Composition containing ciprofloxacin and celecoxib

Abstract

An embodiment relates to a tablet comprising celecoxib, and ciprofloxacin or a pharma- ceutically acceptable salt thereof, and a low viscosity hydroxypropyl methylcellulose having a viscosity of less than 150 cP when measured as a 2% solution in water at 20°C.

Description

[Technical Field]

[0001] Cross-reference of related applications We claim interest in U.S. Provisional Patent Application No. 63 / 257,130, filed on 19 October 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] Dosage forms comprising ciprofloxacin or a pharmaceutically acceptable salt thereof and celecoxib are provided. [Background technology]

[0003] Ciprofloxacin is an antibiotic sold in many countries for the treatment of various bacterial infections and can be administered orally and through other routes. It is available, for example, in the form of a salt, such as hydrochloride, and has the following structure: [ka]

[0004] Celecoxib is a COX-2 inhibitor administered orally and is used to treat pain or inflammation associated with various conditions. The structure of celecoxib is as follows: [ka]

[0005] PCT Patent Application Publication (WO) 2018 / 235082 (incorporated herein by reference) discloses a combination of ciprofloxacin and celecoxib for the treatment of various motor neuron diseases, including but not limited to amyotrophic lateral sclerosis (ALS). [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Patent Application Publication No. 2018 / 235082 [Overview of the project] [Means for solving the problem]

[0007] overview This specification describes sustained-release compositions, such as tablets, containing ciprofloxacin or a pharmaceutically acceptable salt thereof, and celecoxib. For example, provided herein are tablets containing celecoxib, a pharmaceutically acceptable salt of ciprofloxacin, and low-viscosity hydroxypropyl methylcellulose having a viscosity of 2 cP to 150 cP when measured as a 2% aqueous solution at 20°C.

[0008] This specification further includes: A method (step) for producing tablets is described, comprising: forming granules containing celecoxib and ciprofloxacin or a pharmaceutically acceptable salt of ciprofloxacin; adding low viscosity hydroxypropyl methylcellulose, which has a viscosity of less than 150 cP when measured as a 2% aqueous solution at 20°C, to the granules to form a mixture; and compressing the mixture to form tablets.

[0009] Furthermore, this specification describes a method for treating amyotrophic lateral sclerosis (ALS) in patients in need, comprising administering to a patient a composition comprising ciprofloxacin or a pharmaceutically acceptable salt thereof, and celecoxib.

[0010] The above and other objectives, features, and benefits will become clearer from the following detailed explanation, which will proceed with reference to the attached diagrams. [Brief explanation of the drawing]

[0011] [Figure 1] Figure 1 shows a graph of normalized mean plasma concentrations over time in healthy volunteers after administration of ciprofloxacin and celecoxib, compared to administration on day 7, comparing administration with a combination tablet containing ciprofloxacin and celecoxib (PrimeC) and administration with a reference tablet (Ref). [Modes for carrying out the invention]

[0012] Detailed explanation term Unless otherwise specified, technical terms will be used according to their conventional usage. Definitions of common molecular biology terms can be found in: Benjamin Lewin, Genes V, Oxford University Press, 1994 (ISBN 0-19-854287-9); Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, published in 1994 by Blackwell Science Ltd. (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published in 1995 by VCH Publishers, Inc. (ISBN 1-56081-569-8).

[0013] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. Further, all base sizes or amino acid sizes, and all molecular weight or molecular mass values given for nucleic acids or polypeptides are approximate and are provided for illustrative purposes. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The term "comprise" means "include." The abbreviation "e.g." is derived from the Latin "exempli gratia" and is used herein to indicate non-limiting examples. Thus, the abbreviation "e.g." is synonymous with the term "for example."

[0014] In case of conflict, the present specification, including explanations of terms, will control. Further, all materials, methods, and examples are illustrative only and not intended to be limiting.

[0015] Extragranular: In the process of tablet formation, granules containing an active ingredient combined with at least one excipient are often formed. Through the granulation process, fine powders are converted into free-flowing, easily compressible, dust-free granules. The granules can then be mixed by blending with additional excipients or active ingredients. The final blend is either filled into capsules or compressed into tablets. The term "extragranular" refers to the portion of the tablet that is not part of the granules.

[0016] Intragranular: The portion of the composition within the granules in a tablet composition formed through the granulation process.

[0017] Pharmaceutically acceptable salts: A "salt" is a salt of an active compound such as ciprofloxacin, which is modified by forming an acid salt or a base salt of the compound. This refers to the relatively non-toxic inorganic and organic acid or base addition salts of the compounds of the present invention. These salts can be prepared in situ in the process of preparing a pharmaceutical dosage form, or separately, by reacting the purified compound of the present invention in the form of a free base with a suitable organic acid or inorganic acid and isolating the formed salt. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, and mesylate, etc.

[0018] Steady State: A state in which the amount of drug excreted per unit time is equal to the amount of drug reaching the systemic circulation per unit time.

[0019] Summary of Multiple Embodiments Compositions comprising celecoxib and ciprofloxacin or a pharmaceutically acceptable salt of ciprofloxacin are provided herein.

[0020] For example, compositions are provided in which the ratio of celecoxib to ciprofloxacin or its pharmaceutic salt is 1:1 to 1:100, optionally 1:4, 1:10, 1:25, based on the weight of celecoxib relative to the weight of ciprofloxacin free base. The exemplary tablets described herein contain 34 mg of celecoxib and 340 mg of ciprofloxacin or a pharmaceutically acceptable salt of ciprofloxacin per tablet, which is an amount that delivers 340 mg of ciprofloxacin (e.g., 377.41 mg of ciprofloxacin hydrochloride per dosage form or tablet, which corresponds to 340 mg of ciprofloxacin free base), and thus the weight ratio of celecoxib to ciprofloxacin free base is 1:10.

[0021] According to some embodiments, compositions comprising celecoxib and ciprofloxacin or its pharmaceutically acceptable salts have one or more of the following solubility properties: 1. When placed in 750 ml of 0.1 N hydrochloric acid (HCl) at 75 revolutions per minute (RPM) in a Type II apparatus, the dissolution of ciprofloxacin should be less than 70% within 2 hours, preferably between 40% and 65%. 2. When placed in 750 ml of 0.1 N hydrochloric acid at 37°C at 100 revolutions per minute (RPM) in a Type II apparatus, the dissolution of ciprofloxacin should be less than 80% within 2 hours, preferably between 40% and 65%. 3. When a Type II apparatus is placed in 750 ml of 0.1 N hydrochloric acid at 75 RPM and 37°C, and then the medium is changed (modified) after 2 hours to form a pH 6.8 phosphate buffer containing 1% SLS, the total solubility of ciprofloxacin shall be at least 70% within 6 hours and / or less than 75% within 4 hours. 4. When placed in 750 ml of 0.1 N hydrochloric acid at 100 RPM, 37°C in a Type II apparatus, and then after 2 hours the medium is changed to form a pH 6.8 phosphate buffer containing 1% SLS, the total solubility of ciprofloxacin shall be at least 80% within 6 hours and / or less than 80% within 4 hours. 5. When the celecoxib is placed in 750 ml of 0.1 N hydrochloric acid at 75 RPM and 37°C in a Type II apparatus, and then the medium is changed after 2 hours to form a pH 6.8 phosphate buffer containing 1% SLS, the total dissolution of celecoxib is at least 80% within 12 hours and / or less than 85% within 8 hours, more preferably less than 80% within 8 hours. 6. When the celecoxib is placed in 750 ml of 0.1 N hydrochloric acid at 100 RPM, 37°C in a Type II apparatus, and then the medium is changed after 2 hours to form a pH 6.8 phosphate buffer containing 1% SLS, the total solubility of celecoxib shall be at least 80% within 8 hours and / or less than 80% within 6 hours. 7. When a Type II apparatus is used, placed in 750 ml of 0.1 N hydrochloric acid at 75 RPM and 37°C, and then after 2 hours the medium is changed to form a pH 6.8 phosphate buffer containing 1% SLS, the total solubility of both ciprofloxacin and celecoxib shall exceed 45% after 3 hours and be less than 90% after 6 hours. 8. When placed in a Type II apparatus at 75 RPM and 37°C in 900 ml of acetate buffer pH 4.5 containing 1% SLS, the dissolution of ciprofloxacin and celecoxib should be 10% to 30% after 1 hour, 30% to 70% after 4 hours, and over 85% after 12 hours.

[0022] According to some embodiments, the composition comprises low-viscosity hydroxypropyl methylcellulose (HPMC). HPMC is a binder and a controlled-release agent used in the matrix system of oral pharmaceutical dosage forms such as tablets. HPMC is an excipient having monomers in which the cellulose backbone is substituted with methyl and hydroxypropyl groups. The amount of substitution determines the properties of HPMC. One of the properties of HPMC is its viscosity, which is usually measured as a 2% aqueous solution at 20°C. Preferably, the HPMC used in the compositions described herein has a low viscosity of less than 150 centipoise (cP) and more than 2 cP. Preferably, the viscosity of the HPMC used in the composition is 40 to 60 cP.

[0023] Examples of HPMC types are listed below. JPEG0007857044000003.jpg97153

[0024] Pharmacoat 603, 645, 606, and 615 are exemplary HPMCs having a viscosity of less than 150 cP and containing methoxyl: 29% (28.0% to 30.0%) and hydroxypropoxyl: 10% (7.0% to 12.0%).

[0025] Methocel E50 LV is an exemplary HPMC having a viscosity of less than 150 cP and containing methoxyl: 29% (28.0% to 30.0%) and hydroxypropoxyl: 10% (7.0% to 12.0%).

[0026] Methocel E15 Premium LV is an exemplary HPMC with a viscosity of less than 150 cP and containing methoxyl: 29% (28.0% to 30.0%) and hydroxypropoxyl: 10% (7.0% to 12.0%).

[0027] Methocel K100 LV is an exemplary HPMC with a viscosity of less than 150 cP, containing methoxyl: 19.0-24.0%, hydroxypropoxyl: 7.0-12.0%, viscosity (2% in water at 20°C): 80-120 cP, and a maximum moisture content of 3.0 at packaging.

[0028] Preferably, the amount of HPMC present in the composition is 3% to 10% of the composition's weight. Optionally, the amount of HPMC present in the composition is 5% by weight of the tablet core.

[0029] Preferably, the amount of HPMC present in the composition is 4% to 15% of the total weight of celecoxib and ciprofloxacin salt, which are the active ingredients of the tablet. Preferably, the weight of HPMC present in the composition is 6% to 8% of the total weight of the active ingredients of the tablet. Preferably, the amount of HPMC is 7% of the total weight of the active ingredients of the dosage form. Preferably, HPMC is present in the outer part of the tablet granules, and preferably, the active ingredients are present in the inner part of the tablet granules.

[0030] For example, the tablets described herein have an intragranular component comprising ciprofloxacin and celecoxib, a filler, a binder, and optionally a wetting agent; and an extragranular composition comprising HPMC, a filler, and optionally a flowing agent and / or lubricant.

[0031] The active ingredients, celecoxib and ciprofloxacin hydrochloride, differ in that celecoxib is a very poorly soluble drug with an estimated solubility of approximately 4.3 mg / L in ordinary water at 25°C (estimated value), while ciprofloxacin hydrochloride is a soluble drug with a solubility of approximately 30 g / L in water. The difference in solubility is particularly pronounced in acidic media. While not bound by theory, the compositions described herein may provide optimal therapeutic effects by delivering both components through sustained release over more than 4 hours. An in vitro test in which the tablet / dosage form is introduced into 750 ml of 0.1N hydrochloric acid at 100 RPM or 75 RPM in a Type II apparatus for 2 hours, and then the medium is changed to form a pH 6.8 phosphate buffer with 1% SLS, is representative of human subjects in which the tablet / dosage form is introduced into the stomach, where it remains for approximately 2 hours, and then sent to the intestines. The tablets slowly release the active ingredients (ciprofloxacin and celecoxib) over a period of more than two hours.

[0032] In human studies, the compositions described herein were tested to determine the maximum serum concentration of celecoxib after administration in a fed state and once a "steady state" was reached (T max ) is the T of ciprofloxacin max This demonstrated similarity. While not bound by theory, it is suggested that the enhanced synergistic effect of combining ciprofloxacin and celecoxib can be achieved when the Tmax of both active ingredients occurs substantially simultaneously or within a period of 80% to 125% after administration with food and water.

[0033] Treatment methods The compositions described herein can be used to treat ALS in patients who require it. The compositions may be administered to patients who require it once, twice, three times, or four times daily. Administration may reduce or alleviate the symptoms of ALS, or prevent the progression of ALS at the time of administration. The compositions are preferably administered with food and water.

[0034] The following examples are provided to illustrate specific features and / or embodiments. These examples should not be construed as limiting this disclosure to the specific features or embodiments described herein. [Examples]

[0035] Example 1A: Preparation of immediate-release (IR) capsules containing ciprofloxacin hydrochloride and celecoxib IR capsules were prepared by mixing 377.41 mg of ciprofloxacin hydrochloride (HCl) per capsule with 34.00 mg of celecoxib per capsule. This mixture was filled into gelatin capsules numbered 0.

[0036] Example 1B: Dissolution of IR capsules The IR capsules prepared according to Example 1A were dissolved in 750 ml of 0.1 N hydrochloric acid for 1 hour, and then 250 ml of phosphate buffer containing 1% sodium lauryl sulfate was added to form a phosphate buffer with a pH of 6.8, and a dissolution test was performed.

[0037] [Table 1]

[0038] The dissolution test conditions in this example were designed to simulate administration to a human patient, with the capsules prepared as in Example 1A remaining in a gastric acidic state for approximately one hour, and then being delivered to the intestines where the pH was close to 6.8. As can be seen from Table 1, after one hour in 0.1N hydrochloric acid, ciprofloxacin was almost completely dissolved, but celecoxib was not released. After adding 250 ml of phosphate buffer to form a pH 6.8 phosphate buffer with 1% sodium lauryl sulfate, both celecoxib and ciprofloxacin dissolved rapidly, and all ciprofloxacin would be released within a few hours of human administration. A profile that prolonged the release time of ciprofloxacin was desired.

[0039] Example 2A: Preparation of Extended-Release (ER) Tablets Containing Ciprofloxacin Hydrochloride and Celecoxib Considering the different solubility of the two active ingredients, ciprofloxacin and celecoxib, and to prolong the release time of ciprofloxacin, which is initiated under acidic gastric conditions and sustained while the dosage form passes through the intestines, a tablet matrix composition (designated Batch 08) was developed.

[0040] The following active ingredients and excipients from specific suppliers were used in the tablet composition: Ciprofloxacin hydrochloride, United States Pharmacopeia (USP); Neuland, India Celecoxib, USP; HiKAL, India Microcrystalline cellulose, USP, National Medical Collection (NF); FMC International, Cork, Ireland Povidone K-30 USP, NF; BASF, Germany Sodium lauryl sulfate, USP, NF; BASF, Germany Hydroxypropyl methylcellulose, USP, EP Dow Colloidal silicon dioxide USP, NF Evonik Magnesium stearate, European Pharmacopoeia (Ph.Eur.); Peter Greven, Netherlands The amounts used in the tablet composition are shown in Table 2.

[0041] [Table 2]

[0042] The tablets were prepared using the following general procedure: Sifting: Manually, ciprofloxacin hydrochloride was sieved through a 16-mesh screen, celecoxib through a 16-mesh screen, and microcrystalline cellulose / lactose through a 40-mesh screen.

[0043] The amounts of sodium lauryl sulfate, povidone, and PVP K-30 were weighed, and then these were added to purified water while stirring. The binder solution was prepared by continuing to stir until a clear solution was obtained.

[0044] Dry mixing: The sieved material was loaded into a rapid mixer granulator (10L), and dry mixing was performed for 10 minutes using a slow impeller speed with the chopper turned off.

[0045] Granulation: A binder solution was added to the dry mixture, and the wet mass was manually passed through a No. 10 mesh screen.

[0046] Drying: The moist granules were dried in a Lechs dehydrator.

[0047] Sieving and crushing (dried granules): The dried granules were sieved through a 20-mesh screen, and the sieved granules were collected in a polybag.

[0048] Blending and Lubrication: Hydroxypropyl methylcellulose (METHOCEL E 50 PRE LV), microcrystalline cellulose (Avicel PH102), and colloidal silicon dioxide (Aerosil 200) were sieved through a No. 40 mesh screen. The dry granules from inside the granules and the sieved material from outside the granules were then blended at 15 RPM for 15 minutes (Conta Blender 10L).

[0049] Magnesium stearate was sieved through a 60-grit mesh screen and added to the above blend, then lubricated at 15 RPM for 5 minutes. The final blend was compressed.

[0050] Example 2B: Dissolution of ER tablets from batch 08 The dissolution test for batch 08 was performed in 750 mL of 0.1 N hydrochloric acid for 2 hours, followed by transferring the dosage form to 900 mL of pH 6.8 phosphate buffer containing 1% SLS, and dissolving at type II, 100 RPM. The drug release rates at each time point are detailed in Table 3 below.

[0051] [Table 3]

[0052] As can be seen from the table above, after a total of 12 hours, 2 hours in 0.1N hydrochloric acid followed by 10 hours in a phosphate buffer medium pH 6.8 + 1% SLS, only 50% of the celecoxib formulation raw material was released.

[0053] Example 3A: Preparation of further sustained-release (ER) tablets containing ciprofloxacin hydrochloride and celecoxib In this example, we attempted to improve the solubility of celecoxib by using a more soluble filler, such as lactose, instead of the extragranular filler in the batch 08 composition. In addition to the addition of a soluble filler (lactose), we removed the HPMC (METHOCEL E50 LV) polymer, which controls and delays drug release from the matrix and has binding properties.

[0054] Batch 36 was formed using the general manufacturing procedure employed in Example 2A, along with the excipients listed in Table 4 below:

[0055] [Table 4]

[0056] Furthermore, batch 37 was prepared using lactose as an external filler and lactose monohydrate instead of microcrystalline cellulose as an internal filler in the granules. Batch 37 was formed using the general manufacturing procedure employed in Example 2A, along with the excipients listed in Table 5 below:

[0057] [Table 5]

[0058] Furthermore, lactose was used as an external filler for the granules, and batch 38 was prepared by replacing some of the microcrystalline cellulose in the granules of batch 08 with lactose monohydrate. Batch 38 was formed using the general manufacturing procedure adopted in Example 2A, along with the excipients listed in Table 6 below:

[0059] [Table 6]

[0060] Example 3B: Dissolution of ER tablets from batch 08 versus batch 37 Tablets prepared from batches 08 and 37 were dissolved in 0.1N hydrochloric acid for 2 hours, followed by dissolution testing in 900 ml of pH 6.8 phosphate buffer containing 1% SLS, at 100 RPM. The drug release rates at each time point are detailed in Table 7 below.

[0061] [Table 7]

[0062] Comparing tablets from batch 08 and batch 37, we observed increased celecoxib solubility in batch 37 after 12 hours (86%) compared to batch 08. However, ciprofloxacin did not dissolve sufficiently in the acidic medium after 2 hours, as batch 37 had a solubility of only 27% compared to batch 08's solubility of over 50% (59%). Despite the use of more soluble extragranular and intragranular fillers in batch 37, the solubility of ciprofloxacin was negatively affected.

[0063] Example 3C: Dissolution of ER tablets from batch 08 versus batches 36, 37, and 38 A dissolution test was conducted by comparing the solubility of tablets prepared from batch 08 and batch 37 in 0.1N hydrochloric acid at 100 RPM for 2 hours using type II. The drug release rates at each time point are detailed in Table 8 below. Dissolution was performed simultaneously using 12 dissolving devices, with 3 tablets from each batch being dissolved at the same time.

[0064] [Table 8]

[0065] As is evident from Table 8, the dissolution of batches 36, 37, and 38 in 0.1N hydrochloric acid showed insufficient solubility, with less than 50% (and still less than 30%) of ciprofloxacin dissolution from the tablets. Surprisingly, ciprofloxacin was released more rapidly from the tablets of batch 08, despite containing HPMC polymer and microcrystalline cellulose, a non-water-soluble filler. Without being bound by theory, this may be because HPMC has a faster water absorption capacity than lactose, influencing the release rate of ciprofloxacin. HPMC allows more liquid to be absorbed into the matrix, enabling gelation. During this gelation period, in the presence of the dissolution, ciprofloxacin begins to migrate into the solution at a faster rate because its solubility in 0.1N hydrochloric acid is higher than that of celecoxib. However, because celecoxib has very low solubility in 0.1N hydrochloric acid, the drug release of celecoxib is minimally affected by this phenomenon and is more significantly influenced by the presence of a soluble lactose filler, which accelerates drug release during the transfer of the dosage form to phosphate buffer after 2 hours.

[0066] Example 4A: Preparation of further sustained-release (ER) tablets containing ciprofloxacin hydrochloride and celecoxib Further tablet compositions were prepared in the same manner as in batch 08. Batch 39A was prepared using the excipients listed in Table 9 below.

[0067] [Table 9]

[0068] The core tablets were coated with 17.1 mg of Opadry Blue per tablet. In this composition, lactose was used as both an intragranular and extragranular filler, in contrast to the microcrystalline cellulose used in Batch 08. Another HPMC polymer, Methocel E15 LV, was also used.

[0069] Batch 39B was prepared using the excipients listed in Table 10 below.

[0070] [Table 10]

[0071] The core tablets were coated with 17.1 mg of Opa Dry Blue per tablet. The tablets produced in batch 39B were similar to those in batch 39A, but differed in that they used a different type of HPMC.

[0072] Batch 40A was prepared using the excipients listed in Table 11 below.

[0073] [Table 11]

[0074] The core tablets were coated with 17.1 mg of Opa Dry Blue per tablet. This composition was similar to batch 08, but used a different HPMC polymer, Methocel E15 LV.

[0075] Batch 40B was prepared using the excipients listed in Table 12 below.

[0076] [Table 12]

[0077] The core tablets were coated with 17.1 mg of Opa Dry Blue per tablet. This composition was similar to batch 08, but used a different HPMC polymer, Methocel E15 LV.

[0078] Example 4B: Dissolution of ER tablets The dissolution test was performed by comparing the dissolution of tablets prepared from batches 39A, 39B, 40A, and 40B in 0.1N hydrochloric acid at 100 RPM for 2 hours. The drug release rates at various time points in minutes are detailed in Table 13 below.

[0079] [Table 13]

[0080] The presence of various types of low-viscosity HPMCs, such as batches 39A, 39B, 40A, and 40B, was effective in increasing the solubility of ciprofloxacin to an acceptable level of over 50% in 0.1N hydrochloric acid for 2 hours. Comparing the solubility of batches 39A and 39B with that of 40A and 40B, it was observed that the use of lactose as a diluent, in contrast to microcrystalline cellulose, resulted in a faster solubility level of ciprofloxacin.

[0081] Example 5: Alternative Dissolution Method The method described in Example 2B showed that celecoxib release after 12 hours was limited (50%). Because ciprofloxacin is rapidly released in the acidic medium, it leads to partial disintegration of the tablet, and therefore the tablet may not be completely removed from the acidic medium; therefore, alternative methods were also used.

[0082] As an alternative method, the tablets were placed in 750 ml of 0.1 N hydrochloric acid for 2 hours, and then 250 ml of phosphate buffer containing 1% SLS at pH 6.8 was added. This process was carried out with stirring at 100 RPM. This method avoided handling the tablets and their transfer between media.

[0083] The results of the dissolution tests performed on tablets from batch 08 are shown in Table 14 below.

[0084] [Table 14]

[0085] An alternative method was performed in which the tablets were placed in 750 ml of 0.1 N hydrochloric acid for 2 hours, and then 250 ml of phosphate buffer containing 1% SLS at pH 6.8 was added. This process was carried out with stirring at 75 RPM. The results of this dissolution test, performed on tablets from batch 08, are shown in Table 15 below.

[0086] [Table 15]

[0087] As is evident from Tables 14 and 15, when using this method, nearly complete dissolution of celecoxib from batches 08 and 39B at a level exceeding 80% can be achieved within 8–12 hours at 100 RPM or within 12–16 hours at 75 RPM, compared to the method shown in Table 3. Compositions from batches 39A, 40A, and 40B would exhibit similar behavior when subjected to this method. There was no significant difference in dissolution when comparing compositions with soluble and insoluble fillers.

[0088] In summary, compositions containing low-viscosity HPMC were effective in dissolving ciprofloxacin to an acceptable level of less than 70%, preferably 40% to 65%, in 0.1N hydrochloric acid for 2 hours, while maintaining a level of dissolution of over 80% over 10 hours at 75 RPM and over 6 hours at 100 RPM.

[0089] Example 6A: Further tablet composition Further tablet compositions were prepared in the same manner as Batch 08. Batch 2D was prepared using the excipients listed in Table 16 below. Batch 2D represents a batch in which the amount of HPMC was 20% of the tablet weight.

[0090] [Table 16]

[0091] Batch 05E was prepared using the excipients listed in Table 17 below, and this batch shows a batch in which the amount of HPMC was 10% of the tablet weight.

[0092] [Table 17]

[0093] Further tablet compositions were prepared in the same manner as in batch 08. Batch 05B was prepared using the excipients listed in Table 18 below. Batch 05B represents a batch in which the type of HPMC was Methocel K100 LV in an amount of 5% of the tablet weight.

[0094] [Table 18-1]

[0095] Batch 05F represents a batch in which the amount of HPMC Methocel E50LV was 5% of the tablet weight, as in batch 08. [Table 18-2]

[0096] Example 6B: Dissolution of ER tablets from batch 2D versus batches 05E and 05B Dissolution tests were conducted to compare the dissolution of tablets prepared from batches 2D, 05E, and 05B in a medium with pH 12 at 75 RPM. The drug release rates at various time points in minutes are detailed in Table 19 below.

[0097] [Table 19]

[0098] In accordance with pharmacopoeia testing for celecoxib immediate-release tablets, a medium with pH 12 was used. As can be seen from Table 19, compositions 05B and 05F, similar to batch 08, showed similar dissolution profiles and release of each active ingredient in the pH 12 medium. Compositions 05E with 10 wt% HPMC Methocel E 50 LV and 05B with 5 wt% HPMC Methocel K 100 LV showed promising release profiles, releasing over 40% and a further 50% of the active ingredient within 2 hours. Composition 2D, in which the weight of HPMC Methocel K 100 LV was 20% of the tablet weight, showed slower dissolution profiles and release of both active ingredients in the pH 12 medium.

[0099] Example 6C: Further tablet compositions were prepared in the same manner as for batch 08. Batch 19C was prepared using the excipients listed in Table 20 below. Batch 19C represents a batch in which the amount of HPMC is 3% of the tablet weight.

[0100] [Table 20]

[0101] Example 6D: Dissolution of ER tablets from batch 19C To determine the dissolution of tablets prepared from batch 19C, a dissolution test was performed in 900 ml of 0.1 N hydrochloric acid at 100 RPM for 2 hours. The drug release rates at various time points in minutes are detailed in Table 21 below.

[0102] [Table 21]

[0103] In batch 19C, the amount of HPMC used was 3% of the tablet core weight and 4.1% relative to the activator. Despite being a relatively small amount, the solubility of ciprofloxacin exceeded 50% after 2 hours in a 0.1N hydrochloric acid medium.

[0104] Example 6E: Dissolution of ER tablets under conditions equivalent to "ingestion" conditions Sustained-release (ER) tablets were prepared in the same manner as in Example 2A, except that each tablet was coated with a hypromellose-based film of 17.10 mg / tablet, using Opadry® Blue (Opadry blue 13B 5050008 IH; Colorcon, India). These tablets were designated as ERPC.

[0105] A dissolution test was conducted to compare the dissolution of tablets prepared from batch 08 and ERPC in a pH 4.5 medium using a USP II equipped with 1% SLS acetate buffer, 900 ml, 75 RPM. The drug release rates at various time points in minutes are detailed in Table 22 below. This medium was selected to replicate administration to subjects under feeding conditions.

[0106] [Table 22]

[0107] The average release of both celecoxib and ciprofloxacin after 1 hour of dissolution testing was 10%–30%. The average release of both celecoxib and ciprofloxacin after 4 hours of dissolution testing was 30%–70%. The average dissolution of both celecoxib and ciprofloxacin after 12 hours was over 85%. These results indicate that, under feeding conditions, these compositions can provide a similar profile for the dissolution of both celecoxib and ciprofloxacin in humans.

[0108] Example 7: Testing of tablets containing celecoxib and ciprofloxacin hydrochloride in humans Sustained-release (ER) tablets were prepared in the same manner as in Example 2A, except that each tablet was coated with a hypromellose-based film of 17.10 mg / tablet, using Opadry® Blue (Opadry blue 13B 5050008 IH; Colorcon, India). These tablets were used in human trials and designated as ERPC.

[0109] An open-label, randomized, multi-dose, two-treatment, crossover study was conducted to evaluate the comparative bioavailability of ERPC, a fixed-dose combination tablet comprising celecoxib and ciprofloxacin hydrochloride, compared to a reference product. The reference product consisted of CIPRO® tablets (ciprofloxacin hydrochloride, Bayer) and CELBREX® capsules (celecoxib, Pfizer), administered concurrently to healthy adult men and women every 12 hours for 6.5 days, for a total of 13 doses, under feeding conditions.

[0110] Pharmacokinetic analysis: C administered on the morning of day 1 max Concentration data was reviewed to identify pre-administration concentrations exceeding 5% of the target concentration. The pre-administration concentration was the C dose administered on the morning of day 1. max No subjects exceeding 5% of the target group were identified.

[0111] Overview of pharmacokinetic parameters: Using the estimated concentration-time profiles of ciprofloxacin and celecoxib, pharmacokinetic parameters for ciprofloxacin and celecoxib were calculated using a non-compartment model of Phoenix® WinNonlin® version 8.3 (Certara LP).

[0112] The study treatment consists of two ERPC tablets administered in the morning, containing 680 mg orally administered ciprofloxacin and 68 mg orally administered celecoxib, and two ERPC tablets administered in the evening, containing 680 mg orally administered ciprofloxacin and 68 mg orally administered celecoxib. The reference treatment consisted of a morning administration of 750 mg of orally administered Ciprofloxacin (1 x 500 mg tablet and 1 x 250 mg tablet) as Cipro® tablets and 200 mg of orally administered celecoxib (1 x 200 mg capsule) as Celebrex® capsules, and an evening administration of 750 mg of orally administered Ciprofloxacin (1 x 500 mg tablet and 1 x 250 mg tablet) as Cipro® tablets and 200 mg of orally administered Celebrex® capsules (1 x 200 mg capsule). In both studies, the morning administration on days 1-7 was administered to subjects 30 minutes after the start of a standard calorie meal, following at least 10 hours of fasting. The evening administration on days 1-6 was administered to subjects 30 minutes after the start of a standard calorie meal, following at least 2 hours of fasting. The pharmacokinetic parameters (mean values) of ciprofloxacin and celecoxib were calculated, and the values ​​for ciprofloxacin are shown in Table 23, and the values ​​for celecoxib are shown in Table 24.

[0113] [Table 23]

[0114] [Table 24]

[0115] Figure 1 shows the mean plasma concentrations of both ciprofloxacin and celecoxib in volunteers after 7 days of dosing. Since the doses of the group administered ERPC (designated PrimeC) and the doses of the reference tablets are different, the concentrations in the graph are normalized by multiplying the reference concentration of ciprofloxacin by (680 / 750) = 0.906667 and multiplying the reference concentration of celecoxib by (68 / 200) = 0.34. The upper line indicates the ciprofloxacin concentration after dosing, and the lower line indicates the celecoxib concentration. The concentrations of the ERPC group are shown as circles, and the concentrations of the reference group are shown as triangles.

[0116] As can be seen from the above table and Figure 1, when comparing the T max values of celecoxib and ciprofloxacin on Day 7 after administration of the test treatment, when the test product is administered for several days to reach a steady state, the T max (5 hours) of celecoxib is within the range of 80% to 125% of the T max (4 hours) of ciprofloxacin. This is clear from the fact that the peaks of the concentrations of ciprofloxacin and celecoxib occur relatively simultaneously in Figure 1. However, when comparing the T max values of celecoxib and ciprofloxacin on Day 7 after administration of the reference treatment, the T max value of celecoxib is 200% of the T max value of ciprofloxacin. This is clear from the fact that the peak of the concentration of the ciprofloxacin reference product occurs earlier than the peak of the concentration of the celecoxib reference product.

[0117] This specification describes, according to one embodiment, a tablet comprising celecoxib and ciprofloxacin or a pharmaceutically acceptable salt thereof, and low-viscosity hydroxypropyl methylcellulose having a viscosity of 2 cP to 150 cP when measured as a 2% aqueous solution at 20°C. Optionally, the pharmaceutically acceptable salt of ciprofloxacin is ciprofloxacin hydrochloride. Optionally, the hydroxypropyl methylcellulose has 28.0% to 30.0% methoxyl substitution and 7.0% to 12.0% hydroxypropoxyl substitution. Optionally, the hydroxypropyl methylcellulose has 19.0% to 24.0% methoxyl substitution and 7.0% to 12.0% hydroxypropoxyl substitution. Optionally, the hydroxypropyl methylcellulose is present in an amount of 3% to 10% by weight of the tablet. Optionally, the hydroxypropyl methylcellulose is present in an amount of 5% by weight of the tablet. Optionally, hydroxypropyl methylcellulose is present in the tablet in an amount of 4% to 15% by weight relative to the weight of pharmaceutically acceptable salts of celecoxib and ciprofloxacin, which are the active ingredients. Optionally, hydroxypropyl methylcellulose is present in an amount of 6% to 8% by weight relative to the weight of the active ingredients. Optionally, the tablet comprises extragranular and intragranular components, where hydroxypropyl methylcellulose is present in the extragranular component. Optionally, pharmaceutically acceptable salts of celecoxib and ciprofloxacin are present in the intragranular component. Optionally, the tablet further comprises a filler selected from the group consisting of soluble, insoluble, and mixtures of soluble and insoluble components. Optionally, the filler is selected from the group consisting of dicalcium phosphate, starch, pregelatinized starch, powdered cellulose, microcrystalline cellulose, mannitol, sucrose, sorbitol, and lactose. Optionally, the filler is microcrystalline cellulose, lactose, mannitol, or a combination thereof. Optionally, low-viscosity hydroxypropyl methylcellulose has a viscosity of 50 cP when measured as a 2% aqueous solution at 20°C. Optionally, the weight ratio of celecoxib to free ciprofloxacin base is 1:1 to 1:100. Optionally, the weight ratio of celecoxib to free ciprofloxacin base is 1:10 to 1:25.Optionally, the ratio of the weight of celecoxib to the weight of free ciprofloxacin base is 1:10. Optionally, if ciprofloxacin is dissolved in 750 ml of 0.1 N hydrochloric acid in a Type II apparatus at 75 revolutions per minute (RPM), the total volume is less than 70% but greater than 40% within 2 hours. If ciprofloxacin is dissolved in 750 ml of 0.1 N hydrochloric acid in a Type II apparatus at 75 RPM, 37°C, and then after 2 hours the medium is changed to form a pH 6.8 phosphate buffer containing 1% SLS, the total volume is at least 80% within 6 hours. Optionally, when celecoxib is dissolved in 750 ml of 0.1 N hydrochloric acid in a Type II apparatus at 75 RPM and 37°C, and then after 2 hours the medium is changed to form a pH 6.8 phosphate buffer containing 1% SLS, less than 80% is released within 6 hours and at least 80% within 12 hours. Optionally, when celecoxib is dissolved in 750 ml of 0.1 N hydrochloric acid in a Type II apparatus at 75 RPM and 37°C, and then after 2 hours the medium is changed to form a pH 6.8 phosphate buffer containing 1% SLS, more than 45% of both ciprofloxacin and celecoxib are released within 3 hours, and less than 90% are released within 6 hours. When optionally placed in a Type II device at 75 RPM and 37°C in 900 ml of pH 4.5 acetate buffer containing 1% SLS, 10% to 30% of ciprofloxacin and celecoxib are released in 1 hour, 30% to 70% in 4 hours, and over 85% in 12 hours. When the tablets are optionally administered to human subjects with food and water for 7 days, the Tmax of celecoxib in the subjects' serum is within the range of 80% to 125% of the Tmax of ciprofloxacin in the subjects' serum.

[0118] Furthermore, this specification describes a method for producing tablets (manufacturing process) comprising: forming granules containing celecoxib and ciprofloxacin or a pharmaceutically acceptable salt thereof; adding low-viscosity hydroxypropyl methylcellulose having a viscosity of less than 150 cP when measured as a 2% aqueous solution at 20°C to the granules to form a mixture; and compressing the mixture to form tablets.

[0119] Furthermore, this specification describes a method for treating amyotrophic lateral sclerosis (ALS) in patients in need, which includes administering the above-mentioned tablets to the patient.

[0120] Given the many possible embodiments to which the disclosed principles of the present invention may be applied, it should be recognized that the shown embodiments are merely preferred examples of the invention and should not be considered as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. Accordingly, the inventors claim as an invention everything contained within the scope and spirit of these claims.

Claims

1. A tablet comprising celecoxib, ciprofloxacin or a pharmaceutically acceptable salt thereof, and low viscosity hydroxypropyl methylcellulose having a viscosity of 2 cP to 150 cP when measured as a 2% aqueous solution at 20°C, The tablet contains extragranular and intragranular components, and hydroxypropyl methylcellulose is present in the extragranular components, The tablets wherein pharmaceutically acceptable salts of celecoxib and ciprofloxacin are present in the granular components.

2. The tablet according to claim 1, wherein the pharmaceutically acceptable salt of ciprofloxacin is ciprofloxacin hydrochloride.

3. The tablet according to claim 1, wherein the hydroxypropyl methylcellulose has 28.0% to 30.0% methoxyl substitution and 7.0% to 12.0% hydroxypropoxyl substitution.

4. The tablet according to claim 1, wherein the hydroxypropyl methylcellulose has 19.0% to 24.0% methoxyl substitution and 7.0% to 12.0% hydroxypropoxyl substitution.

5. The tablet according to claim 1, wherein hydroxypropyl methylcellulose is present in an amount of 3% to 10% by weight of the tablet.

6. The tablet according to claim 5, wherein hydroxypropyl methylcellulose is present in an amount of 5% by weight of the tablet.

7. The tablet according to claim 1, wherein hydroxypropyl methylcellulose is present in an amount of 4% to 15% by weight relative to the weight of pharmaceutically acceptable salts of celecoxib and ciprofloxacin, which are the active ingredients in the tablet.

8. The tablet according to claim 7, wherein hydroxypropyl methylcellulose is present in an amount of 6% to 8% by weight relative to the weight of the active ingredient.

9. The tablet according to claim 1, further comprising a filler selected from the group consisting of a soluble filler, an insoluble filler, and a mixture of a soluble filler and an insoluble filler.

10. The tablet according to claim 9, wherein the filler is microcrystalline cellulose, lactose, mannitol, or a combination thereof.

11. The tablet according to claim 1, wherein the low-viscosity hydroxypropyl methylcellulose has a viscosity of 50 cP when measured as a 2% aqueous solution at 20°C.

12. The tablet according to claim 1, wherein the ratio of the weight of celecoxib to the weight of ciprofloxacin free base is 1:1 to 1:

100.

13. The tablet according to claim 12, wherein the ratio of the weight of celecoxib to the weight of ciprofloxacin free base is 1:10 to 1:

25.

14. The tablet according to claim 13, wherein the ratio of the weight of celecoxib to the weight of ciprofloxacin free base is 1:

10.

15. The tablet according to claim 1, wherein when the tablet is placed in a Type II apparatus at 75 RPM and 37°C in 900 ml of pH 4.5 acetate buffer containing 1% SLS, 10% to 30% of ciprofloxacin and celecoxib are released in 1 hour, 30% to 70% of ciprofloxacin and celecoxib are released in 4 hours, and more than 85% of ciprofloxacin and celecoxib are released in 12 hours.

16. When the tablets are administered to human subjects with food and water for 7 days, the T1 level of celecoxib in the subjects' serum is reduced. ｍａｘ However, the T of ciprofloxacin in the subject's serum ｍａｘ The tablet according to claim 1, wherein the amount is within the range of 80% to 125%.

17. a. To form granules containing celecoxib and ciprofloxacin or pharmaceutically acceptable salts thereof; b. Adding low-viscosity hydroxypropyl methylcellulose, which has a viscosity of less than 150 cP when measured as a 2% aqueous solution at 20°C, to granules to form a mixture; and c. Compressing the mixture to form tablets. A method (step) for manufacturing the tablets according to claim 1, including the method (step).

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