Compositions Comprising 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 TO RELATED APPLICATIONS Benefit is claimed to U.S. Provisional Patent Application No. 63 / 257,130, filed October 19, 2021, the contents of which are incorporated by reference in their entirety herein.

[0002] A dosage form is provided that includes ciprofloxacin or a pharma- ceutically acceptable salt thereof and celecoxib. [Background technology]

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

[0004] Celecoxib is a COX-2 inhibitor taken orally and indicated for the treatment of pain or inflammation associated with a variety of conditions. The structure of celecoxib is: [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 Summary of the Invention [Means for solving the problem]

[0007] overview Described herein are sustained release compositions, such as tablets, that include ciprofloxacin or a pharma- ceutically acceptable salt thereof, and celecoxib. For example, provided herein are tablets that include celecoxib, a pharma- ceutically 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] Further herein: A process is described for making tablets, comprising forming a granule containing celecoxib and ciprofloxacin or a pharma- ceutically acceptable salt of ciprofloxacin; adding a low viscosity hydroxypropyl methylcellulose having a viscosity of less than 150 cP when measured as a 2% solution in water at 20° C. to the granule to form a mixture; and compressing the mixture to form a tablet.

[0009] Further described herein is a method for the treatment of amyotrophic lateral sclerosis (ALS) in a patient in need thereof, comprising administering to the patient a composition comprising ciprofloxacin or a pharma- ceutically acceptable salt thereof, and celecoxib.

[0010] The above and other objects, features, and advantages will become more apparent from the following detailed description which proceeds with reference to the accompanying drawings. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows a graph depicting normalized mean plasma concentrations over time following administration of ciprofloxacin and celecoxib for healthy volunteers on day 7 of administration, comparing administration with a combination tablet containing ciprofloxacin and celecoxib (PrimeC) versus administration with a reference tablet (Ref). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description term Unless otherwise specified, technical terms are used according to conventional usage. Definitions of common terms in molecular biology 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 by Blackwell Science Ltd. in 1994 (ISBN 0-632-02182-9); and Robert A. Meyers, (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc. in 1995 (ISBN 1-56081-569-8).

[0013] Unless otherwise explained, 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 references unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. Furthermore, it should be understood that all base 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 to practice or test the present disclosure, suitable methods and materials are described below. The term "comprise" means "include." The abbreviation "eg" is derived from the Latin "exempli gratia" and is used herein to indicate a non-limiting example. Thus, the abbreviation "eg" is synonymous with the term "for example."

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

[0015] Extragranular: The process of tablet formation often results in the formation of granules that contain the active ingredient in combination with at least one excipient. The granulation process converts fine powders into free-flowing, dust-free granules that are easy to compress. The granules can then be mixed by blending with additional excipients or active ingredients. The final blend is filled into capsules or compressed into tablets. The term "extragranular" refers to the non-granular portion of a tablet.

[0016] Intragranular: In a tablet composition formed via a granulation process, that portion of the composition that is within a granule.

[0017] Pharmaceutically acceptable salts: "Salts" refers to salts of active compounds, such as ciprofloxacin, modified by forming acid or base salts of the compounds. 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 during the process of preparing the pharmaceutical dosage form, or can be prepared separately by reacting the purified compounds of the present invention in the form of a free base with a suitable organic or inorganic acid and isolating the salt formed. 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 salts.

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

[0019] Overview of Several Embodiments Provided herein are compositions comprising celecoxib and ciprofloxacin or a pharma- ceutically acceptable salt of ciprofloxacin.

[0020] For example, compositions are provided in which the ratio of celecoxib to ciprofloxacin or a pharmaceutical salt thereof 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. An exemplary tablet described herein contains 34 mg of celecoxib and 340 mg of ciprofloxacin or a pharma- ceutically acceptable salt of ciprofloxacin per tablet, which is an amount that delivers 340 mg of ciprofloxacin (e.g., 377.41 mg of ciprofloxacin HCl 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, the composition comprising celecoxib and ciprofloxacin or a pharmaceutical salt thereof has one or more of the following dissolution characteristics: 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 ciprofloxacin dissolves less than 70% within 2 hours, preferably 40%-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 ciprofloxacin dissolves less than 80% within 2 hours, preferably between 40% and 65%. 3. When placed 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 (modified) to form a pH 6.8 phosphate buffer containing 1% SLS, the total dissolution of ciprofloxacin is 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 in a Type II apparatus at 100 RPM and 37°C, and then after 2 hours the medium is changed to form a phosphate buffer, pH 6.8, containing 1% SLS, the total dissolution of ciprofloxacin is at least 80% within 6 hours and / or less than 80% within 4 hours. 5. When placed 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 phosphate buffer, pH 6.8, 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 placed in 750 ml of 0.1 N hydrochloric acid in a Type II apparatus at 100 RPM and 37° C., and then after 2 hours the medium is changed to form a phosphate buffer, pH 6.8, containing 1% SLS, the total dissolution of celecoxib is at least 80% within 8 hours and / or less than 80% within 6 hours. 7. When placed 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 phosphate buffer of pH 6.8 containing 1% SLS, the combined dissolution of both ciprofloxacin and celecoxib is greater than 45% at 3 hours and less than 90% at 6 hours. 8. When placed in 900 ml of acetate buffer pH 4.5 containing 1% SLS in a Type II apparatus at 75 RPM and 37°C, the dissolution of ciprofloxacin and celecoxib is 10% to 30% in 1 hour, the dissolution of ciprofloxacin and celecoxib is 30% to 70% in 4 hours, and the dissolution of ciprofloxacin and celecoxib is greater than 85% in 12 hours.

[0022] According to some embodiments, the composition comprises low viscosity hydroxypropyl methylcellulose (HPMC). HPMC is a binder and controlled release agent used in matrix systems for oral pharmaceutical dosage forms such as tablets. HPMC is an excipient having a monomer in which the cellulose backbone is substituted with methyl and hydroxypropyl groups. The amount of substitution determines the properties of the 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 compositions is 40-60 cP.

[0023] Exemplary HPMC types are listed below. JPEG2024539116000004.jpg97153

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

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

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

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

[0028] Preferably, the amount of HPMC present in the composition is between 3% and 10% by weight of the composition.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% based on the total weight of the active ingredients of the tablet, celecoxib and ciprofloxacin salt. Preferably, the amount of HPMC present in the composition is 6% to 8% based on the total weight of the active ingredients of the tablet. Preferably, the amount of HPMC is 7% based on the total weight of the active ingredients of the dosage form. Preferably, HPMC is present in the extragranular portion of the tablet and preferably the active ingredients are present in the intragranular portion of the tablet.

[0030] For example, contemplated herein are tablets having an intragranular component including ciprofloxacin and celecoxib, a filler, a binder, and optionally a wetting agent; and an extragranular composition including HPMC, a filler, and optionally a flow 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 in normal water of about 4.3 mg / L at 25° C. (estimated value), while ciprofloxacin hydrochloride is a soluble drug with a solubility in water of about 30 g / L. The difference in solubility is particularly pronounced in acidic media. Without being bound by theory, the compositions described herein may provide optimal therapeutic effects by delivering both ingredients in a sustained release manner over a period of more than four hours. An in vitro study in which the tablet / dosage form is introduced into 750 ml of 0.1 N hydrochloric acid at 100 RPM or 75 RPM in a Type II apparatus for two hours, and then the medium is changed to form a phosphate buffer solution at pH 6.8 with 1% SLS, is representative of a human subject in which the tablet / dosage form is introduced into the stomach where it resides for about two hours before being passed into the intestine. The tablets slowly release the active ingredients (ciprofloxacin and celecoxib) over a period of more than two hours.

[0032] Studies of the compositions described herein in humans have demonstrated that the maximum serum concentration of celecoxib after administration in the fed state and when a "steady state" was reached (T max ) is the T of ciprofloxacin max Without being bound by theory, it is suggested that enhanced synergy of the combination of ciprofloxacin and celecoxib can be obtained when the Tmax of both active ingredients occurs substantially simultaneously or within 80%-125% of the time period following administration with food and water.

[0033] Treatment methods The compositions described herein can be used to treat ALS in patients in need thereof. The compositions can be administered to patients in need thereof once a day, twice a day, three times a day, or four times a day. Administration can reduce or alleviate symptoms of ALS, or upon administration can prevent the progression of ALS. The compositions are preferably administered with food and water.

[0034] The following examples are provided to illustrate particular features and / or embodiments and should not be construed as limiting the disclosure to the particular features or embodiments described. EXAMPLES

[0035] Example 1A: Preparation of Immediate Release (IR) Capsules Containing Ciprofloxacin Hydrochloride and Celecoxib IR capsules were prepared by blending 377.41 mg of ciprofloxacin hydrochloride (HCl) per capsule and 34.00 mg of celecoxib per capsule, and filling the blend into number 0 gelatin capsules.

[0036] Example 1B: Dissolution of IR Capsules Dissolution testing was performed on IR capsules prepared as in Example 1A by dissolving them with 750 ml of 0.1 N hydrochloric acid for 1 hour, followed by adding 250 ml of phosphate buffer with 1% sodium lauryl sulfate to form a phosphate buffer at pH 6.8.

[0037] [Table 1]

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

[0039] Example 2A: Preparation of Extended Release (ER) Tablets Containing Ciprofloxacin Hydrochloride and Celecoxib Considering the different solubilities of the two active ingredients, ciprofloxacin and celecoxib, and to provide a longer release time for ciprofloxacin that is initiated in the acidic conditions of the stomach and sustained throughout the transit of the dosage form through the intestine, a tablet matrix composition (designated Batch 08) was developed.

[0040] The following active ingredients and excipients from specific suppliers were used in the tablet compositions: Ciprofloxacin Hydrochloride, United States Pharmacopoeia (USP); Neuland India Celecoxib, USP; HiKAL, India Microcrystalline cellulose, USP, National Formulary (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] Tablets were prepared using the following general procedure: Sieving: Manually, ciprofloxacin hydrochloride was sieved through a No. 16 mesh screen, celecoxib was sieved through a No. 16 mesh screen, and microcrystalline cellulose / lactose was sieved through a No. 40 mesh screen.

[0043] A binder solution was prepared by weighing out the amounts of Sodium Lauryl Sulfate and Povidone, PVP K-30, and then adding them to purified water with stirring, and continuing stirring until a clear solution was obtained.

[0044] Dry Blending: The sieved materials were charged into a rapid mixer granulator (10 L) and dry mixed for 10 minutes using slow impeller speed with the chopper turned off.

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

[0046] Drying: The wet granules were dried in a Retsch dryer.

[0047] Sieving and milling (dried granules): The dried granules were sieved through a No. 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. Both the intragranular dry granules and the extragranular sieved materials were then blended (Conta Blender 10L) at 15 RPM for 15 minutes.

[0049] Magnesium stearate was sieved through a No. 60 mesh screen and added to the above blend and lubricated for 5 minutes at 15 RPM The final blend was compressed.

[0050] Example 2B: Dissolution of ER tablets of batch 08 Dissolution testing of Batch 08 was performed in 750 mL of 0.1 N HCl for 2 hours followed by transferring the dosage form to 900 mL of phosphate buffer, pH 6.8, containing 1% SLS, Type II, 100 RPM. The percentage of drug release at each time point is 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 0.1 N hydrochloric acid, followed by 10 hours in phosphate buffer medium pH 6.8 + 1% SLS, only 50% of the celecoxib drug substance was released.

[0053] Example 3A: Preparation of additional extended release (ER) tablets containing ciprofloxacin hydrochloride and celecoxib In this example, a more soluble filler such as lactose was substituted for the extragranular filler in the Batch 08 composition in an attempt to improve the solubility of celecoxib. In addition to the addition of a soluble filler (lactose), the HPMC (METHOCEL E50 LV) polymer was removed, which controls and delays the release of the drug from the matrix as well as has binder properties.

[0054] The general manufacturing procedure employed in Example 2A was used with the excipients listed in Table 4 below to form Batch 36:

[0055] [Table 4]

[0056] Additionally, Batch 37 was prepared using lactose as the extragranular filler and lactose monohydrate instead of microcrystalline cellulose as the filler in the granules. The general manufacturing procedure employed in Example 2A was used with the excipients listed in Table 5 below to form Batch 37:

[0057] [Table 5]

[0058] Additionally, Batch 38 was prepared using lactose as an extragranular filler, replacing a portion of the microcrystalline cellulose in the granules of Batch 08 with lactose monohydrate. The general manufacturing procedure employed in Example 2A was used with the excipients listed in Table 6 below to form Batch 38:

[0059] [Table 6]

[0060] Example 3B: Dissolution of ER tablets from batch 08 vs batch 37 Tablets prepared from Batch 08 and Batch 37 were dissolved in 0.1N HCl for 2 hours followed by transfer to 900 ml of pH 6.8 phosphate buffer containing 1% SLS, Type II at 100 RPM for dissolution testing. The percentage of drug release at each time point is detailed in Table 7 below.

[0061] [Table 7]

[0062] A comparison of Batch 08 and Batch 37 tablets shows increased dissolution of celecoxib (86%) after 12 hours in Batch 37 compared to Batch 08. However, ciprofloxacin was not sufficiently dissolved in acidic medium at 2 hours, as the solubility was over 50% (59%) in Batch 08 compared to 27% in Batch 37. Ciprofloxacin solubility was negatively affected in Batch 37, despite the use of more soluble extragranular and intragranular fillers.

[0063] Example 3C: Dissolution of ER tablets of batch 08 vs. batches 36, 37 and 38 Dissolution studies were conducted comparing the dissolution of tablets prepared from batch 08 and tablets prepared from batch 37 in 0.1N HCl at 100 RPM for 2 hours in Type II. The percentage of drug release at each time point is detailed in Table 8 below. Dissolution was carried out simultaneously on 12 dissolution apparatus with 3 tablets from each batch.

[0064] [Table 8]

[0065] As can be seen from Table 8, dissolution of batches 36, 37, and 38 in 0.1 N hydrochloric acid showed poor solubility with less than 50% (still less than 30%) of ciprofloxacin dissolved from the tablets. Surprisingly, ciprofloxacin was released more rapidly from the tablets of batch 08, despite the inclusion of HPMC polymer and the water insoluble filler microcrystalline cellulose. Without being bound by theory, this may be due to the fact that HPMC has a higher water absorption capacity compared to lactose, which affects the release rate of ciprofloxacin. HPMC allows more liquid to be absorbed into the matrix, allowing gelation. During this gelation period, in the presence of dissolution fluid, ciprofloxacin begins to go into solution at a faster rate due to its higher solubility in 0.1 N hydrochloric acid than celecoxib. However, since the solubility of celecoxib is very low in 0.1 N hydrochloric acid, the drug release of celecoxib is minimally affected by this phenomenon and is more affected by the presence of soluble lactose filler, which causes faster drug release upon transfer of the dosage form into phosphate buffer after 2 hours.

[0066] Example 4A: Preparation of additional extended release (ER) tablets containing ciprofloxacin hydrochloride and celecoxib Additional tablet compositions were prepared in a similar manner to Batch 08. Batch 39A was prepared with 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 the intragranular and extragranular filler as opposed to microcrystalline cellulose in batch 08. Another HPMC polymer, Methocel E15 LV, was also used.

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

[0070] [Table 10]

[0071] The core tablets were coated with 17.1 mg of Opadry blue per tablet. The tablets made from Batch 39B were similar to those from Batch 39A, with the difference being that a different type of HPMC was used.

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

[0073] [Table 11]

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

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

[0076] [Table 12]

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

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

[0079] [Table 13]

[0080] The presence of various types of low viscosity HPMC, such as batches 39A, 39B, 40A, and 40B, was effective in increasing the dissolution of ciprofloxacin to acceptable levels of more than 50% in 0.1 N hydrochloric acid for 2 hours. Comparing the dissolution of batches 39A and 39B with 40A and 40B, it was observed that the use of lactose as a diluent, as opposed to microcrystalline cellulose, resulted in a more rapid level of dissolution of ciprofloxacin.

[0081] Example 5: Alternative Lysis Methods The method described in Example 2B showed only limited (50%) release of celecoxib after 12 hours. The rapid release of ciprofloxacin in acidic medium led to partial disintegration of the tablet and therefore the tablet may not be completely transferred out of the acidic medium, therefore an alternative method was also used.

[0082] Alternatively, tablets were placed in 750 ml of 0.1N hydrochloric acid for 2 hours, then 250 ml was added to form a pH 6.8 phosphate buffer solution containing 1% SLS, with stirring at 100 RPM. This method avoided handling of the tablets and migration 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 tablets were placed in 750 ml of 0.1 N hydrochloric acid for 2 hours, and then 250 ml was added to form a pH 6.8 phosphate buffer solution containing 1% SLS. This step was performed with stirring at 75 RPM. The results of this dissolution test performed on tablets from batch 08 are shown below in Table 15.

[0086] [Table 15]

[0087] As can be seen from Tables 14 and 15, using this method, near complete dissolution of celecoxib at levels in excess of 80% for batches 08 and 39B is obtained within 8-12 hours at 100 RPM, or 12-16 hours at 75 RPM, as compared to the method shown in Table 3. Compositions from batches 39A, 40A, and 40B will behave similarly when subjected to this method. Dissolution was not significantly different when comparing compositions having soluble and non-soluble fillers.

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

[0089] Example 6A: Further tablet compositions An additional tablet composition was prepared in a manner similar to Batch 08. Batch 2D was prepared with the excipients set forth below in Table 16. 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 with the excipients listed in Table 17 below, and represents a batch in which the amount of HPMC was 10% of the tablet weight.

[0092] [Table 17]

[0093] An additional tablet composition was prepared in a manner similar to Batch 08. Batch 05B was prepared using the excipients set forth below in Table 18. Batch 05B represents a batch in which the HPMC type 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 of batch 2D vs. batches 05E and 05B A dissolution study was conducted comparing the dissolution of tablets prepared from batches 2D, 05E, and 05B at 75 RPM in a medium having a pH of 12. The percentage of drug release at various time points in minutes is detailed in Table 19 below.

[0097] [Table 19]

[0098] This medium with pH 12 was used in light of the pharmacopoeia test of immediate release tablets of celecoxib. As can be seen from Table 19, the compositions of batch 05B and 05F, which are similar to batch 08, had similar dissolution profile release of each active ingredient in a medium of pH 12. The compositions of batch 05E with 10 wt% HPMC Methocel E 50 LV and batch 05B with 5 wt% HPMC Methocel K100LV showed promising release profiles, releasing more than 40% and even 50% of the active substance within 2 hours. The composition of batch 2D, where the weight of HPMC Methocel K 100 LV is 20% of the tablet weight, had a slower dissolution profile release of both active ingredients in a medium of pH 12.

[0099] Example 6C: Additional tablet compositions were prepared in a manner similar to Batch 08. Batch 19C was prepared using the excipients set forth below in Table 20. Batch 19C represents a batch in which the amount of HPMC was 3% of the tablet weight.

[0100] [Table 20]

[0101] Example 6D: Dissolution of ER tablets of batch 19C To determine the dissolution of tablets prepared from Batch 19C, dissolution tests were carried out in a medium of 900 ml of 0.1 N hydrochloric acid at 100 RPM for 2 hours. The percentage of drug release at various time points in minutes is detailed in Table 21 below.

[0102] [Table 21]

[0103] Although the amount of HPMC used in batch 19C was 3% of the tablet core weight and 4.1% relative to the active agent, which was a relatively small amount, the solubility of ciprofloxacin was greater than 50% after 2 hours in 0.1 N hydrochloric acid medium.

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

[0105] Dissolution studies were conducted using USP II with acetate buffer 1% SLS, 900 ml, 75 RPM, weight to compare the dissolution of tablets prepared from batch 08 and ERPC in pH 4.5 media. The percentage of drug release at various time points in minutes is detailed below in Table 22. This media was chosen to replicate dosing to subjects under fed conditions.

[0106] [Table 22]

[0107] The average release of both celecoxib and ciprofloxacin in the 1 hour dissolution study was 10%-30%. The average release of celecoxib and ciprofloxacin in the 4 hour dissolution study was 30%-70%. The average dissolution of both celecoxib and ciprofloxacin in the 12 hour study was greater than 85%. These results indicate that under fed conditions, these compositions can provide similar dissolution profiles for both celecoxib and ciprofloxacin in humans.

[0108] Example 7: Study of tablets containing celecoxib and ciprofloxacin hydrochloride in humans Extended release (ER) tablets were prepared similarly to Example 2A, except that each tablet was film-coated with 17.10 mg / tablet of a hypromellose-based film, Opadry® blue (Opadry blue 13B 5050008 IH; Colorcon, India). These tablets were used in human studies and were designated ERPC.

[0109] An open-label, randomized, multiple-dose, two-treatment, crossover study was conducted to evaluate the comparative bioavailability of ERPC, a fixed-dose combination tablet consisting of celecoxib and ciprofloxacin hydrochloride, versus a reference product, CIPRO® tablets (ciprofloxacin hydrochloride, Bayer) co-administered with CELBREX® capsules (celecoxib, Pfizer), administered every 12 hours for 6.5 days, a total of 13 doses, under fed conditions, to healthy adult males and females.

[0110] Pharmacokinetic Analysis: C given in the morning on day 1 max The concentration data was reviewed to identify pre-dose concentrations that were 5% greater than the C max No subjects with >5% of the mean were identified.

[0111] Summary of pharmacokinetic parameters: The estimated concentration-time profiles of ciprofloxacin and celecoxib were used to calculate the pharmacokinetic parameters of ciprofloxacin and celecoxib using a noncompartmental model in Phoenix® WinNonlin® version 8.3 (Certara LP).

[0112] The study treatment consisted of two ERPC tablets, 680 mg oral ciprofloxacin and 68 mg oral celecoxib, given in the morning, and two ERPC tablets, containing 680 mg oral ciprofloxacin and 68 mg oral celecoxib, given in the evening. The reference treatment consisted of a morning dose of ciprofloxacin, Cipro® tablets, 750 mg orally (1×500 mg tablet and 1×250 mg tablet) co-administered with celecoxib, Celebrex® capsules, 200 mg orally (1×200 mg capsule) and an evening dose of ciprofloxacin, Cipro® tablets, 750 mg orally (1×500 mg tablet, 1×250 mg tablet) co-administered with celecoxib, Celebrex® capsules, 200 mg orally (1×200 mg capsule). In both studies, the morning dose on Days 1-7 was administered to subjects 30 minutes after the start of a normocaloric meal, following a fast of at least 10 hours. The evening dose on Days 1-6 was administered to subjects 30 minutes after the start of a normocaloric meal, following a fast of at least 2 hours. The pharmacokinetic parameters (mean values) of ciprofloxacin and celecoxib were calculated and are shown in Table 23 for ciprofloxacin and Table 24 for celecoxib:

[0113] [Table 23]

[0114] [Table 24]

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

[0116] As can be seen from the above table and Figure 1, the T of celecoxib and ciprofloxacin on Day 7 after administration of the test treatment was max When comparing values, the T of celecoxib was measured after several days of administration of the test product to reach steady state. max (5 hours) is the T max (4 hours). This is evident from the relatively simultaneous peak concentrations of ciprofloxacin and celecoxib in Figure 1. However, the T of celecoxib and ciprofloxacin on the 7th day after administration of the reference treatment was within 80% to 125% of the T of 100 mg / kg / day. max When comparing values, the T max The value is the T max This is evident from the fact that the concentration peak for the ciprofloxacin reference product occurs earlier than the concentration peak for the celecoxib reference product.

[0117] Described herein, according to one embodiment, is a tablet comprising celecoxib and ciprofloxacin or a pharma- ceutically acceptable salt thereof, and a 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 pharma- ceutically acceptable salt of ciprofloxacin is ciprofloxacin hydrochloride. Optionally, the hydroxypropyl methylcellulose has a methoxyl substitution of 28.0% to 30.0%, and a hydroxypropoxyl substitution of 7.0% to 12.0%. Optionally, the hydroxypropyl methylcellulose has a methoxyl substitution of 19.0% to 24.0%, and a hydroxypropoxyl substitution of 7.0% to 12.0%. 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, the hydroxypropyl methylcellulose is present in an amount of 4% to 15% by weight based on the weight of the active ingredients celecoxib and the pharma- ceutically acceptable salt of ciprofloxacin in the tablet. Optionally, the hydroxypropyl methylcellulose is present in an amount of 6% to 8% by weight based on the weight of the active ingredients. Optionally, the tablet comprises an extragranular component and an intragranular component, wherein the hydroxypropyl methylcellulose is present in the extragranular component. Optionally, the celecoxib and the pharma- ceutically acceptable salt of ciprofloxacin are present in the intragranular component. Optionally, the tablet further comprises a filler selected from the group consisting of soluble, insoluble, and a mixture of soluble and insoluble. Optionally, the filler is selected from the group consisting of dibasic calcium 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, the low viscosity hydroxypropyl methylcellulose has a viscosity of 50 cP when measured as a 2% aqueous solution at 20° C. Optionally, the ratio of the weight of celecoxib to the weight of ciprofloxacin free base is 1:1 to 1:100. Optionally, the ratio of the weight of celecoxib to the weight of ciprofloxacin free base is 1:10 to 1:25.Optionally, the ratio of weight of celecoxib to weight of ciprofloxacin free base is 1: 10. Optionally, dissolution of ciprofloxacin is less than 70% and more than 40% within 2 hours when placed in 750 ml of 0.1 N hydrochloric acid in a Type II apparatus at 75 revolutions per minute (RPM), and dissolution of ciprofloxacin is at least 80% in total within 6 hours when placed in 750 ml of 0.1 N hydrochloric acid in a Type II apparatus at 75 RPM at 37°C and then after 2 hours, the medium is changed to form a pH 6.8 phosphate buffer containing 1% SLS. Optionally, the dissolution of celecoxib is less than 80% within 6 hours and at least 80% within 12 hours when placed 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 with 1% SLS. Optionally, when placed 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 with 1% SLS, greater than 45% of both ciprofloxacin and celecoxib are released in 3 hours and less than 90% are released in 6 hours. Optionally, when placed in 900 ml of acetate buffer, pH 4.5, containing 1% SLS, in a Type II apparatus at 75 RPM and 37° C., 10% to 30% of the ciprofloxacin and celecoxib are released in 1 hour, 30% to 70% of the ciprofloxacin and celecoxib are released in 4 hours, and greater than 85% of the ciprofloxacin and celecoxib are released in 12 hours. Optionally, when the tablets are administered to a human subject with food and water for 7 days, the Tmax of celecoxib in the subject's serum is within the range of 80% to 125% of the Tmax of ciprofloxacin in the subject's serum.

[0118] Further described herein is a method for making a tablet (manufacturing process) that includes forming a granule containing celecoxib and ciprofloxacin or a pharma- ceutically acceptable salt thereof; adding a low viscosity hydroxypropyl methylcellulose having a viscosity of less than 150 cP when measured as a 2% aqueous solution at 20° C. to the granule to form a mixture; and compressing the mixture to form a tablet.

[0119] Further described herein is a method for the treatment of amyotrophic lateral sclerosis (ALS) in a patient in need thereof, comprising administering to the patient the tablet described above.

[0120] In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are merely preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

1. A tablet comprising celecoxib, ciprofloxacin or a pharmaceutically acceptable salt thereof, and a low-viscosity hydroxypropyl methylcellulose having a viscosity of 2 cP to 150 cP when measured as a 2% aqueous solution at 20°C.

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

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

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

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

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

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

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

9. 10. The tablet of claim 1, wherein the tablet comprises an extragranular component and an intragranular component, and the hydroxypropyl methylcellulose is present in the extragranular component.

10. 10. The tablet of claim 9, wherein the celecoxib and the pharmaceutically acceptable salts of ciprofloxacin are present in the intragranular component.

11. 10. The tablet of claim 1, further comprising a filler selected from the group consisting of a soluble filler, a non-soluble filler, and a mixture of a soluble filler and a non-soluble filler.

12. 12. The tablet of claim 11, wherein the filler is microcrystalline cellulose, lactose, mannitol, or a combination thereof.

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

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

100.

15. 15. The tablet of claim 14, wherein the ratio of the weight of celecoxib to the weight of ciprofloxacin free base is 1:10 to 1:

25.

16. 16. The tablet of claim 15, wherein the ratio of the weight of celecoxib to the weight of ciprofloxacin free base is 1:

10.

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

18. When the tablets were administered to human subjects with food and water for 7 days, the T value of celecoxib in the serum of the subjects was ｍａｘ However, the T of ciprofloxacin in the serum of the subjects ｍａｘ The tablet according to claim 1, wherein the viscosity is in the range of 80% to 125% of the above.

19. a. forming granules comprising celecoxib and ciprofloxacin or a pharmaceutically acceptable salt thereof; b. adding a 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 c. compressing the mixture to form tablets; 2. A method (step) for producing the tablet of claim 1, comprising:

20. 10. A method for the treatment of amyotrophic lateral sclerosis (ALS) in a patient in need thereof, comprising administering to the patient the tablet of claim 1.

Images