Source: http://www.google.com/patents/EP2339328A2?cl=en
Timestamp: 2015-08-29 21:16:33
Document Index: 735600150

Matched Legal Cases: ['Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60']

Patent EP2339328A2 - Pharmaceutical co-crystal compositions of celecoxib - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsThe invention relates to methods of screening mixtures containing a pharmaceutical compound and an excipient to identify properties of the pharmaceutical compound/excipient combination that retard solid-state nucleation. The invention further relates to increasing the solubility, dissolution and bioavailability...http://www.google.com/patents/EP2339328A2?cl=en&utm_source=gb-gplus-sharePatent EP2339328A2 - Pharmaceutical co-crystal compositions of celecoxibAdvanced Patent SearchPublication numberEP2339328 A2Publication typeApplicationApplication numberEP20100193736Publication dateJun 29, 2011Filing dateDec 24, 2003Priority dateDec 30, 2002Also published asEP2339328A3Publication number10193736, 10193736.5, 2010193736, EP 2339328 A2, EP 2339328A2, EP-A2-2339328, EP10193736, EP20100193736, EP2339328 A2, EP2339328A2InventorsMark Tawa, Julius Remenar, Matthew Peterson, Orn Almarsson, Hector Guzman, Hongming Chen, Mark OliveiraApplicantTransform Pharmaceuticals, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (52), Non-Patent Citations (8), Classifications (10), Legal Events (5) External Links: Espacenet, EP RegisterPharmaceutical co-crystal compositions of celecoxib
EP 2339328 A2Abstract
The invention relates to methods of screening mixtures containing a pharmaceutical compound and an excipient to identify properties of the pharmaceutical compound/excipient combination that retard solid-state nucleation. The invention further relates to increasing the solubility, dissolution and bioavailability of a drug with low solubility in gastric fluids conditions by combining the drug with a precipitation retardant and an optional enhancer.
Images(113) Claims(15)
A propylene glycol solvate of a sodium salt of celecoxib having a stoichiometric ratio of 1 celecoxib: 1 sodium: 1 propylene glycol, or a propylene glycol solvate of celecoxib sodium trihydrate having a stoichiometric ratio of 1 celecoxib: 1 sodium: 1 propylene glycol: 3 hydrate.'
A propylene glycol solvate of celecoxib sodium trihydrate according to claim 1 characterized by a thermogravimetric analysis of FIG. 44 or FIG. 46.
A propylene glycol solvate of celecoxib sodium trihydrate according to claim 1 or claim 2 characterized by a thermogravimetric analysis of FIG. 44.
A propylene glycol solvate of celecoxib sodium trihydrate according to claim 1 or claim 2 characterized by a thermogravimetric analysis of FIG. 46.
A propylene glycol solvate of a sodium salt of celecoxib according to claim 1 characterized by a thermogravimetric analysis of FIG. 39.
A propylene glycol solvate of celecoxib sodium trihydrate according to any of claims 1 to 4 characterized by the PXRD pattern of FIG. 45 or FIG. 47.
A propylene glycol solvate of a sodium salt of celecoxib according to claim 1 or claim 5 characterized by a PXRD pattern of FIG. 40A, 40B, 40C or 40D.
A propylene glycol solvate of celecoxib sodium trihydrate according to claim 1 or claim 6 characterized by the PXRD pattern of FIG. 45.
A propylene glycol solvate of celecoxib sodium trihydrate according to claim 1 or claim 6 characterized by the PXRD pattern of FIG. 47.
A propylene glycol solvate of a sodium salt of celecoxib according to claim 1 or claim 7 characterized by a PXRD pattern of FIG. 40A.
A propylene glycol solvate of a sodium salt of celecoxib according to claim 1 or claim 7 characterized by a PXRD pattern of FIG. 40B
A propylene glycol solvate of a sodium salt of celecoxib according to claim 1 or claim 7 characterized by a PXRD pattern of FIG. 40C
A propylene glycol solvate of a sodium salt of celecoxib according to claim 1 or claim 7 characterized by a PXRD pattern of FIG. 40D
A propylene glycol solvate of celecoxib sodium trihydrate according to any of claims 1 to 4, 6, 8, and 9, wherein the propylene glycol solvate of celecoxib sodium trihydrate is comprised in a pharmaceutical composition, and wherein the pharmaceutical composition further comprises an excipient.
A propylene glycol solvate of a sodium salt of celecoxib according to any of claims 1, 5, 7, and 10 to 13 wherein the propylene glycol solvate of a sodium salt of celecoxib is comprised in a pharmaceutical composition, and wherein the pharmaceutical composition further comprises an excipient.
[0001] This application has been converted from U.S. Provisional Application No. 60/390,881, filed on June 21, 2002 which is hereby incorporated by reference for all purposes. This application also claims priority to U.S. Provisional Application No. 60/426,275, filed on November 14, 2002 ; U.S. Provisional Application No. 60/427,086 filed on November 15, 2002 ; U.S. Provisional Application No. 60/429,515 filed on November 26, 2002 ; U.S. Provisional Application No. 60/437,516 filed on December 30, 2002 ; and U.S. Provisional Application No. 60/456,027 filed on March 18, 2003 which are hereby incorporated by reference for all purposes.
[0002] The present invention relates to pharmaceutical compositions and methods for preparing same.
[0003] Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide) is a substituted pyrazolylbenzenesulfonamide represented by the structure (I):
[0004] Celecoxib belongs to the general class of non-steroidal anti-inflammatory drugs (NSAIDs), Unlike traditional NSAIDs, celecoxib is a selective inhibitor of cyclooxygenase II (COX-2) that causes fewer side effects when administered to a subject. The synthesis and use of celecoxib are further described in U.S. Pat. Nos. 5,466,823 , 5,510,496 , 5,563,165 , 5,753,688 , 5,760,068 , 5,972,986 , 6,156,781 , and 6,579,895 , the contents of which are incorporated by reference in their entireties. Orally deliverable liquid formulations of celecoxib are discussed in U.S. Patent Application Publication No. 2002/0107250 , the contents of which are incorporated herein by reference in their entirety.
[0005] Other COX-2 inhibitory drugs are related to celecoxib, which form part of a larger group of drugs, all of which are benzene sulfonamides. These include: deracoxib, which is 4-[3-fluoro-4-methoxyphenyl)-3-difluoromethyl-1H-pyrazol-1-yl]benzene sulfonamide; valdecoxib, which is 4-[5-methyl-3-phenyl isoxazol-4-yl]benzene sulfonamide; rofecoxib, which is 3-phenyl-4-[-(methylsulfonyl)phenyl]-5H-furan-2-one; and etoricoxib, which is 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine. These drugs are described in further detail in WO 01/78724 and WO 02/102376 .
[0006] In its commercially available form, trademarked as CELEBREX, celecoxib is a neutral molecule that is essentially insoluble in water. Celecoxib typically exists as needle-like crystals, which tend to aggregate into a mass. Aggregation occurs even when celecoxib is mixed with other substances, such that a non-uniform mixture is obtained. These properties are shared by other pyrazolylbenzenesulfonamides and present significant problems in preparing pharmaceutical formulations of the drugs, particularly oral formulations.
[0007] It would be advantageous to provide new forms of drugs that have low aqueous dissolution which have improved properties, in particular as oral formulations. In particular, even where an active pharmaceutical ingredient (API) of low aqueous solubility is provided in a form which has improved aqueous solubility, there still exists a problem when dissolution of the API is required, for example after having been taken as an oral formulation where the API becomes diluted in the alimentary canal. (The terms "API" and "pharmaceutical" are used herein interchangeably.) In this situation, APIs having low aqueous solubility tend to come out of solution. When this happens, for example by a process of crystallization or precipitation, the bioavailability of the API is significantly decreased. It would therefore be desirable to improve the properties of formulations containing such APIs so as to increase the bioavailability of the API in an orally-administered form, thereby providing a more rapid onset to therapeutic effect.
[0008] It has now been found that stable, crystalline salts and co-crystals of celecoxib can be synthesized. The celecoxib compositions of the present invention have a greater solubility, dissolution, total bioavailability (area under the curve or AUC), lower Tmax, the time to reach peak blood serum levels, and higher Cmax,, the maximum blood serum concentration, than neutral celecoxib. The celecoxib compositions of the present invention also include compounds that are less hygroscopic and more stable. The celecoxib salts of the present invention when in crystalline form convert to either an amorphous free form of celecoxib upon neutralization of the salt, which subsequently converts to a neutral metastable crystalline form or directly to a neutral metastable crystalline form. These amorphous and metastable crystalline forms of neutral celecoxib are more readily available forms of the API than is presently-marketed neutral celecoxib. Neutral crystalline celecoxib is presently-marketed as CELEBREX, and is designated as "neutral" to distinguish it from the ionized salt form of celecoxib. In addition, acidification or neutralization of a solution of the celecoxib salt in situ yields amorphous celecoxib, which subsequently converts to a metastable crystalline form or directly to a neutral metastable crystalline form of neutral celecoxib before finally converting into stable, neutral celecoxib.
[0009] An aspect of the present invention relates to methods of increasing dissolution, solubility, and or the time an API (either alone or as part of a pharmaceutical composition), can be maintained, upon dissolution, as a supersaturated solution, before precipitating out of solution. The increase in dissolution (or concentration as a function of time) results in, and thus can be represented by an increase in bioavailability, AUC, reduced time to Tmax or increased Cmax. The methods comprise the steps of making a salt or co-crystal from an API (e.g. free acid) and combining the salt or co-crystal with a precipitation retardant and optionally, a precipitation retardant enhancer (referred to as enhancer hereafter). The term "precipitation" refers to either a crystalline or amorphous solid form separating or "coming out of" the solution. The salt may be amorphous or crystalline, but is preferably crystalline. Normally the salt or co-crystal form used is in a crystalline form that dissolves and then recrystallizes and precipitates out of solution, which is why the term "crystallization" retardant may be used in place of "precipitation" for greater specificity. The term "crystallization" retardant can also be used to specify a salt or co-crystal that was in amorphous form prior to dissolution, and precipitates out of solution in crystalline form after dissolution. Crystalline salts are superior to amorphous salts as the initial compound, with an amorphous salt being superior to a neutral amorphous or crystalline form. Free acid forms are not preferred initial compounds unless first solubilized in a solubilizer resulting in a liquid formulation comprising a precipitation retardant and optional enhancer. The precipitation retardant is often a surfactant, preferably a surfactant with an ether functional group, preferably a repeating ether group, e.g., an ether group repeated at least two or three times wherein the oxygen atoms are separated by 2 carbon atoms. Further preferred surfactants have an interfacial tension of less than 10 dynes per centimeter when measured at a concentration of 0.1 percent w/w in water at 25 degrees C and/or the surface tension of the precipitation retardant (e.g., poloxamers) is less than 42 dynes/cm when measured as a concentration of 0.1 %w/w in water at 25 degrees C. The combination of salt or co-crystal, precipitation retardant and an optional enhancer (or precipitation retardant, an optional enhancer and some other form) preferably prevents or delays precipitation of a supersaturated solution by about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes or greater than 1 hour in an aqueous solution, preferably water or gastric fluid conditions such as the gastric fluids of an average human stomach fasted for 12 hours or simulated gastric fluid (SGF). Preferably, the solution remains supersaturated for more than 15, 20, or 30 minutes to allow the composition to move out of the stomach and into an environment with a higher pH. The SGF may be diluted by 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold to represent water intake. For example, the SGF may be diluted 5 fold to represent a patient drinking a glass of water at the time a composition of the present invention is taken orally. The degree of increase in solubility, dissolution, and/or supersaturation may be specified, such as by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or by 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 fold greater than neutral celecoxib (e.g., free acid) in the same solution. The increase in dissolution may be further specified by the time the composition remains supersaturated.
[0010] The enhancer preferably comprises a cellulose ester such as hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC). Thus according to the methods of the present invention, supersaturated concentrations upon which a drug may be maintained upon dissolution and/or the degree of dissolution of a drug in gastric fluid conditions (e.g., SGF) is enhanced.
[0011] Normally, the enhancer does not improve or only minimally improves (less than/equal to 10%) the length of time the API can remain supersaturated without the additional presence of the precipitation retardant. The methods of the present invention are used to make a pharmaceutical drug formulation with greater solubility, dissolution, and bioavailability, AUC, reduced time to Tmax, the time to reach peak blood serum levels, and higher Cmax,, the maximum blood serum concentration, when compared to the neutral form or salt alone. AUC is the area under the plot of plasma concentration of drug (not logarithm of the concentration) against time after drug administration. The area is conveniently determined by the "trapezoidal rule": the data points are connected by straight line segments, perpendiculars are erected from the abscissa to each data point, and the sum of the areas of the triangles and trapezoids so constructed is computed. When the last measured concentration (Cn, at time tn) is not zero, the AUC from tn to infinite time is estimated by Cn/kel.
[0012] The AUC is of particular use in estimating bioavailability of drugs, and in estimating total clearance of drugs (C1T). Following single intravenous doses, AUC = D/C1T, where D is the dose, for single compartment systems obeying first-order elimination kinetics; alternatively, AUC = C0/Kel, where kel is the drug elimination rate constant. With routes other than the intravenous, AUC = F • D/C1T, where F is the absolute bioavailability of the drug.
[0013] The invention further relates to wherein a precipitation retardant and an optional enhancer is combined with a pharmaceutical that is already in a salt or co-crystal form. The invention further relates to wherein a precipitation retardant and an optional enhancer is combined with a pharmaceutical that is a solvate, desolvate, hydrate, dehydrate, or anhydrous form of a salt or co-crystal form.
[0014] Accordingly, in a further aspect, the present invention provides a pharmaceutical composition comprising:
(a) an API having low aqueous solubility or dissolution, preferably in gastric fluid conditions; (b) a precipitation retardant; and (c) an optional enhancer. [0015] In a further aspect, the present invention provides a pharmaceutical composition comprising:
(a) an API having low aqueous solubility or dissolution, preferably in gastric fluid conditions; (b) a precipitation retardant having an interfacial tension of less than 10 dyne/cm or a surface tension of less then 42 dyne/cm; and (c) an optional enhancer. [0016] In a further aspect, the present invention provides a pharmaceutical composition comprising:
(a) an API having low aqueous solubility or dissolution, preferably in gastric fluid conditions; (b) a surfactant; and (c) an optional enhancer. [0017] In a further aspect, the present invention provides a pharmaceutical composition comprising:
(a) an API having low aqueous solubility or dissolution, preferably in gastric fluid conditions; (b) a poloxamer having an interfacial tension of less than 10 dyne/cm or surface tension less then 42 dyne/cm; and (c) an optional enhancer. [0018] In a further aspect, the present invention provides a pharmaceutical composition comprising:
(a) an API having low aqueous solubility or dissolution, preferably in gastric fluid conditions; (b) a surfactant; and (c) a cellulose ester. [0019] In a further aspect, the present invention provides a pharmaceutical composition comprising:
(a) an API having low aqueous solubility or dissolution, preferably in gastric fluid conditions; (b) a surfactant having an interfacial tension of less than 10 dyne/cm or surface tension less then 42 dyne/cm; and (c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC). [0020] In a further aspect, the present invention provides a pharmaceutical composition comprising:
(a) an API having low aqueous solubility or dissolution, preferably in gastric fluid conditions; (b) a poloxamer; and (c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC). [0021] In a further aspect, the present invention provides a pharmaceutical composition comprising:
(a) an API having low aqueous solubility or dissolution, preferably in gastric fluid conditions; (b) a poloxamer having an interfacial tension of less than 10 dyne/cm or surface tension less then 42 dyne/cm; and (c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC). [0022] In a further aspect, the present invention provides a pharmaceutical composition comprising
(a) celecoxib; (b) a poloxamer surfactant having an interfacial tension at a concentration of 0.1% of less than 10 dyne/cm or surface tension less then 42 dyne/cm; and (c) hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC). [0023] In a further aspect, the present invention provides a process for producing a pharmaceutical composition for delivering a supersaturated concentration of a drug having low aqueous dissolution, preferably in gastric fluid conditions, which comprises intimately mixing together the components of the above aspects or elsewhere herein.
[0024] In a further aspect, the surfactant is at a concentration of less than 5 %, 4 %, 3 %, 2 %, 1%, 0.9 %, 0.8 %, 0.7 %, 0.6 %, 0.5 %, 0.4 %, 0.3 %, 0.2 %, or 0.1 % or at a concentration of 0.1 % (w/w) upon dissolving in the dissolution medium.
[0025] The present invention further provides a process for producing a pharmaceutical composition, which comprises:
(1) providing a plurality of containers; (2) providing a plurality of excipient solutions; (3) providing a plurality of compound solutions, each having dissolved therein a pharmaceutical compound; (4) dispensing into each container one of the excipient solutions with one of the compound solutions so as to form an intimate mixture, a property of each mixture being varied in different containers; (5) incubating the mixture; (6) determining onset of solid-state nucleation or precipitation; (7) selecting a pharmaceutical compound/excipient combination whereby onset of solid-state nucleation is retarded; and (8) producing a pharmaceutical composition comprising the pharmaceutical compound/excipient combination. [0026] Applicants found that it is possible to screen mixtures containing a pharmaceutical compound and an excipient in a rapid and simple manner so as to identify which properties of the pharmaceutical compound/excipient combination retard (inhibit) solid-state nucleation. The term "solid-state nucleation" is used herein to refer to the initiation of solidification, whether amorphous or crystalline, but may be specified as being amorphous or crystalline. In this way, those excipients or other properties of the combination can be chosen for the production of a pharmaceutical composition in which the API remains in solution for a sufficient time after administration to a subject. In this way, pharmaceutical compositions which attain at least a minimum bioavailability of the API may be readily produced based on a straightforward in vitro screen.
[0027] Various properties of a pharmaceutical composition may affect the onset of solid-state nucleation or precipitation of the API. Such properties include the identity or amount of the excipient and the identity or amount of the pharmaceutical compound in the composition. Other properties may include the amount of other diluents or carriers such as salts or buffering compounds. The pharmaceutical compound itself may be screened in a variety of different forms if it is capable of polymorphism. Additionally, different salt, solvate, hydrate, co-crystal and other forms of the API may be screened in accordance with the invention.
[0028] The invention is readily applicable to screening a large variety of different excipients. Accordingly, in a preferred aspect, the present invention provides a process for producing a pharmaceutical composition, which comprises:
(1) providing a plurality of containers; (2) providing a plurality of excipient solutions; (3) providing a plurality of compound solutions, each having dissolved therein a pharmaceutical compound; (4) dispensing into each container one of the excipient solutions with one of the compound solutions so as to form an intimate mixture, the excipient being varied in different containers; (5) incubating the mixture; (6) determining onset of solid-state nucleation or precipitation; (7) selecting an excipient which is found to retard onset of solid-state nucleation or precipitation; and (8) producing a pharmaceutical composition comprising the pharmaceutical compound and the selected excipient. [0029] According to this embodiment, it is the excipient which is varied. Different excipients may be used in different containers and may be present as a single excipient or in a combination of a plurality of excipients, for example, a binary, ternary, tertiary or higher order combination.
[0030] In a further aspect, the present invention provides a pharmaceutical composition obtained by processes according to the invention. The pharmaceutical composition may comprise a further excipient, diluent or carrier. In a preferred aspect, the pharmaceutical composition is formulated for oral administration.
[0031] The invention further provides a method for assessing excipient-mediated retardation of solid-state nucleation or precipitation of a pharmaceutical compound, which method comprises:
(1) providing a plurality of containers; (2) providing a plurality of excipient solutions; (3) providing a plurality of compound solutions, each having dissolved therein a pharmaceutical compound; (4) dispensing into each container one of the excipient solutions with one of the compound solutions so as to form an intimate mixture, a property of each mixture being varied in different containers; (5) incubating the mixture; (6) determining onset of solid-state nucleation or precipitation; and (7) ranking the property of the mixture according to time of onset of solid-state nucleation or precipitation. [0032] In a further aspect the present invention provides a method for screening excipients that retard solid-state nucleation or precipitation of a pharmaceutical compound, which method comprises:
(1) providing a plurality of containers; (2) providing a plurality of excipient solutions; (3) providing a plurality of compound solutions, each having dissolved therein a pharmaceutical compound; (4) dispensing into each container one of the excipient solutions with one of the compound solutions so as to form an intimate mixture, the excipient being varied in different containers; (5) incubating the mixture; (6) determining onset of solid-state nucleation or precipitation; and (7) ranking the excipient according to time of onset of solid-state nucleation or precipitation. [0033] Generally speaking, the active pharmaceutical ingredient (API) is typically capable of existing as a supersaturated solution, preferably in an aqueous-based medium. The API may be a free acid, free base, co-crystal or salt, or a solvate, hydrate or dehydrate thereof. The invention is particularly applicable to pharmaceutical compositions comprising an API which, when in contact with a body fluid such as gastric juices or intestinal fluids, would be likely to precipitate or crystallize from solution in a nucleation event. Accordingly, the invention is particularly applicable to pharmaceutical compounds which may have relatively low solubility, or dissolution, as defined herein, when in contact with bodily fluids but possibly relatively high solubility, or dissolution, in appropriate in vitro conditions.
[0034] According to the invention, the compound solution is a solution wherein the compound is solubilized and may be a non-aqueous solution or an aqueous solution with a pH adjusted to accommodate the compound. For example, in order to achieve high solubility of the compound, a free base-type compound would be dissolved in aqueous solution at acidic pH whereas a free acid-type compound would be dissolved in an aqueous solution of basic pH. The compound solution may therefore be, and preferably is, a supersaturated solution when compared to water, gastric fluids or intestinal fluids. It would also be preferred for the excipient to be in a solution comprising water, usually deionised water, or another aqueous based solution. In one aspect, the mixture simulates gastric fluid (SGF) or intestinal fluids (SIF, 0.68% monobasic potassium phosphate, 1% pancreatin, and sodium hydroxide where the pH of the final solution is 7.5.) and in this aspect it is preferred that the excipient is added in a solution simulating those body fluids. Alternatively, further additives, usually in solution, may be added to form the mixtures creating an environment appropriate for the screening to be undertaken.
[0035] One advantage of the present invention is that the plurality of containers may be presented in a multiple well plate format or block and tube format such that at least 24, 48, 96, 384, or 1536 samples are assayed in parallel. Multiple block and tubes or multiwell plates may be assayed such that at least 1000, 3000, 5000, 7000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, or 100000 total samples are assayed. This is advantageous because the process may be operated in a semi-automated or automated way using existing multiple well plate format-based apparatus. At least the step of dispensing may be performed with automated liquid handling apparatus. Accordingly, it is possible to operate the process as a high throughput screen. Additionally, using a multiple well plate format, the scale of the screening is relatively low. For example, each sample may contain less than 100 mg, 50mg, 25mg, 10, mg, 5 mg, 750 micrograms, 500 micrograms, 250, micrograms, 100 micrograms, 75 micrograms, 50 micrograms, 25 micrograms, 10 micrograms, 1 microgram, 750 ng, 500 ng, 250 ng, 100 ng, or less than 50 ng, depending on the API, sample size, etc. This, therefore, minimizes the amount of API which is needed to identify excipients or properties of the combination of pharmaceutical compound and excipient that retard onset of nucleation. In this way, improved speed and relatively low cost are advantages.
[0036] The intimate mixture formed in the process may be achieved by any conventional method, including the use of a mixer during or after dispensing of the solutions. Once the mixture has been formed, it is generally advantageous to incubate the mixture at a constant temperature, such as approximately 37 degrees C, to simulate in vivo conditions.
[0037] Measurement of onset of solid-state nucleation or precipitation may be determined for example, by measuring the light scattering of a mixture. This may be achieved by any conventional light scattering measurement, such as the use of a nephelometer. It is also possible to include a further step in which the crystallinity of the products of the solid-state nucleation or precipitation is determined. This step is conveniently performed before selecting the pharmaceutical compound/excipient combination for use in the pharmaceutical composition. Crystallinity may be determined, e.g., by birefringence screening.
[0038] Neither the light scattering measurement nor the birefringence screening are invasive measurement techniques. Advantageously, a portion or all of the sample solution does not need to be transferred to a second container and the containers or wells can be sealed with a transparent seal to allow use of these techniques.
[0039] In its most general aspect, the present invention relates to a pharmaceutical composition which includes an API having a low aqueous solubility or dissolution (as defined herein). Typically, low aqueous solubility in the present application refers to a compound having a solubility in water which is less than or equal to 10 mg/mL, when measured at 37 degrees C, and preferably less than or equal to 1 mg/mL. The invention relates more particularly to drugs which have a solubility of not greater than 0.1 mg/mL. The invention further relates to compounds that cannot be maintained as a supersaturated solution in gastric or intestinal fluid or in SGF or SIF. Such drugs include some sulfonamide drugs, such as the benzene sulfonamides, particularly those pyrazolylbenzenesulfonamides discussed above, which include 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.
[0040] It is preferred that the pharmaceutical composition is formulated for oral administration. Drugs according to the invention may be prepared in a form having reduced time to onset of therapeutic effectiveness (the time when an effect for which the drug is administered can be identified or measured, e.g., the point in time when a reduction in fever or pain felt by a patient begins to occur) or increased bioavailability. The pharmaceutical compositions according to the invention are therefore particularly suitable for administration to human subjects.
[0041] Fig. 1 shows a reproduction of a differential scanning calorimetry (DSC) thermogram of the sodium salt of celecoxib prepared by Example 1 between 50 degrees C and 110 degrees C.
Fig. 2 shows a reproduction of a thermogravimetric analysis (TGA) thermogram of the sodium salt of celecoxib prepared by Example 1, which was conducted from about 30 degrees C to about 160 degrees C.
Fig. 3 shows a reproduction of a PXRD diffractogram of the sodium salt of celecoxib prepared by Example 1.
Figs. 4A and 4B show pharmacokinetics in male Sprague-Dawley rats after 5 mg/kg oral doses of the celecoxib crystal form used in the marketed formulations and the sodium salt of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, as obtained following the protocol described in Example 4.
Figs. 5A and 5B show the formulations and mean pharmacokinetic parameters (and standard deviations thereof) of celecoxib in the plasma of male dogs following a single oral or single intravenous dose of celecoxib or celecoxib sodium salt.
Fig. 5C shows a linear dose response with a plot of AUC versus dose.
Fig. 6 shows the mean concentrations of celecoxib in plasma following the administration of a single oral dose of celecoxib or celecoxib sodium or a single intravenous dose of celecoxib in male dogs.
Fig. 7 shows the effect of varying ratios of ethylene glycol to propylene glycol subunits in poloxamers on the concentration of celecoxib sodium salt in solution.
Fig. 8 shows the effect of different celluloses on the dissolution of various compositions comprising equal weights of cellulose (hydroxypropylcellulose (HPC, 100,000 kDa), low-viscosity hydroxypropylmethylcellulose (low-density HPMC, viscosity 80-120 cps), high-viscosity hydroxypropylmethylcellulose (high-density HPMC, viscosity 15,000 cps), or microcrystalline cellulose (Avicel PH200)), in d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TPGS) and celecoxib sodium.
Fig. 9 shows the dissolution at 37 degrees C for compositions comprising various weight ratios of d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TGPS), hydroxypropylcellulose, and celecoxib sodium salt.
Fig. 10 shows the dissolution profile of celecoxib sodium salt in simulated gastric fluid (SGF) from solid mixtures with excipients at room temperature. The legend indicates the excipient and the weight ratio of excipient to celecoxib sodium (if unmarked, 1:1). Excipients include polyvinylpyrrolidone (PVP), poloxamer 188 (P188), poloxamer 237 (P237), d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TPGS), and Gelucire™ 50/13.
Fig. 11 shows the effect of Avicel microcrystalline cellulose and silica gel on the dissolution of mixtures of celecoxib sodium salt, d-alpha-tocopherol polyethylene glycol-1000 succinate (vit E TGPS), and hydroxypropylcellulose (HPC) mixtures in simulated gastric fluid (SGF) at 37 degrees C. The legend indicates the weight ratios of the components.
Fig. 12 shows the dissolution of celecoxib sodium salt in 5-times diluted simulated gastric fluid, with excipients including d-alpha-tocopherol polyethylene glycol-1000 succinate (vitamin E TPGS), hydroxypropylcellulose (HPC), and poloxamer 237. The legend indicates the weight ratios of the components.
Figs. 13A and 13B show the PXRD diffractogram and Raman spectrum, respectively, of the sodium salt of celecoxib prepared by the method of Example 6.
Fig. 14 shows a differential scanning calorimetry (DSC) thermogram of celecoxib lithium salt MO-116-49B.
Fig. 15 shows a thermogravimetric analysis (TGA) thermogram of celecoxib lithium salt MO-116-49B.
Fig. 16 shows the RAMAN spectrum of celecoxib lithium salt MO-116-49B.
Fig. 17 shows the PXRD diffractogram of celecoxib lithium salt MO-116-49B.
Fig. 18 shows a differential scanning calorimetry (DSC) thermogram of celecoxib potassium salt MO-116-49A.
Fig. 19 shows a thermogravimetric analysis (TGA) thermogram of celecoxib potassium salt MO-116-49A.
Fig. 20 shows the RAMAN spectrum of celecoxib potassium salt MO-116-49A.
Fig. 21 shows the PXRD diffractogram of celecoxib potassium salt MO-116-49A.
Fig. 22 shows a thermogravimetric analysis (TGA) thermogram of celecoxib potassium salt MO-116-55D.
Fig. 23 shows the RAMAN spectrum of celecoxib potassium salt MO-116-55D.
Fig. 24 shows the PXRD diffractogram of celecoxib potassium salt MO-116-55D.
Fig. 25 shows a thermogravimetric analysis (TGA) thermogram of celecoxib calcium salt MO-116-62A.
Fig. 26 shows the RAMAN spectrum of celecoxib calcium salt MO-116-62A.
Fig. 27 shows the PXRD diffractogram of celecoxib calcium salt MO-116-62A.
Fig. 28 shows the PXRD diffractogram of commercially-available celecoxib.
Fig. 29 shows the RAMAN spectrum of commercially-available celecoxib.
Fig. 30 shows crystal retardation time for celecoxib as a function of excipient in simulated gastric fluid (SGF).
Fig. 31A shows interfacial tension of selected PLURONIC excipients in water.
Fig. 31B shows that Pluronic concentrations greater than or equal to the CMC are preferred for effective precipitation inhibition.
Fig. 32 shows dissolution of celecoxib sodium hydrate from compositions containing PLURONIC P123 and F127.
Fig. 33 shows dissolution of celecoxib sodium hydrate from PLURONIC P123, F127 and F87, in the presence of HPC.
Fig. 34 shows dissolution of celecoxib sodium hydrate using PLURONIC F127, HPC and a granulating fluid.