, 3, 4, 5, 6, 7, 8, 9 or more, or any one or any combination of the 2θ angles of FIG. it can.

Celecoxib: 15-crown-5 solvate To a solution of celecoxib (165.2 mg, 0.4332 mmol) in diethyl ether (5.0 ml) was added 15-crown-5 (0.095 mL, 0.48 mmol) in diethyl ether (1.0 ml). The solution was added. Volatiles were slowly evaporated to give an oil. The oil was then recrystallized with ethanol (5 ml). Recrystallization also gave an oil that crystallized after one week without shaking. The solid was found to be a 15-crown-5 solvate of celecoxib.

  The solid was characterized by TGA, DSC and PXRD. The TGA data shows a weight loss of 34.67%, which corresponds to 1 molar equivalent of 15-crown-5 per mole of celecoxib (see FIG. 87). DSC shows a melting point of 91.2 ° C., which is extremely lower than 18-crown-6 (189 ° C.) and free celecoxib (156-159 ° C.). The DSC thermogram is shown in FIG. FIG. 89 shows a PXRD diffractogram of celecoxib 15-crown-5 solvate. Peaks are 2θ angles and include, but are not limited to, 7.67, 13.57, 14.61, 20.61, 21.69, 23.07 and 24.81 °. The crystal can be characterized by one or a combination of two, three, four, five, six, seven or more of the above angles, or any one or any combination of the 2θ angles of FIG.

Celecoxib diglyme solvate To a solution of celecoxib (129.3 mg, 0.3390 mmol) in diethyl ether (5.0 ml) was added a solution of diglyme (0.100 mL, 0.698 mmol) in diethyl ether (3.0 ml). Volatiles were slowly evaporated to give a white solid. The white solid continued to crystallize and the solvent was reduced (2 ml) followed by cooling. White powder was collected by filtration and air dried. The solid was found to be a diglyme solvate of celecoxib.

  The solid was characterized by TGA, DSC and PXRD. The TGA data shows a weight loss of 24.85%, which corresponds to 1 molar equivalent of diglyme per mole of celecoxib (see FIG. 90). The melting point of the solvate is shown by DSC to be 98.2 ° C., considerably lower than celecoxib (156-159 ° C.). A DSC thermogram is shown in FIG. FIG. 92 shows the PXRD diffractogram of celecoxib diglyme solvate. The peaks are 2θ angles and include, but are not limited to, 6.71, 10.77, 16.15, 20.53, 21.05, 21.81 and 22.69 °. The crystal can be characterized by one or a combination of two, three, four, five, six, seven or more of the above angles, or any one or any combination of the 2θ angles of FIG.

Valdecoxib: 18-crown-6 co-crystal To a solution of valdecoxib (33.3 mg, 0.107 mmol) in tetrahydrofuran (2.0 ml) was added 18-crown-6 (30.2 mg, 0.114 mmol) in tetrahydrofuran (2.0 ml). added. The solution was stirred and slowly evaporated. After evaporation to dryness, the residual solid was a white crystalline material. Single crystals were removed for single crystal X-ray diffraction and were found to be 2: 1 adducts with two independent supramolecular complexes in asymmetric units. A TGA analysis of the valdecoxib: 18-crown-6 co-crystal is shown in FIG. FIG. 94 shows a PXRD diffractogram of valdecoxib: 18-crown-6 co-crystal. Peaks are 2θ angles and include, but are not limited to, 11.31, 13.23, 16.01, 17.69, 18.19, 21.11, 21.59, 22.51, 23.23 and 24.03 °. The crystal can be characterized by one or a combination of the above angles of 2, 3, 4, 5, 6, 7, 8, 9, 10, or any one or any combination of the 2θ angles of FIG. . FIG. 95 shows the single crystal structure of valdecoxib: 18-crown-6 co-crystal.

Single crystal X-ray data of valdecoxib: 18-crown-6 co-crystal 2: 1 are as follows.
Theoretical structural formula C44 H52 N4 012 S2
Structural weight 893.02
Temperature 100 (2) K
Wavelength 0.71073 Angstrom Unit cell diameter a = 10. 1721 (11) Angstrom α = 83. 127 (2) °
b = 13. 7178 (15) Angstrom β = 73.362 (2) °
c = 16. 7202 (18) Angstrom γ = 89.017 (2) °
Volume 2219.0 (4) A ³
Z, calculated density 2,1. 337 Mg / m ³
Absorption coefficient 0.187 mm ^-1
F (000) 944
Reflection collection / specific 13432/9849 [R (int) = 0.0330]
Purification method Full matrix least squares method in F2 Data / restraints / parameter 9849/0/559
Goodness of fit in F2 0.995
Final R index [I> 2 Sigma (I)] Rl = 0.0594, wR2 = 0.1345
R index (all data) RI = 0.1097, wR2 = 0.1573
The co-crystals and solvates illustrate the importance of the ether-sulfonamide interaction. This ether-sulfonamide interaction is highly preferred and plays an important role in the formulations of the present invention.

Example 33
Celecoxib NMP solvate To solid celecoxib (127 mg, 0.333 mmol) was added N-methyl-2-pyrrolidone (0.75 mL) to give a white suspension. The mixture was heated to 75 ° C. and held at this temperature for 3 minutes, at which point the solid dissolved and a colorless solution was obtained. The solution was cooled to room temperature and then cooled to 5 ° C. for 3 days. After 3 days, colorless hexagonal crystals were formed. The mother liquor was decanted and the solid was suspended in pentane (2 mL) and filtered. The solid was air dried and collected. The solid was found to be a 1: 1 N-methyl-2-pyrrolidone (NMP) solvate of celecoxib.

The solid was characterized by TGA, Raman spectroscopy and PXRD. TGA data shows a major loss of 7.40% weight loss from room temperature to 60 ° C., due to residual solvent (see FIG. 96). From about 95 ° C. to about 165 ° C., the solvent loss was 19.39% by weight. This loss represents a 1: 1 molar equivalent of NMP relative to celecoxib. Residual solvent could be removed and a pure solvate was obtained. Raman scattering peaks were seen at 1615, 1451, 1375, 1159, 973, 799, 741 and 626 cm ⁻¹ , for example. Any one of the above, any two, any three, any four, any five, any six, any seven, all eight, or any one of the peaks in FIG. One or any combination can be used for crystal characterization. FIG. 98 shows a PXRD diffractogram of celecoxib NMP solvate. Peaks are 2θ and include, but are not limited to, 8.19, 12.69, 15.01, 15.65, 16.37, 17.89, 19.37, 21.05 and 23.01 °. The crystal has any one of the above corners, any two, any three, any four, any five, any six, any seven, any eight, all nine, Alternatively, any one or combination of 2θ angles in FIG. 98 can be used for crystallization.

Single crystal X-ray data of celecoxib: NMP co-crystal at 100K is as follows.
Theoretical structural formula C22 H23 F3 N4 03 S
Structural weight 480.50
Temperature 100 (2) K
Wavelength 0.71073 Angstrom Crystal system Monoclinic space group P2 (1) / n
Unit cell diameter a = 21.1232 (14) Angstrom α = 90 °
b = 9.2669 (6) Angstrom β = 102.5320 (10) °
c = 23.8250 (16) Angstrom γ = 90 °
Volume 4552.5 (5) A ³
Z 8
Density (calculated value) 1.402 Mg / m ³
Absorption coefficient 0.199 mm ^-1
F (000) 2000
Crystal size 0.20 × 0.15 × 0.10mm ³
Θ range for data collection 1.17 to 28. 33 °
Exponential range -26 <= h <= 28, -11 <= k <= 12, -31 <= 1 <= 25
Reflection correction 27520
Independent reflection 10573 [R (int) = 0.0366]
Completeness for θ = 28.33 ° 93.0%
Absorption correction None Purification method Full matrix least squares method in F2 Data / restraints / parameter 10573/0/729
Goodness of fit in F2 1.026
Final R index [I> 2 sigma (I)] Rl = 0.0580, wR2 = 0.1386
R index (all data) RI = 0.0873, wR2 = 0.1547
Maximum diffraction peak and hole 0.694 and -0.655 e.Å ^-3
FIG. 99 shows the celecoxib: NMP solvate packing diagram at 100K.

Single crystal X-ray data of celecoxib: NMP co-crystal at 571K is as follows.
Theoretical structural formula C22 H23 F3 N4 03 S
Structural weight 480.50
Temperature 571 (2) K
Wavelength 0.71073 Angstrom Crystal System Monoclinic Space Group P2 (1) / c
Unit cell diameter a = 12. 0017 (10) Angstrom α = 90 °
b = 99.0910 (7) Angstrom β = 101.338 (2) °
c = 21.9595 (18) Angstrom γ = 90 °
Volume 2349.2 (3) A ³
Z 4
Density (calculated value) 1.359 Mg / m ³
Absorption coefficient 0.192 mm ^-1
F (000) 1000
Crystal size 0.20 × 0.15 × 0.15mm ³
Θ range for data collection 1.73 to 28. 33 °
Exponential range -14 <= h <= 15, -12 <= k <= 11, -29 <= 1 <= 24
Reflection correction 14668
Independent reflection 5509 [R (int) = 0.0226]
Completeness for θ = 28.33 ° 94.2%
Absorption correction None Purification method Full matrix least squares method in F2 Data / restraints / parameter 5509/0/328
Goodness of fit in F2 1.041
Final R index [I> 2 Sigma (I)] Rl = 0.0597, wR2 = 0.1968
R index (all data) RI = 0.0950, wR2 = 0. 1958
Maximum diffraction peak and hole 0.455 and -0.217 e.Å ^-3
FIG. 100 shows the packing diagram of celecoxib: NMP solvate at 571K.

Example 34
Solubility of Celecoxib Sodium Formulation with Potential Precipitation Inhibitor The dissolution profile in SGF of a solid mixture of celecoxib sodium and excipients was tested at room temperature. These mixtures, which give a concentration of 0.10 mg / mL at any time, are included in FIG.
Poloxamer 237, Vitamin E TPGS (TPGS) and Gellucire 50/13 were all effective in giving elevated concentrations at any time. PVP and poloxamer 188 were less effective but maintained measurable concentrations at least at some time points. The TPGS solution was almost clear and was clear after filtration. The poloxamer 237 sample was milky even after filtration.

Mixtures with poloxamers 237 and 188 showed very different solubility profiles (other poloxamers were similarly tested) and evaluated the relationship between poloxamer structure and dissolution profile (see FIG. 7). The weight ratio of drug to poloxamer is 1: 1 for all propofol files shown in the plot. Poloxamers 237 and 407 have clearly enhanced efficacy compared to poloxamers 188 and 338.
Poloxamer is a block copolymer of polyethylene glycol (PEG) and polypropylene glycol. FIG. 7 shows the block composition of each poloxamer tested. Solubility is enhanced by poloxamers that contain a high composition of PPG blocks.

FIG. 8 shows the effect of cellulose on the solubility of 1: 1 TPGS: celecoxib sodium at room temperature. The effect of loaded excipients and the ratio in dissolution profile were tested and found to have a significant effect on the dissolution profile (see FIG. 9). FIG. 10 shows the dissolution profile of celecoxib sodium in SGF from a solid mixture with excipients at room temperature. FIG. 11 shows the effect of Avicel and silica gel on the solubility of celecoxib sodium, TPGS, HPC formulation in SGF at 37 ° C. FIG. 12 shows the solubility of celecoxib sodium salt in several formulations at 37 ° C. in SGF diluted 5-fold.
It should be noted that in the use of the figure, the terms “TPI336” and “TPI-336” refer to celecoxib or celecoxib salts depending on the context.

Claims (27)

  A pharmaceutical composition comprising a sodium salt of celecoxib. The salt form is characterized by an X-ray powder diffraction pattern comprising a peak expressed in 2θ angle;
(a) the form is celecoxib sodium salt, the X-ray diffraction pattern includes peaks at 3.57, 8.91 and 10.69 °;
(b) the form is celecoxib sodium salt, and the X-ray diffraction pattern includes peaks at 11.29, 16.69 and 17.13 °;
(c) the form is celecoxib sodium salt and the X-ray diffraction pattern includes peaks at 9.49, 18.29 and 19.85 °;
(d) the form is celecoxib sodium salt and the X-ray diffraction pattern includes peaks at 3.57, 10.69 and 19.85 °;
(e) the form is celecoxib sodium salt and the X-ray diffraction pattern includes peaks at 13.69, 19.85 and 21.53 °;
(f) the form is celecoxib sodium salt and the X-ray diffraction pattern includes peaks at 11.29, 22.39 and 23.35 °;
(g) the form is celecoxib sodium salt and the X-ray diffraction pattern includes a peak at 19.85 °;
(h) the form is celecoxib sodium salt and the X-ray diffraction pattern includes peaks at 8.91 and 10.69 °, or
The pharmaceutical composition of claim 1, wherein (i) the form is celecoxib sodium salt and the X-ray diffraction pattern includes peaks at 3.57, 10.69, 13.69 and 19.85 °.   A pharmaceutical composition comprising a potassium salt of celecoxib. The salt form is characterized by an X-ray powder diffraction pattern comprising a peak expressed in 2θ angle;
(a) the form is celecoxib potassium salt and the X-ray diffraction pattern includes peaks at 9.11, 12.23 and 19.79 °;
(b) the form is celecoxib potassium salt, and the X-ray diffraction pattern includes peaks at 9.11, 20.97, and 22.81 °;
(c) the form is celecoxib potassium salt, and the X-ray diffraction pattern includes peaks at 12.23, 19.79, and 24.71 °;
(d) the form is celecoxib potassium salt, and the X-ray diffraction pattern includes peaks at 8.13, 12.23 and 19.79 °,
(e) the form is celecoxib potassium salt, the X-ray diffraction pattern includes peaks at 4.99, 9.11 and 24.71 °,
(f) the form is celecoxib potassium salt, and the X-ray diffraction pattern includes a peak at 19.79 °;
(g) the form is celecoxib potassium salt and the X-ray diffraction pattern includes peaks at 12.23 and 15.35 °, or
(h) The pharmaceutical composition according to claim 3, wherein the form is celecoxib potassium salt and the X-ray diffraction pattern includes peaks at 4.03, 10.61, 15.35 and 22.81 °.   A pharmaceutical composition comprising a lithium salt of celecoxib. The salt form is characterized by an X-ray powder diffraction pattern comprising a peak expressed in 2θ angle;
(a) the form is a celecoxib lithium salt, and the X-ray diffraction pattern includes peaks at 4.14, 9.04 and 10.71 °,
(b) the form is a celecoxib lithium salt, and the X-ray diffraction pattern includes peaks at 18.71, 20.52 and 23.00 °;
(c) the form is a celecoxib lithium salt, and the X-ray diffraction pattern includes peaks at 10.71, 18.71 and 21.55 °,
(d) the form is a celecoxib lithium salt, and the X-ray diffraction pattern includes peaks at 9.04, 10.71, and 12.47 °,
(e) the form is a celecoxib lithium salt, and the X-ray diffraction pattern includes peaks at 12.47, 15.75 and 20.52 °;
(f) the form is a celecoxib lithium salt, and the X-ray diffraction pattern includes a peak at 10.71 °;
(g) the form is a celecoxib lithium salt and the X-ray diffraction pattern includes peaks at 9.04 and 15.08 °, or
(h) The pharmaceutical composition according to claim 5, wherein the form is a celecoxib lithium salt, and the X-ray diffraction pattern includes peaks at 12.46, 15.75, 20.52 and 21.55 °.   A pharmaceutical composition comprising a calcium salt of celecoxib. The salt form is characterized by an X-ray powder diffraction pattern comprising a peak expressed in 2θ angle;
(a) the form is celecoxib calcium salt, the X-ray diffraction pattern includes peaks at 7.82, 9.27 and 20.56 °,
(b) the form is celecoxib calcium salt, the X-ray diffraction pattern includes peaks at 3.91, 9.27 and 27.35 °,
(c) the form is celecoxib calcium salt, and the X-ray diffraction pattern includes peaks at 11.66, 14.93 and 23.08 °,
(d) the form is celecoxib calcium salt, the X-ray diffraction pattern includes peaks at 9.27, 20.56 and 27.35 °,
(e) the form is celecoxib calcium salt, the X-ray diffraction pattern includes peaks at 16.96, 19.03 and 23.08 °,
(f) the form is a celecoxib calcium salt, and the X-ray diffraction pattern includes a peak at 9.27 °, or
(g) The pharmaceutical composition of claim 7, wherein the form is celecoxib calcium salt and the X-ray diffraction pattern includes peaks at 3.91 and 20.56 °.   9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the active pharmaceutical ingredient is celecoxib and the salt further comprises water or solvent molecules.   The pharmaceutical composition according to claim 9, wherein the solvent molecule is propylene glycol.   A pharmaceutical composition comprising celecoxib sodium salt propylene glycol solvate. The solvate form is characterized by an X-ray powder diffraction pattern comprising a peak expressed in 2θ angle;
(a) the form is a celecoxib sodium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 3.77, 7.57 and 11.33 °;
(b) the form is a celecoxib sodium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 11.33, 18.69 and 20.65 °;
(c) the form is a celecoxib sodium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 16.13, 22.69 and 24.77 °;
(d) the form is a celecoxib sodium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 8.21, 18.69 and 22.69 °;
(e) the form is a celecoxib sodium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 14.23, 20.65 and 24.77 °;
(f) the form is a celecoxib sodium salt propylene glycol solvate, the X-ray diffraction pattern includes a peak at 3.77 °;
(g) the form is a celecoxib sodium salt propylene glycol solvate and the X-ray diffraction pattern includes peaks at 7.57 and 20.65 °, or
12. The pharmaceutical composition of claim 11, wherein (h) the form is a celecoxib sodium salt propylene glycol solvate and the X-ray diffraction pattern includes peaks at 11.33, 16.13, 18.69 and 22.69 °.   The pharmaceutical composition of claim 11, wherein the celecoxib sodium salt propylene glycol solvate is a hydrate.   The pharmaceutical composition according to claim 11, wherein the celecoxib sodium salt propylene glycol solvate is an anhydride or a dihydrate.   A pharmaceutical composition comprising celecoxib potassium salt propylene glycol solvate. The solvate form is characterized by an X-ray powder diffraction pattern comprising a peak expressed in 2θ angle;
(a) the form is a celecoxib potassium salt propylene glycol solvate, the X-ray diffraction pattern includes peaks at 3.75, 7.47 and 18.31 °;
(b) the form is a celecoxib potassium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 11.33, 18.31 and 21.73 °;
(c) the form is a celecoxib potassium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 15.65, 20.49 and 22.51 °;
(d) the form is a celecoxib potassium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 14.89, 18.31 and 24.97 °;
(e) the form is a celecoxib potassium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 15.65, 20.49 and 23.03 °;
(f) the form is a celecoxib potassium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 7.47, 15.65 and 22.51 °;
(g) the form is a celecoxib potassium salt propylene glycol solvate, the X-ray diffraction pattern includes a peak at 3.75 °;
(h) the form is a celecoxib potassium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 7.47 and 18.31 ° , or
(i) said form is a celecoxib potassium salt propylene glycol solvate, X-ray diffraction pattern of claim 1, 5 of a pharmaceutical composition comprising peaks at 11.33,15.65,21.73 and 24.97 °.   16. The pharmaceutical composition of claim 15, wherein the celecoxib potassium salt propylene glycol solvate is an anhydride.   A pharmaceutical composition comprising a celecoxib lithium salt propylene glycol solvate. The solvate form is characterized by an X-ray powder diffraction pattern comprising a peak expressed in 2θ angle;
(a) the form is a celecoxib lithium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 3.79, 11.41 and 15.93 °;
(b) the form is a celecoxib lithium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 18.29, 19.87 and 20.63 °;
(c) the form is a celecoxib lithium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 9.83, 20.63 and 25.09 °;
(d) the form is a celecoxib lithium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 8.19, 16.45 and 19.87 °;
(e) the form is a celecoxib lithium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 19.19, 21.13 and 25.09 °;
(f) the form is a celecoxib lithium salt propylene glycol solvate, and the X-ray diffraction pattern includes a peak at 11.41 °;
(g) the form is a celecoxib lithium salt propylene glycol solvate and the X-ray diffraction pattern includes peaks at 18.29 and 20.63 °, or
(h) said form is a celecoxib lithium salt propylene glycol solvate, X-ray diffraction pattern, the pharmaceutical composition of claim 1 8 comprising peaks at 3.79,8.19,15.93 and 25.09 °.   A pharmaceutical composition comprising trihydrate of celecoxib sodium salt propylene glycol solvate. The trihydrate form is characterized by an X-ray powder diffraction pattern containing a peak expressed in 2θ angle;
(a) the form is a trihydrate of celecoxib sodium salt propylene glycol solvate, the X-ray diffraction pattern includes peaks at 6.95, 13.95 and 25.71 °;
(b) the form is a trihydrate of celecoxib sodium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 3.43, 6.95 and 19.43 °;
(c) the form is a trihydrate of celecoxib sodium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 11.83, 16.39 and 21.21 °;
(d) the form is a trihydrate of celecoxib sodium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 10.25, 18.21 and 22.61 °;
(e) the form is a trihydrate of celecoxib sodium salt propylene glycol solvate, and the X-ray diffraction pattern includes peaks at 12.95, 16.39 and 22.61 °;
(f) the form is a trihydrate of celecoxib sodium salt propylene glycol solvate, the X-ray diffraction pattern contains a peak at 16.39 °,
(g) the form is a trihydrate of celecoxib sodium salt propylene glycol solvate and the X-ray diffraction pattern includes peaks at 6.95 and 21.21 °, or
(h) said form is a trihydrate of celecoxib sodium salt propylene glycol solvate, X-ray diffraction pattern, claim 2 0 pharmaceutical composition comprising peaks at 3.43,10.25,13.95 and 25.71 °.   A pharmaceutical composition comprising celecoxib sodium salt isopropanol solvate. The solvate form is characterized by an X-ray powder diffraction pattern comprising a peak expressed in 2θ angle;
(a) the form is celecoxib sodium salt isopropanol solvate, the X-ray diffraction pattern includes peaks at 3.43, 7.03 and 10.13 °;
(b) the form is a celecoxib sodium salt isopropanol solvate and the X-ray diffraction pattern includes peaks at 11.75, 14.11 and 16.61 °;
(c) the form is celecoxib sodium salt isopropanol solvate, and the X-ray diffraction pattern includes peaks at 17.61, 18.49 and 22.81 °;
(d) the form is celecoxib sodium salt isopropanol solvate, the X-ray diffraction pattern includes peaks at 10.13, 20.97 and 22.81 °;
(e) the form is a celecoxib sodium salt isopropanol solvate and the X-ray diffraction pattern includes peaks at 17.61, 22.81 and 25.93 °;
(f) the form is celecoxib sodium salt isopropanol solvate, the X-ray diffraction pattern includes peaks at 7.03, 16.61 and 18.49 °;
(g) the form is celecoxib sodium salt isopropanol solvate, the X-ray diffraction pattern includes a peak at 16.61 °,
(h) the form is a celecoxib sodium salt isopropanol solvate and the X-ray diffraction pattern includes peaks at 11.75 and 20.97 °, or
(i) said form is a celecoxib sodium salt isopropanol solvate, X-ray diffraction pattern, claim 2 second pharmaceutical composition comprising peaks at 7.03,14.11,17.61 and 22.81 °.   A pharmaceutical composition comprising a hydrate of celecoxib potassium salt. The hydrate is characterized by an X-ray powder diffraction pattern containing a peak expressed in 2θ angle;
(a) the form is a hydrate of celecoxib potassium salt, the X-ray diffraction pattern includes peaks at 3.69, 8.99 and 13.35 °;
(b) the form is a hydrate of celecoxib potassium salt, and the X-ray diffraction pattern includes peaks at 10.65 , 13.35 and 20.05 ° ,
(c) the form is a hydrate of celecoxib potassium salt, and the X-ray diffraction pattern includes peaks at 18.85, 21.45, and 22.39 °;
(d) the form is a hydrate of celecoxib potassium salt, and the X-ray diffraction pattern includes peaks at 3.69, 13.35 and 24.77 °;
(e) the form is a hydrate of celecoxib potassium salt, and the X-ray diffraction pattern includes peaks at 10.65, 18.85 and 26.71 °;
(f) the form is a hydrate of celecoxib potassium salt, the X-ray diffraction pattern includes a peak at 20.05 °,
(g) the form is a hydrate of celecoxib potassium salt and the X-ray diffraction pattern includes peaks at 3.69 and 13.35 °, or
(h) said form is a hydrate of celecoxib potassium salt, the X-ray diffraction pattern, claims 2 to 4 of a pharmaceutical composition comprising peaks at 8.99,18.85,20.05 and 22.39 °.   A pharmaceutical composition comprising a hydrate of celecoxib sodium salt. The pharmaceutical composition according to claim 26 , wherein the hydrate form is a monohydrate or a trihydrate.