Stable ciprofloxacin compositions

Abstract

A stable pharmaceutical dosage form that includes ciprofloxacin or a pharmaceutically acceptable salt thereof and one or more antioxidants up to percent by weight of the dosage. The dosage form is prepared with a wet granulation method, and the antioxidant is incorporated into a sprayable liquid for combining with the composition. The stable dosage form has a limited amount of formation of an N-nitroso ciprofloxacin impurity after storage for up to six months in accelerated conditions of temperature or humidity.

Description

Stable Ciprofloxacin CompositionsField

[0001] The invention relates to stable solid compositions containing ciprofloxacin as an active ingredient and, in particular, oral compositions containing ciprofloxacin, and an antioxidant and / or pH modulating agent, that are stable when stored.Background

[0002] In its ICH M7 assessment, the European Medicines Agency considers N-nitrosamine impurities to be undesirable and the impurities are considered to be high potency mutagenic compounds. Nitrosamines are formed by the reaction of secondary or tertiary amines together with nitrosating agents, such as nitrite salt under acidic conditions. Nitrosamine Drug Substance Related Impurities (NDSRIs) are a class of nitrosamines that have one of the key reactants as the active pharmaceutical ingredient (API) itself. Controlling NDSRIs in drug products presents a challenge as the API is purposefully present. Other prerequisites for formation of nitrosamine impurity are a nitrite originating through API synthesis or from excipient(s) present in the drug product. Controlling nitrites are also challenging as the substances occur naturally in soil, water and air.

[0003] It has been identified during risk assessment analysis that there is formation of N-nitroso ciprofloxacin in ciprofloxacin-containing drug products. Thus, there remains a need for a ciprofloxacin-containing drug product that offers long-term storage stability. Presentation of ciprofloxacin as a stable oral drug product or composition will reduce or prevent significant formation of N-nitroso ciprofloxacin.Summary

[0004] Described herein are pharmaceutical dosage forms or solid compositions of ciprofloxacin or salts thereof (e.g., ciprofloxacin HCI). In a first aspect, there is disclosed amethod for preventing or inhibiting the formation of N-nitroso ciprofloxacin in a ciprofloxacin composition, the method includes adding at least one of antioxidants or a pH modulating agent to the ciprofloxacin composition.

[0005] In an example of aspect 1, the ciprofloxacin composition contains an antioxidant, a pH modulating agent or a combination of both.

[0006] In another example of aspect 1, the ciprofloxacin composition is prepared by a wet granulation process and the composition can be a tablet formed by compressing granulated ingredients. The antioxidant and / or pH modulating agent may be added to a spray solution used in the wet granulation process for preparing the solid composition of ciprofloxacin or salts thereof.

[0007] In another example of aspect 1, the antioxidant is selected from ascorbic acid, a cysteine (e.g., L-cysteine) and a combination of both. The composition may optionally include only one antioxidant such that the selected antioxidant is the sole antioxidant present in the composition.

[0008] In another example of aspect 1, ascorbic acid and / or a cysteine (e.g., L-cysteine) is added to during the manufacturing of the composition such that ascorbic acid and / or a cysteine (e.g., L-cysteine) is present from in a range of 1 to 10%, 1 to 5%, or 1, 2, 3, 4 or 5% weight percent based on the total weight of the ciprofloxacin composition.

[0009] In another example of aspect 1, the sole active ingredient in the ciprofloxacin composition is ciprofloxacin or a pharmaceutically acceptable salt thereof, for example, ciprofloxacin hydrochloride, and the ciprofloxacin or salt thereof (e.g., hydrochloride) is present from 50 to 85% weight percent based on the total weight of the ciprofloxacin composition.

[0010] In another example of aspect 1, the ciprofloxacin composition further includes one of the following: corn starch present from 2 to 10% weight percent based on the total weight of the ciprofloxacin composition; sodium starch glycolate present from 2 to 8% weight percent based on the total weight of the ciprofloxacin composition; microcrystalline cellulose present from 5 to 25% weight percent based on the total weight of the ciprofloxacin composition; hydrogenated vegetable oil present from 0.1 to 3% weight percent based on the total weight of the ciprofloxacin composition; colloidal silicon dioxide present from 0.1 to 3% weight percentbased on the total weight of the ciprofloxacin composition; magnesium stearate present from 1 to 5% weight percent based on the total weight of the ciprofloxacin composition; and a coating or coating material present from 1 to 5% weight percent based on the total weight of the ciprofloxacin composition.

[0011] In a second aspect, there is a pharmaceutical dosage form, the dosage includes a ciprofloxacin or a pharmaceutically acceptable salt thereof and 1 to 10 weight percent of an antioxidant based on the total weight of the solid pharmaceutical composition. The composition is stable such that the pharmaceutical dosage form contains less than 2 parts per million (ppm) of N-nitroso ciprofloxacin impurity based on one million parts of the pharmaceutical dosage form after storage of the pharmaceutical dosage form for at least one month at 40° C and 75% relative humidity or at 25° C and 60% relative humidity.

[0012] In an example of aspect 2, the dosage form is a solid composition, for example, a tablet.

[0013] In another example of aspect 2, the antioxidant being ascorbic acid, a cysteine, or a combination thereof.

[0014] In another example of aspect 2, the antioxidant or total amount of antioxidant being present at about 1 to 5 weight percent, or 1, 2, 3, 4 or 5 weight percent based on the total weight of the solid pharmaceutical composition.

[0015] In another example of aspect 2, the ciprofloxacin being ciprofloxacin HCI, and the ciprofloxacin hydrochloride is present from 50 to 85 weight percent based on the total weight of the solid pharmaceutical composition.

[0016] In another example of aspect 2, the antioxidant being a combination of ascorbic acid and a cysteine.

[0017] In another example of aspect 2, the total antioxidant being present at 5 or less, or 4 or less weight percent based on the total weight of the dosage form.

[0018] In another example of aspect 2, the dosage form further including at least one of sodium bicarbonate, citric acid, histidine, sodium ascorbate or any combination thereof.

[0019] In another example of aspect 2, the dosage form having a pH of 4.5 or less, 4.1 or less, 4 or less, 3.5 or less or 3 or less.

[0020] In another example of aspect 1, the pharmaceutical dosage form contains less than 1 or less than 0.8 parts per million of N-nitroso ciprofloxacin impurity based on one million parts of the pharmaceutical dosage form after storage of the pharmaceutical dosage form for at least one, two, three, six or eighteen months at 40° C and 75% relative humidity or at 25° C and 60% relative humidity.

[0021] In another example of aspect 2, the pharmaceutical dosage form contains less than 1 parts per million (ppm) of N-nitroso ciprofloxacin impurity based on one million parts of the pharmaceutical dosage form after storage of the pharmaceutical dosage form for at least six or eighteen months at 40° C and 75% relative humidity or at 25° C and 60% relative humidity.

[0022] Any one of the above aspects (or examples of those aspects) may be provided alone or in combination with any one or more of the examples of that aspect discussed above; e.g., the first aspect may be provided alone or in combination with any one or more of the examples of the first aspect discussed above; and the second aspect may be provided alone or in combination with any one or more of the examples of the second aspect discussed above; and so-forth.

[0023] Additional features and advantages will be set forth in the detailed description which follows, and in part will be readily apparent to those skilled in the art from that description or recognized by practicing the embodiments as described herein, including the detailed description which follows, and the claims. It is to be understood that both the foregoing general description and the following detailed description are merely exemplary, and are intended to provide an overview or framework to understanding the nature and character of the claims.Detailed Description

[0024] Herein, when a range such as 5-25 (or 5 to 25) is given, this means preferably at least or more than 5 and, separately and independently, preferably not more or less than 25. In an example, such a range defines independently 5 or more, and separately and independently, 25 or less. Moreover, all ranges disclosed herein are to be understood to encompass any and all values and sub-ranges between the stated values.

[0025] As used herein, the term "about" means that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors. When the term "about" is used in describing a value or an end-point of a range, the disclosure should be understood to include the specific value or end-point referred to. Whether or not a numerical value or endpoint of a range in the specification recites "about," the numerical value or end-point of a range is intended to include two embodiments: one modified by "about," and one not modified by "about." It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0026] The present disclosure is directed to stable solid compositions or dosage forms containing ciprofloxacin. The control of the formation of the nitrosamine drug substance related impurities in a ciprofloxacin composition is achieved by introducing selective compounds that prevent the impurity-formation reactions. Nitrosamine impurity is a result of a multi-factor interaction of one or more of ciprofloxacin, starting materials, impurities, excipients, and / or water used in the formulation manufacturing process. The present disclosure controls and reduces potential nitrosamine impurity formation in ciprofloxacin compositions and dosage forms containing ciprofloxacin by reducing one or more key reactant nitrite traces in ciprofloxacin, non-ciprofloxacin excipients in the composition and / or switching the formulation manufacturing process to a dry granulation method or other method that avoids the use of water. Removal of water during the formulation manufacturing process reduces the formation of nitrosamine impurities.

[0027] Provided herein are pharmaceutical dosage forms of ciprofloxacin or a pharmaceutically acceptable salt thereof including an antioxidant or a pH modulating agent, or a combination of both. The term "pharmaceutical dosage form" or "dosage" as used herein, may include solid compositions, tablets, capsules, granules, and the like.

[0028] The term "ciprofloxacin," as used herein, refers to ciprofloxacin free base or pharmaceutically acceptable salts thereof, in particular pharmaceutically acceptable acid addition salts including, for example, citrate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, tartarate, succinate, malate, maleate, oxalate, fumarate, gluconate, saccharate, benzoate, methansulfonate, ethanesulfonate, benzenesulfonate, and the like.

[0029] The dosage forms described herein include from about 100 mg to about 1,000 mg of ciprofloxacin or an equivalent amount of ciprofloxacin in the form of a pharmaceutically acceptable salt. In one example, the dosage form includes 500 mg of ciprofloxacin. In other examples, the dosage form includes 100 mg, 250 mg or 750 mg of ciprofloxacin.

[0030] The amount of ciprofloxacin or an equivalent amount of ciprofloxacin in the form of a pharmaceutically acceptable salt in the pharmaceutical dosage form is in the range of about 50% to about 90%, about 55% to about 85%, about 60% to about 80%, or about 65% to about 78% by weight, based on the total weight of the composition or dosage form.

[0031] The ciprofloxacin pharmaceutical dosage forms of the present invention preferably contain one or more antioxidants. The term "antioxidant" refers to a substance capable of slowing or preventing the oxidation of other substances. Oxidation reactions can generate free radicals, which can set off chain reactions that can be damaging. Antioxidants prevent these chain reactions by removing free radical intermediates and inhibit other oxidation reactions by being oxidized themselves; thus, antioxidants can be considered reducing agents. The antioxidant may be present in the form of a single compound or in the form of a mixture of compounds. Antioxidants include but are not limited to, zwitterion compounds, a sulfite, bisulfite, metabisulfite compound, ascorbic acid, ascorbates, cysteine (e.g., L-cysteine), fumaric acid, ethylene diamine tetraacetic acid (EDTA) or its sodium or calcium salt, tocopherol, gallate,vitamin E phenolic substituted compounds, monophenolic compounds, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).

[0032] The antioxidant, combination of antioxidants or total antioxidants may be present in the ciprofloxacin pharmaceutical dosage form in an amount of about 0.1% to about 20%, about 0.25% to about 15%, about 0.5% to about 10%, about 1% to about 8%, or about 2, 3, 4 or 5% by weight, based on the total weight of the composition or dosage form.

[0033] The weight ratio of the total weight of ciprofloxacin in the dosage form to the total weight of antioxidant in the dosage form contributes to obtaining a desirable stability profile. The weight ratio of the total weight of ciprofloxacin in the dosage form to the total weight of the antioxidant in the dosage form disclosed herein is from about 80:1 to about 5:1, from about 60:1 to about 10:1, from about 50:1 to about 15:1, or from about 40:1 to about 20:1. In one or more embodiments, the pharmaceutical dosage form can include a weight ratio of the total weight of ciprofloxacin to an ascorbic acid, cysteine, or a combination thereof in a range of about 80:1 to about 10:1 from about 78:1 to about 15:1, or from about 40:1 to about 30:1.

[0034]

[0035] The ciprofloxacin pharmaceutical dosage forms of the present invention may further include one or more pharmaceutically acceptable ingredients or excipients in addition to those disclosed herein. As used herein, term "pharmaceutically acceptable excipients" includes any physiologically inert additives that are routinely used in pharmaceutical dosage forms.Pharmaceutically acceptable excipients may be selected from the group including, but not limited to, for example, binders, glidants, lubricants, plasticizers, surfactants, opacifiers, disintegrants, acidifiers, among others, and combinations thereof.

[0036] Suitable glidants include, but are not limited to, magnesium stearate, stearic acid, calcium stearate, colloidal silicon dioxide, starch, talc, and combinations thereof.

[0037] Suitable lubricants include, but are not limited to, magnesium stearate, talc, oils (e.g., hydrogenated vegetable oil) and silica and combinations thereof.

[0038] Suitable plasticizers include, but are not limited to, triethyl citrate, dibutyl sebacate, acetylated triacetin, tributyl citrate, glyceryl tributyrate, monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyloxalate, diethylphthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, and combinations thereof.

[0039] Suitable surfactants include, but are not limited to, sorbitan monolaurate, sorbitan trioleate, polyoxyethylene sorbital, sorbitan tristearate, polyoxyethylene sorbital hexastearate, ethylene glycol fatty acid ester, propylene glycol fatty acid ester, propylene glycol monostearate, glycerol monostearate, sorbitan monooleate, and combinations thereof.

[0040] Suitable opacifiers include, but are not limited to, titanium dioxide.

[0041] Suitable disintegrants include, but are not limited to, croscarmellose sodium, hydroxypropyl cellulose (L-HPC), crospovidone, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, sodium starch glycolate, gums, alginic acid or alginates, pregelatinized starch, corn starch, modified starch, carboxymethyl starch, polyacrylates, and combinations thereof.

[0042] Suitable binders include, but are not limited to, polyvinylpyrrolidone (povidone, PVP); polyethylene glycol (PEG); cross-linked polyvinylpyrrolidone; cellulose derivatives including hydroxymethyl cellulose, hydroxypropylcellulose, carboxy-methylcellulose sodium, ethyl cellulose, hydroxylethylcellose, and hydroxypropylmethylcellulose; sucrose; alginic acid or sodium alginate; carbomer; cottonseed oil; dextrin; dextrose; guar gum; hydrogenated vegetable oil type I; magnesium aluminium silicate; maltodextrin; maltose; mannitol, sorbitol, saccharose, macrogols, polydextrose; polyethylene oxide stearic acid and zein or combination thereof.

[0043] Optionally, the pharmaceutical dosage form, solid core, tablet core or the like may be additionally coated with a film coating, such as those provided under the trade name Opadry®. The film coating may constitute the outermost coating of the pharmaceutical dosage form and directly overlie and contact the solid core. In one or more embodiments, the film coating ingredient (e.g., Opadry®) may be included directly into one of the coatings surrounding the core for the core itself.

[0044] The ciprofloxacin pharmaceutical dosage forms of the present disclosure are suitable for oral administration, for example, to a broad spectrum antimicrobial agent, or to treat infections in mammals caused by susceptible strains of microorganisms and / or conditions and patient populations in the following groups, urinary tract infections, acute uncomplicatedcystitis (in females), chronic bacterial prostatitis, lower respiratory tract infections, acute sinusitis, skin and skin structure infections, bone and joint infections, complicated intraabdominal infections, infectious diarrhea, typhoid fever (enteric fever), uncomplicated cervical and urethral gonorrhea, pediatric patients (1 to 17 years of age), complicated urinary tract infections and pyelonephritis, and inhalation anthrax (post-exposure) in adults and pediatric patients, and other indications where broad spectrum antimicrobial agents would be desirable.

[0045] In one example, the mammal is a human. Example methods include administering the ciprofloxacin pharmaceutical dosage form to a human subject in need thereof in an amount effective to treat infections in mammals caused by susceptible strains of microorganisms and / or conditions and patient populations in the following groups, urinary tract infections, acute uncomplicated cystitis (in females), chronic bacterial prostatitis, lower respiratory tract infections, acute sinusitis, skin and skin structure infections, bone and joint infections, complicated intra-abdominal infections, infectious diarrhea, typhoid fever (enteric fever), uncomplicated cervical and urethral gonorrhea, pediatric patients (1 to 17 years of age), complicated urinary tract infections and pyelonephritis, and inhalation anthrax (post-exposure) in adults and pediatric patients.

[0046] The ciprofloxacin pharmaceutical dosage form may be administered, for example, once a day, twice a day, three times a day, or as needed for a period of time necessary to treat the above indications and patient populations. In one example, the ciprofloxacin pharmaceutical dosage forms described herein are administered once a day, such that the dosage form is characterized as once daily, twice a day, such that the dosage form is characterized as twice daily, or three times a day. Treatment with the ciprofloxacin pharmaceutical dosage form can be for any suitable time period, and may include 1 to 60 days, 3 to 42 days, 7 to 28 days, or 10 days, 14 days or 21 days.

[0047] Ciprofloxacin pharmaceutical dosage forms according to the present disclosure will be illustrated in the following non-limiting examples. The examples should not, however, be viewed as limiting the scope of the invention. The claims will serve to define the invention.EXAMPLES

[0048] The following examples illustrate specific and exemplary embodiments and / or features of the embodiments of the present disclosure. The examples are provided solely for the purposes of illustration and should not be construed as limitations of the present disclosure. Numerous variations of these specific examples are possible without departing from the scope of the presently disclosed embodiments. More specifically, the particular coatings, arrangement of components or coatings, ingredient amounts, and other ingredients utilized in the examples should not be interpreted as limiting since other such ingredients consistent with the disclosure in the Detailed Description can utilized in substitution. That is, the particular ingredients in the compositions, as well as their respective amounts and relative amounts should be understood to apply to the more general content of the Detailed Description.EXAMPLE 1

[0049] In an initial evaluation, a control ciprofloxacin composition was prepared. The control ciprofloxacin composition was prepared to have the formulation shown below in Table

[0050] Table 1Material W / w% in ControlCompositionCiprofloxacin HCI 78.1%Corn Starch 7.1%Sodium Starch Glycolate 4%Microcrystalline Cellulose 7.6%Hydrogenated vegetable oil 0.7%Colloidal Silicon Dioxide 0.6%Magnesium stearate 1.8%Opadry 2%

[0051] The control ciprofloxacin composition was prepared by two separate formulation manufacturing methods - dry compaction and top spray wet granulation. The formation of N-nitroso ciprofloxacin in the control ciprofloxacin compositions was measured after initial formation of the control ciprofloxacin compositions. The N-nitroso ciprofloxacin measurements in parts per million (ppm) based on the concentration of a specific component per one million parts of the control composition are shown below in Table 2. As used in the examples and shown in the tables below, the presence of N-nitroso ciprofloxacin was measured using a liquid chromatograph with mass spectrometry (LC-MS) analytical method.

[0052] Table 2Initial N-nitroso ciprofloxacinamount (ppm)Dry Spray Wet Compaction GranulationControl Composition 0.69 2.70

[0053] As can be seen in Table 2, the wet granulation method resulted in a higher presence or concentration of N-nitroso ciprofloxacin, likely due to the presence of liquids (e.g., water) during the formation process.EXAMPLE 2

[0054] Controlling the presence of nitrites in the ciprofloxacin and / or excipients in the composition presents difficulty in manufacturing and ingredient selection. Formulation design can include addition of substances to control the formation of nitrosamine impurities in spite of the presence of traces of nitrites. Nitrosamines impurities can form under acidic conditions. The invention is directed to the addition of pH modulators and / or nitrite scavengers to prevent the formation of nitrosamines in the ciprofloxacin composition. In one or more embodiments, considering nitrosamine impurity formation is resultant of multi-factor interaction, the reduction or avoidance of water in the formulation manufacturing process in addition to the incorporation of a pH modulator and / or nitrite or nitrosamine scavenger is used to reduce the formation of nitrosamines in the ciprofloxacin composition.

[0055] The addition of pH modulators / modifiers and antioxidants to reduce or prevent the formation of N-nitroso ciprofloxacin in the composition as compared to the use of two separateformulation manufacturing methods - dry compaction and top spray wet granulation - that were used to prepare the control ciprofloxacin composition are shown.

[0056] It was found that cysteine (e.g., L-cysteine) and / or ascorbic acid resulted in preventing the formation N-nitroso ciprofloxacin impurity in the drug product manufactured by a wet granulation method as compared to the formation of N-nitroso ciprofloxacin impurity in a dry granulation / compaction method. The measurements in parts per million (ppm) based on the concentration of a specific component, N-nitroso ciprofloxacin impurity, per one million parts of the control composition and compositions containing stabilizers are shown below in Table 3.

[0057] Table 3Description Initial N-nitroso ciprofloxacin amount(ppm)Dry Compaction Spray Wet GranulationControl Composition 0.69 2.701% Sodium Bi Carbonate 0.56 0.201% Citric acid 1.10 2.401% Ascorbic acid 0.74 0.501% L-Cysteine 1.00 0.52

[0058] As evidenced in Table 3, sodium bicarbonate was found to modulate the pH and thereby reduce the formation of N-nitroso ciprofloxacin initially, however, during the storage as further discussed below, it was further evidenced that sodium bicarbonate, being an alkaline material, can react with HCI salt portion of ciprofloxacin and convert the ciprofloxacin hydrochloride (HCI) to its ciprofloxacin base, which can further impact the solubility of the API and also, as a result, the efficacy of the active drug molecule. Increases in the formation of the N-nitroso ciprofloxacin impurity at accelerated storage conditions can be attributed to the change in the micro environmental pH range due to the above-noted breakdown of HCI salt portion of the ciprofloxacin HCI in the composition. The storage results of parts per million (ppm) presence of N-nitroso ciprofloxacin when utilizing a 1% sodium bicarbonate in the spray wet granulation method for preparing the compositions are shown below in Table 4. Relative humidity is referenced as "RH" in Table 4.

[0059] Table 4Spray Wet Granulation N-nitroso ciprofloxacin amount data [ppm] at storage conditions of 40°C / 75% RHInitial IM 2MControl Composition 2.70 7.30 6.901% Sodium 0.20 0.80 1.50bicarbonate

[0060] As seen in the table, after storage of the dosage form for 2 months at 40° C and 75% relative humidity, N-nitroso ciprofloxacin started to form more rapidly as compared to the initial amount of N-nitroso ciprofloxacin at the time of formation.

[0061] The use of antioxidants can prevent the formation of nitrosamine impurities by converting nitrite present in the composition to nitric oxide and thereby depleting any available nitrites present in the ciprofloxacin or salt thereof and / or excipients in the ciprofloxacin composition. Ascorbic acid as an antioxidant was used and tested as a nitrite scavenger in the ciprofloxacin composition. Ascorbic acid can oxidize by taking oxygen from a nitrite and reduce the nitrite to nitric oxide and thus reducing a key reactant required for the formation of nitrosamine impurity. The storage results of parts per million (ppm) presence of N-nitroso ciprofloxacin when utilizing antioxidants, namely ascorbic acid and l-cysteine, in the spray wet granulation method for preparing the ciprofloxacin compositions are shown below in Table 5. Relative humidity is referenced as "RH" in Table 5.

[0062] Table 5Spray Wet Granulation N-nitroso ciprofloxacin amount data (pp m) at storage conditions of 40°C / 75% RHInitial IM 2M 3M 6M Control Composition 2.70 7.30 6.90 6.90 10.50 1% Ascorbic acid 0.50 0.68 0.63 0.41 0.80 1% L-Cysteine 0.52 0.52 0.33 0.47 0.43

[0063] The cysteine antioxidant is a non-essential amino acid that exists as a zwitterion. The thiol side chain in cysteine can participate in reactions as a nucleophile and is easily oxidized.Due to the ability of thiols to undergo redox reactions, cysteine has antioxidant properties and is used in the ciprofloxacin compositions to promote stability and reduction in the formation of N-nitroso ciprofloxacin. Moreover, cysteine is an antioxidant, and being primary amine, it can competitively react with nitrite and depletes the nitrites present in the ciprofloxacin composition and thereby reduces the nitrite concentration and nitrosamine formation potential. This benefit is evidenced in Table 5 and further below in a study that increased the concentration of cysteine linearly, which decreased the formation of N-nitroso ciprofloxacin impurity in the compositions.

[0064] As also shown in Table 5, the presence of a single antioxidant in the control composition can effectively control the formation of the N-nitroso ciprofloxacin impurity under accelerated storage conditions (40° C and 75% relative humidity). The incorporation of about 1 weight percent of an antioxidant, such as ascorbic acid or a cysteine, based on the total weight of the composition in a wet granulation formulation method can limit the formation of total N-nitroso ciprofloxacin impurity to less than 5 ppm, less than 3 ppm, less than 2 ppm, less than 1 ppm, less than 0.8 ppm, less than 0.6 ppm, less than 0.5 ppm or less than 0.4 ppm after storage of the dosage form for 1, 2, 3 or 6 months at 40° C and 75% relative humidity.

[0065] In order to demonstrate the further practice of the present invention, the following examples were prepared and tested. The control ciprofloxacin composition was compared to similar ciprofloxacin compositions formed with the same spray wet granulation formulation method but with the addition of an antioxidant. The compositions are shown below in Tables 6 and 7.

[0066] Table 6Material Control 1% L- 2% L-Cysteine 5% L-Cysteine Comp CysteineCiprofloxacin HCI 78.1% 78.1% 78.1% 78.1% Corn Starch 7.1% 7.1% 7.1% 7.1% Sodium Starch Glycolate 4% 4% 4% 4% L-Cysteine - 1% 2% 5% Microcrystalline Cellulose 7.6% 6.6% 5.6% 2.6% Hydrogenated vegetable oil 0.7% 0.7% 0.7% 0.7% Colloidal Silicon Dioxide 0.6% 0.6% 0.6% 0.6%Magnesium stearate 1.8% 1.8% 1.8% 1.8%Opadry 2% 2% 2% 2%Material 2% Ascorbic 1% Ascorbic 2% Ascorbic 5% AscorbicAcid + 2% L- Acid Acid AcidCysteine Ciprofloxacin HCI 78.1% 78.1% 78.1% 78.1% Corn Starch 7.1% 7.1% 7.1% 7.1% Sodium Starch Glycolate 4% 4% 4% 4% L-Cysteine - - - 2% Ascorbic Acid 1% 2% 5% 2% Microcrystalline Cellulose 6.6% 5.6% 2.6% 3.6% Hydrogenated vegetable oil 0.7% 0.7% 0.7% 0.7% Colloidal Silicon Dioxide 0.6% 0.6% 0.6% 0.6% Magnesium stearate 1.8% 1.8% 1.8% 1.8%Opadry 2% 2% 2% 2%

[0067] Table ?Material 2% Ascorbic2% L- 5% AscorbicAcid + 2% L- Cysteine AcidCysteine Ciprofloxacin HCI 76.3% 74.2% 74.9%Corn Starch 7% 6.8% 6.8%Sodium Starch Glycolate 3.9% 3.8% 3.8%L-Cysteine 2% - 1.9% Ascorbic Acid - 4.7% 1.9%Red Iron oxide - 0.04% 0.04%Yellow Iron oxide - 0.04% 0.04% Microcrystalline Cellulose 7.6% 7.3% 7.2% Hydrogenated vegetable oil 0.6% 0.6% 0.6% Colloidal Silicon Dioxide 0.7% 0.7% 0.7% Magnesium stearate 2% 2% 2%Opadry 2% 1.9% 1.9%

[0068] The ciprofloxacin compositions of Table 7 were tested for N-nitroso ciprofloxacin impurity presence in parts per million (ppm) of the impurity based on the concentration of one million parts of the composition after storage of the compositions in accelerated conditions (40° C and 75% relative humidity) and certain compositions at general storage conditions (25° C and 60% relative humidity). The results of the testing are shown below in Table 8.

[0069] Table 8Description N-nitroso Ciprofloxacin Impurity (ppm) (Limit NMT 1 ppm)APIResult Initial IM 2M 3M 6M 6M 18 M 40 / 75 40 / 75 40 / 75 40 / 75 25 / 60 25 / 60 Control Trial 0.09 2.7 7.3 6.9 6.9 10.5Control Trial 0.29 1.4 3.6 5.7 3.7 5.7(Repetition)2% L-Cysteine 0.09 0.31 0.14 0.36 0.26 0.272% L-Cysteine 0.29 0.54 0.84 0.54 0.73 0.58 0.632% L-Cysteine (Scale 0.09 0.40 0.28 0.36 0.37 0.34 0.39 0.19 up trial)5% Ascorbic Acid 0.09 0.17 0.36 0.28 0.18 0.215% Ascorbic Acid 0.29 0.5 0.67 0.48 0.63 0.56 0.555% Ascorbic Acid 0.09 0.36 0.36 0.46 0.50 0.47 0.50 0.27 (Scale up trial)2% Ascorbic Acid + 0.09 0.17 0.16 0.15 0.16 0.122% L-Cysteine2% Asc. Acid + 0.29 0.44 0.63 0.43 0.56 0.53 0.502% L-Cysteine2% Ascorbic Acid + 0.09 0.28 0.22 0.31 0.31 0.28 0.30 0.16 2% L-Cysteine (Scaleup trial)

[0070] As also shown in Table 8, the presence of a single antioxidant in the control composition can effectively control the formation of the N-nitroso ciprofloxacin impurity under accelerated and general storage conditions (40° C and 75% relative humidity and 25° C and 60% relative humidity, respectively). Stability can be measured by, for example, the total amount of a specific impurity that is formed after formation of the pharmaceutical dosage form (initial) for a specified period of time at specified storage conditions (e.g., temperature, humidity).Stability of a ciprofloxacin dosage forms or compositions is measured over time after an initial time point measured shortly after formation of the dosage form or composition. Storage conditions can be, for example, 2-8° C, 25° C, 40° C, or 50° C for a period of 1, 2, 3, 6 or 18 months. Relative humidity of the storage conditions can include 40%, 60% and up to 75%.

[0071] As shown, the incorporation of about 2 total weight percent of an antioxidant, such as a cysteine, based on the total weight of the composition in a wet granulation formulation method can limit the formation of total N-nitroso ciprofloxacin impurity to less than 2 ppm, less than 1 ppm, less than 0.8 ppm, less than 0.6 ppm, less than 0.5 ppm or less than 0.4 ppm after storage of the dosage form for 1, 2, 3, 6 or 18 months at 40° C and 75% relative humidity or at 25° C and 60% relative humidity.

[0072] In another example, the incorporation of about 5 total weight percent of an antioxidant, such as a ascorbic, based on the total weight of the composition in a wet granulation formulation method can limit the formation of total N-nitroso ciprofloxacin impurity to less than 2 ppm, less than 1 ppm, less than 0.8 ppm, less than 0.6 ppm, less than 0.5 ppm, less than 0.4 ppm or less than 0.3 ppm after storage of the dosage form for 1, 2, 3, 6 or 18 months at 40° C and 75% relative humidity or at 25° C and 60% relative humidity.

[0073] In yet another example as evidenced in Table 8, incorporation of about 4 total weight percent of a combination of antioxidants, such as a cysteine and ascorbic acid, based on the total weight of the composition in a wet granulation formulation method can limit the formation of total N-nitroso ciprofloxacin impurity to less than 2 ppm, less than 1 ppm, less than 0.8 ppm, less than 0.6 ppm, less than 0.5 ppm, less than 0.4 ppm or less than 0.3 ppm after storage of the dosage form for 1, 2, 3, 6 or 18 months at 40° C and 75% relative humidity or at 25° C and 60% relative humidity. The combination of antioxidants can be in the weight ratio range of 3:1 to 1:3, 2:1 to 1:2, 1.5:1 to 1:1.5, 1.2:1 to 1:1.2 or 1:1.

[0074] Table 8 further evidences that the addition of one or more antioxidants can maintain or even lower the N-nitroso ciprofloxacin impurity content as compared to its presence at the initial time the composition is prepared. For instance, incorporation of about 2 total weight percent of an antioxidant, such as a cysteine, based on the total weight of the composition in a wet granulation formulation method can decrease the amount N-nitroso ciprofloxacin impurity content as compared to the initial content of the impurity in the composition after storage of the dosage form for 1, 2, 3, 6 or 18 months at 40° C and 75% relative humidity or at 25° C and 60% relative humidity. In another example, incorporation of about 4 total weight percent of an antioxidant or combination of antioxidants, such as a cysteine and ascorbic acid, based on thetotal weight of the composition in a wet granulation formulation method can decrease or maintain the same amount N-nitroso ciprofloxacin impurity content as compared to the initial content of the impurity in the composition after storage of the dosage form for 1, 2, 3, 6 or 18 months at 40° C and 75% relative humidity or at 25° C and 60% relative humidity. In yet another example, the addition of one or more antioxidants can limit the increase of the N-nitroso ciprofloxacin impurity content as compared to its presence at the initial time the composition is prepared.

[0075] As evidenced in the examples, incorporation of about 2, 4 or 5 total weight percent of an antioxidant or a combination of antioxidants, such as a ascorbic acid and cysteine, based on the total weight of the composition prepared by a wet granulation formulation method can limit the increase in formation of N-nitroso ciprofloxacin impurity content as compared to an initial amount of the impurity present upon formation. For example, incorporation of about 2, 4 or 5 total weight percent of an antioxidant or a combination of antioxidants, such as a ascorbic acid and cysteine, based on the total weight of the composition prepared by a wet granulation formulation method can limit the increase in formation of N-nitroso ciprofloxacin impurity to be 50 or less ppm percent, 40 or less ppm percent, 35 or less ppm percent, 30 or less ppm percent, 25 or less ppm percent, 20 or less ppm percent, 15 or less ppm percent, 10 or less ppm percent, 5 or less ppm percent or 0 ppm percent as measured relative to the initial content (ppm) of the N-nitroso ciprofloxacin impurity in the composition after storage of the dosage form for 1, 2, 3, 6 or 18 months at 40° C and 75% relative humidity or at 25° C and 60% relative humidity.

[0076] The example ciprofloxacin compositions of Table 8 provided above were prepared using the following formulation manufacturing process.

[0077] Formulation Manufacturing Process (steps):

[0078] 1: Preparation of granulation solution by dispersing the stabilizer and 50% of corn starch in deionized water.

[0079] 2: Granulation for Ciprofloxacin HCI, Sodium Starch Glycolate, 50% of corn starch and red iron oxide and yellow iron oxide using the granulation dispersion on Fluid bed granulator.

[0080] 3: Drying for the granules using fluid bed drier.

[0081] 4: Milling for the granules using oscillator with mesh 20

[0082] 5: Blending for the granules with Microcrystalline cellulose, Colloidal silicon dioxide, Hydrogenated vegetable oil and magnesium stearate.

[0083] 6: Compression for the final blend on the target tablet weight to produce Ciprofloxacin 250 mg, Ciprofloxacin 500 mg and Ciprofloxacin 750 mg tablets.

[0084] 7: Coating for the compressed tablets using Opadry white and colors.

[0085] Example ciprofloxacin compositions of Tables 6 and 7 were further tested to evaluate the impact of using a stabilizer such as an antioxidant and / or pH modulator on the release of ciprofloxacin from the dosage form. Dissolution testing evidenced as a percentage release, as shown in Table 9 below, that no significant impact on the release of ciprofloxacin was observed with the use of 1 to 5 weight percent of ascorbic acid and / or a cysteine added to the control ciprofloxacin composition.

[0086] Table 9% Release of CiprofloxacinControl1% 5%Time Comp 1% L- 2% L- 2% L-Cysteine +Reference Ascorbic Ascorbic (min) Without Cysteine Cysteine 2% Ascorbic Acid acid Acidstabilizer0 0 0 0 0 0 0 0 5 65 68 70 85 80 29 79 10 88 77 93 99 100 78 94 15 96 93 99 102 102 95 98 20 101 98 101 102 102 99 10030 102 100 102 103 102 101 101

[0087] The example ciprofloxacin compositions of Tables 6 and 7 were further tested to evaluate the impact of using a stabilizer such as an antioxidant and / or pH modulator on the pH of the composition. The concentration of the antioxidant and / or pH modulator impact the pH of a formulation, which is relative to the environment for the formation of the N-nitroso ciprofloxacin impurity. As shown in Table 10 below, the use of 1 to 10 weight percent, 1 to 5 weight percent, or 1, 2, 3, 4 or 5 weight percent of an antioxidant (e.g., ascorbic acid and / or L-cysteine) can modulate the pH of the composition downward as compared to the control composition such that the pH of the ciprofloxacin composition is controlled by the antioxidantpresence to be at or below 4.11. In certain instances, the pH of the ciprofloxacin composition was reduced and maintained at less than 4, less than 3.5, less than 3, less than 2.8 or less than 2.5. The pH was measured by dispersing the composition in 50 mL of deionized water and then measuring the pH of the dispersion by a pH meter.

[0088] Table 10Spray Wet Granulation pHFormulationControl Composition 4.511% Ascorbic acid 4.111% L-Cysteine 3.282% L-Cysteine 2.695% L-Cysteine 2.21

[0089] The use of a variety of antioxidants and pH modulators were tested to determine impact on the formation of N-nitroso ciprofloxacin impurities, in parts per million of the impurity based on one million parts of the composition, during storage of the solid ciprofloxacin compositions from Tables above at accelerated conditions. Ciprofloxacin compositions also including 1 weight percent of citric acid, histidine or sodium ascorbate were tested. As evidenced in Table 11 below, over a 2-month storage time period, the use of ascorbic acid and / or L-cysteine in the ciprofloxacin compositions resulted in the lowest presence of the N-nitroso ciprofloxacin impurities.

[0090] Table 11Spray Wet Granulation N-nitroso cipr ofloxacin data (ppm) at storage Formulations cond itions of 40°C / 75% RHInitial IM 2M Control Composition 2.70 7.30 6.901% Sodium Bi Carbonate 0.20 0.80 1.501% Citric acid 2.40 2.30 NA1% Histidine 0.42 1.60 NA1% Sodium Ascorbate 0.69 0.50 NA1% Ascorbic acid 0.50 0.68 0.631% L-Cysteine 0.52 0.52 0.332% L-Cysteine 0.31 0.14 0.365% L-Cysteine 0.18 0.18 0.22

[0091] While various aspects and embodiments of the compositions and methods have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the claims.

Claims

Claims:

1. A method for preventing or inhibiting the formation of N-nitroso ciprofloxacin impurity in a ciprofloxacin composition, the method comprising adding an antioxidant to the ciprofloxacin composition, the antioxidant being present in 0.5 to 10 weight percent based on the total weight of the ciprofloxacin composition.

2. The method of claim 1, wherein the ciprofloxacin composition is prepared by a wet granulation process.

3. The method of claim 1, wherein the antioxidant is selected from the group consisting of ascorbic acid, a cysteine and a combination thereof.

4. The method of claim 3, wherein the ascorbic acid is added to present from 1 to 10% weight percent based on the total weight of the ciprofloxacin composition.

5. The method of claim 3, wherein the cysteine is added to present from 1 to 10% weight percent based on the total weight of the ciprofloxacin composition.

6. The method of claim 3, the antioxidant being the sole antioxidant in the ciprofloxacin composition.

7. The method of claim 1, wherein the sole active ingredient in the ciprofloxacin composition is ciprofloxacin hydrochloride, and the ciprofloxacin hydrochloride is present from 50 to 85% weight percent based on the total weight of the ciprofloxacin composition.

8. The method of claim 1, wherein the ciprofloxacin composition further comprises one or more of corn starch present from 2 to 10% weight percent based on the total weight of the ciprofloxacin composition, sodium starch glycolate present from 2 to 8% weightpercent based on the total weight of the ciprofloxacin composition, microcrystalline cellulose present from 5 to 25% weight percent based on the total weight of the ciprofloxacin composition, hydrogenated vegetable oil present from 0.1 to 3% weight percent based on the total weight of the ciprofloxacin composition, colloidal silicon dioxide present from 0.1 to 3% weight percent based on the total weight of the ciprofloxacin composition, or magnesium stearate present from 1 to 5% weight percent based on the total weight of the ciprofloxacin composition.

9. The method of claim 1, wherein the ciprofloxacin composition further comprises a coating material present from 1 to 5% weight percent based on the total weight of the ciprofloxacin composition.

10. A pharmaceutical dosage form, the dosage form comprising:a. ciprofloxacin or a salt thereof;b. 1 to 10 weight percent of an antioxidant based on the total weight of the pharmaceutical dosage form,wherein the pharmaceutical dosage form contains less than 2 parts per million of N-nitroso ciprofloxacin impurity after storage of the pharmaceutical dosage form for at least one month at 40° C and 75% relative humidity.

11. The pharmaceutical dosage form of claim 10, the pharmaceutical dosage form is a tablet.

12. The pharmaceutical dosage form of claim 10, the antioxidant being selected from the group consisting of ascorbic acid, a cysteine and a combination thereof.

13. The pharmaceutical dosage form of claim 10, the antioxidant being present at 1 to 5 weight percent based on the total weight of the pharmaceutical dosage form.

14. The pharmaceutical dosage form of claim 10, the ciprofloxacin being ciprofloxacin hydrochloride, and the ciprofloxacin hydrochloride is present from 50 to 85 weight percent based on the total weight of the pharmaceutical dosage form.

15. The pharmaceutical dosage form of claim 10, the antioxidant being a combination of ascorbic acid and a cysteine, and the total weight percent of antioxidant present in the pharmaceutical dosage form being the in range of 1 to 5 weight percent.

16. The pharmaceutical dosage form of claim 10, the antioxidant being present at 2 or less weight percent based on the total weight of the solid pharmaceutical composition.

17. The pharmaceutical dosage form of claim 10, further comprising at least one of sodium bicarbonate, citric acid, histidine, and sodium ascorbate.

18. The pharmaceutical dosage form of claim 10, the pharmaceutical dosage form having a pH of 4.1 or less.

19. The pharmaceutical dosage form of claim 10, the pharmaceutical dosage form contains less than 1 parts per million of N-nitroso ciprofloxacin impurity after storage of the pharmaceutical dosage form for at least one month at 40° C and 75% relative humidity.

20. The pharmaceutical dosage form of claim 10, the pharmaceutical dosage form contains less than 1 parts per million of N-nitroso ciprofloxacin impurity after storage of the pharmaceutical dosage form for at least three months at 40° C and 75% relative humidity.

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