CZ20022883A3 - Formulation in the form of a tablet - Google Patents

Abstract

A once daily tablet formulation for oral administration in humans for the controlled release of ciprofloxacin comprising a pharmaceutically effective amount of ciprofloxacin, from about 0.1 % to about 8.0 % of a viscolyzing agent and/or a gelling agent, about 5.0% to about 15 % of a gas generating agent, and about 3.0 % to about 15 % of a swelling agent, said percentages being w/w of the composition.

Description

Drug delivery system ριυ once daily ciprofloxacin »

Technical field

The invention relates to a pharmaceutical composition in the form of tablets or capsules which provides a combination of spatial and temporal control of the delivery of a drug, specifically a ciprofloxacin drug, to a patient in order to achieve effective treatment results. The pharmaceutical composition consists of ciprofloxacin, a gas generating agent, a blowing agent and comprises either a viscolyzing agent or a gelatinous agent. The blowing agent belongs to the group of high absorption compounds commonly referred to as superdisintegrants. This class of compounds includes, for example, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose. The viscolyzing agent is a highly viscous material that, upon contact with gastric juices, captures the gas produced by the gas generating agent. The viscolyzing agent comprises, for example, a carbohydrate gum, for example xanthan gum or a cellulose ether, for example hydroxypropylmethylcellulose (methocel). The gelling agent is preferably a cross-linkable gelling agent, such as a water-soluble salt of one or more polyuronic acids, for example sodium alginate.

The improved controlled drug delivery system of the invention is designed to efficiently deliver ciprofloxacin to a patient over a period of time (time control) and from a particular portion of the patient's gastrointestinal tract (spatial control). The improved controlled drug delivery system prevents under-utilization of the dose by the organism and ensures the best therapeutic benefit of administering ciprofloxacin to the subject.

It is well known to those skilled in the art that in diseases requiring multiple doses of a given drug, blood levels of the drug must be maintained above their minimum effective level and below their minimum toxicity level in order to achieve the desired therapeutic effects while avoiding undesirable toxic effects. and side effects were minimal. Once the blood level of the drug is within this range, the drug is removed from the body at a certain rate. The controlled drug delivery system is typically designed to deliver the drug at this particular rate; maintain safe and effective blood levels and maintain as long as the system delivers the drug at this rate. Controlled drug delivery usually results in substantially more stable levels of the active ingredient in the blood as compared to uncontrolled fluctuations that can be observed when administering multiple doses of conventional rapid release dosage forms to a patient. Controlled drug delivery results in optimal therapy and not only reduces the frequency of dosing, but can also reduce the severity and frequency of side effects.

The above-mentioned basic drug delivery systems are well known to those skilled in the art. In recent decades, efforts have been made to develop new pharmaceutically functional and therapeutically effective drug delivery systems. Particular attention has been focused on orally administered controlled drug delivery systems for ease of administration by the oral route as well as for the easy and economical production of oral dosage forms such as tablets and capsules. Several different controlled drug delivery systems have been developed based on different release mechanisms. These oral controlled drug strict systems are based on different functional principles and have different names such as dissolution controlled systems, diffusion controlled systems, ion-exchange resins, osmotically controlled systems, decomposable matrix systems, pH-independent formulations, swelling controlled systems and the like.

An orally administered controlled drug delivery system encounters a wide range of very different conditions in the gastrointestinal tract, such as pH, agitation intensity, and gastric and intestinal juice compositions. Ideally, an orally administered controlled delivery system delivers the drug at a constant and reproducible rate regardless of various conditions. Therefore, considerable efforts have been made to create orally administered controlled delivery systems that overcome these drawbacks and deliver the drug at a constant rate in the digestive tract.

It is known to those skilled in the art that the drug need not be absorbed with the same intensity along the entire digestive tract, and that absorption of the drug in the colon is usually uncertain and ineffective. Some drugs are absorbed only in the stomach or upper parts of the small intestine. Another important factor that may adversely affect the function of an orally administered controlled drug delivery system is that the dosage form can be rapidly transported from the most absorbing upper intestinal regions to the lower regions where the drug is less well absorbed. Thus, in cases where the drug is not absorbed uniformly along the digestive tract, the rate of drug absorption may not be constant, although the drug delivery system delivers the drug at a constant rate to the digestive juices. In particular, where the drug has a clearly defined "absorption window", which means that the drug is only absorbed in specific areas of the stomach and upper intestine, it may not be completely absorbed when administered as a typical orally administered controlled drug delivery system. Obviously, for a drug with such an "absorption window", it is necessary not only to provide drug delivery at a controlled rate, but also to keep the drug in the upper parts of the gastrointestinal tract for a long time.

U.S. Pat. U.S. Patent No. 5,651,985 to Bayer AG discloses a composition comprising a pharmacologically active ingredient, a pharmaceutically acceptable excipient, polyvinylpyrrolidone and a methacrylic acid polymer with an acid number between 100 and 1200 mg KOH / g solid polymeric substance. Optionally, the composition may also contain a gas-forming additive. The composition absorbs an amount of acidic water that is several times greater than its weight and forms a highly swollen gel of high mechanical and bulk stability. The gelling agent should be sufficient to swell upon administration to a size that prevents passage through the pylorus for a relatively long time. At least 30% by weight to 90% by weight of the composition is made of polymers and therefore dosage forms containing a large dose of drug would be large and unsuitable for oral administration.

It is generally known in the art of controlled drug delivery systems that in order to make a particular drug available in the form of a once daily tablet or capsule, it is necessary to experiment with a particular drug along with specific excipients. Therefore, the formulation of a once daily formulation from a particular excipient in specific relative amounts may work for a particular active ingredient or drug, but is unlikely to work for another drug.

Nishioka et al. (JP 06024959) is a Japanese patent publication that describes an attempt to release ciprofloxacin over a prolonged period of time by leaving a tablet containing ciprofloxacin suspended in the stomach. The release period for Nishioka tablets is so low that only 46% will dissolve in 24 hours (see graph). A practical and significant effect of this slow dissolution is that the Nishioka formulation could not be as effective as the once daily formulation of ciprofloxacin.

For these reasons, none of the previously described oral drug delivery systems is fully satisfactory as a once-per-day controlled release formulation of ciprofloxacin.

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BACKGROUND OF THE INVENTION

It is an object of the present invention to provide a pharmaceutical composition in the form of tablets or capsules that form a controlled release formulation of ciprofloxacin for once daily administration such that:

a. Generates and captures gas in the hydrated matrix until contact with aqueous medium or gastric juice and retains a substantially homogeneous form in the stomach;

b. it stays longer in the stomach and therefore the drug delivery system stays in the gastrointestinal tract for a longer time,

c. delivers the drug at a controlled rate so that the drug is released into the body for a period equal to or less than the time that the drug delivery system remains in the absorption regions of the gastrointestinal tract; and

d. provides increased drug absorption compared to other oral controlled drug delivery systems, while strongly absorbing in the upper gastrointestinal tract.

It is also an object of the present invention to provide a once-daily controlled release formulation of ciprofloxacin that retains physical integrity, i.e., remains intact or takes on a substantially homogeneous form in contact with an aqueous medium, even though the amount of drug is large and where the amount of polymers is small compared to other components of the system. The invention further provides a once daily administered formulation for the controlled delivery of ciprofloxacin, in which a large dose of drug is incorporated without losing any of its advantageous properties mentioned above, and having a system of acceptable size for oral administration.

SUMMARY OF THE INVENTION

The invention provides a novel pharmaceutical composition in the form of tablets or capsules that form a once-daily orally administered controlled release formulation of ciprofloxacin. The pharmaceutical composition comprises ciprofloxacin, a gas generating agent, a blowing agent (eg, cross-linked polyvinylpirrolidone or cross-linked sodium carboxymethylcellulose), further comprising either a viscolyzing agent (eg, a carbohydrate gum such as xanthan gum or a cellulose ether such as hydroxypropylmethylcellulose) eg sodium alginate).

• ·· ·

Preferably, the novel orally administered controlled drug delivery system, which is a pharmaceutical composition in the form of tablets or capsules, comprises a pharmaceutically effective amount of ciprofloxacin, about 0.1 to 8% by weight of the viscolyzing agent or gelling agent, or both, about 5% to 15%. % of a gaseous agent and from about 3 to 15 wt. % blowing agent.

More preferably, the amount of viscolyzing agent or gelling agent or both is from about 0.2 to 5% and the amount of blowing agent is from about 3% to 15%.

Most preferably, the invention relates to a once-daily formulation in the form of a tablet for oral administration to humans for the controlled release of ciprofloxacin, comprising a pharmaceutically effective amount of ciprofloxacin, sodium alginate from about 0.2 to 0.5%, xanthan gum from about 0 5 to 2.0%, about 10.0 to 25% sodium bicarbonate, and about 5.0% to 20% cross-linked polyvinylpyrrolidone, wherein said percentages are by weight of the total weight of the composition, wherein the ratio of sodium alginate to xanthan gum is about 1: 1 to about 1:10.

The blowing agents used herein (cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethylcellulose) belong to a class of compounds known as superdisintegrants, which generally aid in tablet disintegration by absorbing large amounts of water while swelling the tablet. This expansion, like the hydrostatic pressure, causes the tablet to crack. For a tablet that also contains a gas generating component (which may be a gas generating vapor), one would expect the tablet to disintegrate immediately upon contact with an aqueous liquid if it does not burst directly. It is noteworthy that in the presence of the immediately reacting viscolyzing agent and / or gelling agent, the forming gas is collected and the super-disintegrant behaves as a blowing agent, which swells preferably to twice its original volume. Therefore, the combination of a gas generating agent, a blowing agent that is virtually a superdisintegrant, and a viscolyzing agent or a gelling agent allows the formulation to act as a controlled drug delivery system. In addition, over time, the gelling agent and / or viscolyzing agent form a cross-linked three-dimensional molecular network resulting in a hydrodynamically balanced system that enters the stomach and releases the drug over an extended period of time.

Surprisingly, it has been found that a tablet or capsule formed from the formulation of the invention is retained in the stomach for a longer time (local control) than previously known hydrophilic matrix tablets, buoyant capsules and bioadhesive tablets when administered with food. The formulation of the invention results in the release of the drug into a better drug.

• φ φ φ φφ · absorbing areas of the gastrointestinal tract, ie more into the stomach and small intestine than into the large intestine, where drug absorption is weak or uncertain. Therefore, it can be expected that if the drug is released at a constant and controlled rate, it will also be absorbed at a more or less constant rate.

Even more surprisingly, even for a drug absorbed only in the upper part of the gastrointestinal tract (i.e. from the stomach down to the sphincter), such as ciprofloxacin, the formulation of the invention provides the desired absorption at such a rate that effective plasma levels are maintained for longer is particularly suitable for once-daily administration (time control). In addition, the formulation provides increased drug absorption compared to other oral controlled drug delivery systems, such as hydrophilic matrix tablets and buoyant capsules. This is accomplished by adjusting the drug release period to be about the same or shorter than the retention time of the tablets at the site of absorption. Thus, the tablet or capsule will not pass past the "absorption window" before releasing all of the drug, thereby obtaining maximum bioavailability.

The formulation of the invention comprises ciprofloxacin, a blowing agent and a viscolyzing agent, or a gelling agent, or both. Together, these components form a hydrated gel matrix. The formulation further comprises a gas generating agent such that the gas (usually CO 2, but in some cases SO 2) is formed controlled and entrapped in a hydrated gel matrix. The blowing agent, which belongs to a group of compounds called superdisintegrants, absorbs a large amount of liquid and causes considerable swelling of the matrix. The gas-forming agent gas also causes the matrix to expand. Nevertheless, the swelling of the matrix according to the invention is controlled by a viscolyzing agent and / or a gelling agent, which behave in the same way as the swelling controlling means and also as the drug release controlling means.

The properties of the hydrated gel matrix can be modified by varying the ratio of the amount of blowing agent, viscolyzing agent and / or gelling agent and gas generating agent without losing the physical integrity of the hydrated gel system. Therefore, the composition can be adjusted to an optimal release rate of ciprofloxacin. It has also been found that when administered with food, such a composition retains longer in the stomach so that it retains longer in the gastrointestinal tract without losing its physical cohesion.

The gas produced affects the drug delivery from tablets or capsules in a way that is not yet sufficiently explained. For example, examples of factors that may affect drug delivery include:

«· · ·

a. The presence of gas entrapped in the matrix can affect the length of the drug diffusion pathway and thereby control release;

b. The presence of gas trapped in the matrix can affect the erosion rate of the surface of the hydrated gel matrix and thus exhibits both a hydrodynamic effect and a release control effect;

c. The increasing pressure and presence of gas affects the internal structure of the hydrated gel and thus exhibits both a hydrodynamic effect and a release control effect; and

d. The presence of entrapped gas and its increasing pressure affect the pouring of acidic gastric juices into the pores of the matrix and thus control release.

It will be appreciated that the gas formed in the small volume of the matrix may create high pressure. If this pressure exceeds the capillary pressure formed by the surface tension of the aqueous liquid, the aqueous liquid from the pores will be expelled and the gas will expand until the internal gas pressure equals the capillary pressure. This phenomenon therefore affects the rate of hydration of the matrix and plays a role in determining the rate of drug release. In systems that cross-link it will also affect the development of the gel structure.

The individual components of the new formulation are described in more detail below.

Drug

The pharmaceutical composition of the invention is in the form of tablets or capsules that allow the rate of delivery (i.e., time control) of ciprofloxacin to be controlled. The invention is particularly suitable for controlling the rate of drug delivery such as ciprofloxacin, which does not exhibit uniform dissolution and absorption throughout the digestive tract.

The new pharmaceutical composition is most suitable for the controlled delivery of drugs that are absorbed only in the upper parts of the gastrointestinal tract with a specific absorption window (ie local control), i.e. ciprofloxacin (which is only absorbed from the stomach to the sphincter). The pharmaceutical composition is particularly suitable for ciprofloxacin because drug absorption is dependent on dissolution characteristics. Ciprofloxacin dissolves at lower pH values and therefore the absorption window is predominantly in the stomach or upper parts of the small intestine. In the case of medicines such as ciprofloxacin, the tablet does not pass through the 'absorption window' before all the drug is released, thus achieving maximum bioavailability.

Ciprofloxacin alone or a pharmaceutically acceptable salt or ester thereof may be used in the invention. The amount of ciprofloxacin in the composition is the same as that of β 9 · 0 · 0 · 9 · 0 0 0 W

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conventional administration over a given period. The pharmaceutical composition of the invention may contain a large dose of medicament. Therefore, the amount of ciprofloxacin used in the invention is usually from about 0.5 mg to about 1200 mg.

Gas generating agent

The gas generating agent comprises a substance which produces gas when in contact with gastric juice. Examples of gas generating agents that can be used in the invention include carbonates such as calcium carbonate, potassium carbonate or sodium carbonate, and bicarbonates such as sodium bicarbonate.

The gaseous agent interacts with the acid source to accelerate contact with water or gastric juice to form carbon dioxide that is trapped in the hydrated gel matrix of the swelling composition. Gaseous agents such as carbonates or bicarbonates may be present in amounts of from about 5% to about 15% by weight of the composition.

These salts can be used alone or in combination with an acid source as a pair. The acid source may be one or more edible organic acids, an edible organic acid salt, or a mixture thereof. Examples of organic acids that can be used as the acid source of the invention include: citric acid or salts thereof such as sodium citrate or calcium citrate; malic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, or salts thereof; ascorbic acid or its salts such as sodium or calcium ascorbate; glycine, sarcosine, alanine, taurine, glutamic acid and the like. Examples of organic acid salts that can be used as an acid source in the invention include a monoalkalic salt of an organic acid having more than one carboxylic function, a bi-alkaline metal salt of an organic acid containing more than two acidic carboxylic functional groups, and the like. The acid source may be present in an amount of from about 0.5% to 15% by weight, preferably from about 0.5% to about 10% by weight, and more preferably from about 0.5% to about 5% by weight of the total weight of the composition.

Blowing agent

The pharmaceutical composition of the invention comprises a blowing agent capable of swelling to a volume greater than the original volume upon contact with an aqueous liquid, such as digestive juice. The blowing agent is preferably cross-linked polyvinylpyrrolidone; other blowing agents include cross-linked sodium carboxymethylcellulose and the like. These compounds belong to a class of compounds known as superdisintegrants. The blowing agent, which typically swells several times its original volume in water, exhibits controlled swelling in the presence of a viscolyzing agent and / or a gelling agent. The blowing agent may be present in an amount of from about 3% to about 15% by weight of the total weight of the composition. More preferably, the blowing agent may be present in an amount of from about 5% to about 15% by weight of the total weight of the composition.

Viscolyzing agent and gelling agent

The pharmaceutical composition of the invention comprises a viscolyzing agent which, upon contact with the digestive juice, immediately viscolyses and captures the gas formed by the gas generating agent. Preferably, the viscolyzing agent comprises a carbohydrate gum, such as xanthan gum. Other examples of carbohydrate gums include tragacanth, karaya gum, guar gum, acacia, and the like. Cellulose esters of medium to high viscosity such as hydroxypropylmethylcellulose can also be used. It has been found in the invention that xanthan gum helps to maintain the integrity of the tablet when mixed in an aqueous medium and helps to maintain drug release.

The pharmaceutical composition of the invention comprises either a viscolyzing agent or a gelling agent, or both. The gelling agent is preferably sodium alginate. The gelling agent crosslinks over time to form a stable structure that captures the generated gas. Therefore, over time, the gelling agent becomes a hydrodynamically balanced system so that the matrix retains in the stomach for a longer period of time. The concomitant use of a viscolyzing agent and a gelling agent provides an indirect diffusion pathway for the drug, resulting in controlled drug release.

The viscolyzing agent and / or gelling agent are preferably present in an amount of from about 0.1% to about 8% by weight of the total weight of the composition. More preferably, the viscolyzing agent and / or gelling agent is present in an amount of from about 0.2% to about 5% by weight of the total weight of the composition.

The successful use of already small amounts of a viscolyzing agent and / or a gelling agent such as xanthan gum in assuring the integrity of a tablet is surprising in that the pharmaceutical composition of the invention comprises a gas generating component and a blowing agent most commonly used as a disintegrant. Those skilled in the art are well aware that both components can cause rapid disintegration of the tablets.

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Tablets containing hydroxypropylcellulose in amounts approximately equal to the amount of carbohydrate gum in the invention disintegrate within 10 to 15 minutes when mixed in acidic medium. Such disintegration can lead to a dose dumping effect, i.e. a rapid release of large amounts of drug from the system, and this effect is particularly undesirable because controlled drug delivery systems contain multiple amounts of drug in a conventional formulation. The disintegrating granules are also released from the stomach in less time than intact tablets. The invention prevents such disintegration by using small amounts of a viscolyzing agent, such as a heteropolysaccharide gum, so that tablets or capsules containing a high dose of drug have an acceptable size for oral administration.

In preferred embodiments of the invention, the viscolyzing agent is xanthan gum. Xanthan gum, also known as corn sugar gum, is a large molecular weight (about 2x10 ⁶ ) biosynthetic polysaccharide gum produced by aerobic fermentation of pure sugar culture with Xanthomonas campestris. It is particularly enzymatically resistant.

In preferred embodiments of the invention, the xanthan gum has a particle size such that at least 50% by weight passes through a 44 µm mesh screen (Sieve No. 325, ASTM). In more preferred embodiments of the invention, the xanthan gum has a particle size such that they all pass through a 44 µm mesh screen (Sieve No. 325, ASTM).

The viscolyzing agent is preferably present in an amount of from about 0.1% to about 8% by weight of the total weight of the composition. More preferably, the viscolyzing agent is present in an amount of from about 0.2% to about 5% by weight of the total weight of the composition.

Other auxiliaries

The pharmaceutical composition may also contain other conventional pharmaceutical excipients such as water-soluble solvents such as lactose, dextrose, mannitol, sorbitol and the like; water-insoluble solvents such as starch, microcrystalline cellulose, powdered cellulose and the like; or lubricants such as talc, stearic acid or a salt thereof, magnesium stearate and the like.

• ·

Preparation process

The pharmaceutical composition of the invention is prepared by mixing the drug with a gas generating agent, a blowing agent, and either a viscolyzing agent or a gelling agent, or both, with other excipients and lubricants. The mixture is immediately compressed into tablets or can be filled into capsules. Optionally, the pharmaceutical composition is prepared by mixing the preceding ingredients with only half the lubricants. The mixture is compressed between rolls and then crosslinked to obtain granules. The granules are then mixed with the remaining lubricants and filled into capsules or compressed into tablets.

The following table shows the different particle sizes of ciprofloxacin base (as determined by the Malvern Master Sizer) used in the examples described below:

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Particle size distribution - ciprofloxacin base

Packaging

The pharmaceutical composition of the invention in the form of tablets may be coated with a thin layer of pharmaceutical excipient which dissolves rapidly in water. Coating with a water-soluble excipient results in faster hydration and gas formation than in a water-soluble polymer coating and acts as a preferred coating.

Examples of water-soluble pharmaceutical excipients include film-forming agents such as cellulose ether polymers, or soluble pharmaceutical solvents such as lactose, sucrose, dextrose, mannitol, xylitol and the like. In an embodiment of the invention lactose is preferably used as the water-soluble coating aid.

The tablets may be coated to a weight increase of 1% to about 4%, preferably 1% to about 2%. The packaging also helps to mask any bitter taste associated with the drug.

The invention is further illustrated, but not limited, by the following examples:

Brief description of the pictures

Giant. 1 is a graph illustrating the mean concentration of free base drug ciprofloxacin and ciprofloxacin HCl salt over time when placed in an oral controlled drug delivery system compared to Cipro ™ (Bayer Corp.) immediate release tablets; that are currently on sale.

Giant. Figures 2 and 3 are graphs illustrating the average plasma concentration of ciprofloxacin in blood over time when placed in an oral controlled drug delivery system compared to Cipro ™ instant-release tablets on saturation and fasting.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

This example illustrates the invention when the active ingredient is ciprofloxacin hydrochloride. Ciprofloxacin is an example of a drug that is only absorbed in the upper intestine. The pharmaceutical composition is shown in Table 1.

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Table 1

Component mass (mg / tablet) wt. % ciprofloxacin hydrochloride monohydrate 598.47 55.16 xanthan gum 20,00 1.84 sodium aiginate (Kelton LVCR) 15.00 1.38 cross-linked carboxymethylcellulose (Ac-Di-Sol) 110.00 10.14 sodium bicarbonate 230,00 21.20 Microcrystalline cellulose (Avicel PH 101) 16.53 1.52 sodium chloride 25.0 2.30 citric acid 20.0 1.84 cross-linked polyacrylic acid (Carbopol 971P) 10.0 0.93 talc 10.00 0.93 magnesium stearate 20,00 1.84 aerosil 10.00 0.93 total 1085.00 100%

Ciprofloxacin, xanthan gum, sodium aiginate, cross-linked carboxymethylcellulose, sodium bicarbonate, microcrystalline cellulose, sodium chloride, citric acid and half of the lubricants are mixed and sieved through a British Standard Sieve (BSS) # 44. The mixture is compressed between rollers and the compact is sieved through (BSS # 22) to give granules. The granules are mixed with the rest of the lubricants and Carbopol and then compressed into tablets. The tablets are coated by spraying with an aqueous coating composition comprising 15.8% by weight of lactose, 3.18% by weight of talc and 1.587% by weight of titanium white to a weight increase of 1% to 1.5%.

The tablets were examined for solubility in 0.1 N HCl using USP Apparatus 1 at a drum speed of 100 rpm. The dissolution results are shown in Table 2.

Table 2

time (hours) cumulative percent release 1 21.16 2 33.22

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4 58.72 6 74.6 8 85.83 10 93.58

Example 2

This example illustrates the invention when the active ingredient is ciprofloxacin base. The pharmaceutical composition is shown in Table 3.

Table 3

component mass (mg / tablet) wt. % tablets % by weight of the drug ciprofloxacin base 1000,00 71.43 100.0 xanthan gum (Ketrol TF) 15.00 1.07 1.5 sodium alginate (Kelton LVCR) 10.00 0.71 1.0 cross-linked polyvinylpyrrolidone (Kollidon CL-M) 150.00 10.71 15.0 sodium bicarbonate 200.00 14.28 20.0 magnesium stearate 15.00 1.07 1.5 talc 10.00 0.71 10.0 total 1400,00 100 ALIGN! -

Ciprofloxacin is sieved through British Standard Sieve (BSS) # 22. Xanthan gum, sodium alginate, sodium bicarbonate, crospovidone, and half the amount of lubricants, namely magnesium stearate and talc, are sieved through a sieve (BSS # 44). All of the above screened ingredients were blended uniformly, pressed on a roller press, and the pressed pieces were sieved through a sieve (BSS # 18) to obtain granules. The remaining magnesium stearate and talc were passed through a sieve (BSS No. 60) and mixed with the granules and a limited portion of the fine granules (finer than BSS No. 60) and then compressed into tablets. Optionally, the tablets are spray coated with an aqueous coating composition comprising 15.8% by weight of lactose, 3.18% by weight of talc and 1.587% by weight of titanium dioxide until the weight gain is 1% to 1.5%.

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The dissolution results are shown in Table 4. Table 4

time (hours) cumulative percent release 1 24.9 2 37.8 4 60.5 6 80.6 8 85.4 10 98.8

Example 3

This example illustrates the invention where the active ingredient is ciprofloxacin hydrochloride. The pharmaceutical composition is shown in Table 5.

Table 5

component mass (mg / tablet) wt. % ciprofloxacin hydrochloride monohydrate 600,00 61.54 xanthan gum (Keltrol TF) 10.00 1,02 sodium alginate (Kelton LVCR) 25,00 2.57 cross-linked carboxymethylcellulose (Ac- Di-Sol) 60.00 6.16 sodium bicarbonate 250.0 25.64 Microcrystalline cellulose (Avicel PH 101) 15.00 1.54 talc 5.00 0.52 magnesium stearate 10.00 1,02 total 975.00 100%

Tablets were prepared as described in Example 1, except that Ac-Di-Sol was added between the granules. The tablets were tested for dissolution as shown in Example 1. The dissolution results are shown in Table 6.

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Table 6

time (hours) cumulative percent release 1 28.16 2 38.32 4 52.37 6 64.03 8 74.23 10 82.80

Example 4

Gastric retention and bioavailability study

This example demonstrates that tablets prepared according to the invention are retained in the stomach for an extended period of time.

The bioadhesive tablet was prepared as a bilayer tablet. The composition of the drug layer is shown in Table 7 and the composition of the bioadhesive layer is shown in Table 8.

Table 7

component weight (mg / tablet) ciprofloxacin hydrochloride monohydrate 599.99 hydroxypropylcellulose-L 20,00 medium sodium phosphate 25,00 citric acid 25,00 talc 7.00 magnesium stearate 15.00 Aerosil 200 10.00 total 701,99

Table 8

component weight (mg / tablet) hydroxypropyl methylcellulose (Methocel K4M) 215,00 cross-linked polyacrylic acid (Carbopol 934 P) 75,00 Middle calcium phosphate 145.00

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sodium benzoate 8.00 talc 2.00 Aerosil-200 2.50 Sunset Yellow 2.50 total 405.00

Tablets were prepared by conventional methods of blending, rolling, screening, blending with lubricants, and compressed into bilayer tablets. 70 mg of barium sulfate was added to the bioadhesive layer as an X-ray contrast medium. Gastric retention studies of bioadhesive bilayer tablets were conducted in healthy male volunteers given two tablets after a normal breakfast. X-ray images were taken periodically. Bioadhesive tablets were retained in the stomach for 2.5 hours to 3.5 hours.

Hydrophilic matrix tablets have also been prepared, the composition of which is shown in Table 9.

Table 9

component weight (mg / tablet) ciprofloxacin hydrochloride monohydrate 599.9 hydroxypropyl methylcellulose (Methocel K4M) 20,00 hydroxypropylcellulose-L 40.00 citric acid 25,00 medium sodium phosphate 25,00 talc 10.00 magnesium stearate 10 00 total 729.99

70 mg of barium sulfate was also added to the above composition. Tablets were prepared by conventional methods of blending, rolling, screening, blending with lubricants, and compressed into tablets.

In addition, buoyant capsules were prepared containing the composition shown in Table 10.

· · * * * * * * * · · · · · · · · ·

Table 10

component weight (mg / capsule) ciprofloxacin hydrochloride monohydrate 599.99 hydroxypropylmethylcellulose (Methocel K4M) 30,00 hydroxypropylcellulose-L 30,00 citric acid 5.00 medium sodium phosphate 5.00 talc 4.00 magnesium stearate 6.00 total 679.99

50 mg of barium sulfate was added to the above composition. Gastric retention studies of bioadhesive bilayer tablets were conducted in healthy male volunteers given two tablets / capsules after a normal breakfast. X-ray images were taken periodically. The hydrophilic matrix tablets were retained for 2 hours to 2.5 hours and the buoyant capsules for 3.5 hours to 4.5 hours.

Gastric retention studies were also performed for formulations with ciprofloxacin base of similar composition as shown in Example 2. Two tablets were administered to volunteers after a regular breakfast. Magnetic resonance imaging confirmed that the tablets of the invention were retained in the stomach for 5 hours to 7 hours.

In another experiment, a randomized, crossover, three-treatment and three-period bioavailability study was conducted for formulation A (two 500 mg once daily ciprofloxacin hydrochloride tablets prepared according to Example 1) for formulation B (1000 mg free tablets). ciprofloxacin bases for once-daily administration, prepared according to Example 2), and for reference formulation R (Ciprofloxacin ™ (Bayer Corp.) containing 500 mg immediate-release tablets administered twice daily). The tablets were administered 30 minutes after regular breakfast. The mean time profile of serum concentration is shown in Figure 1. Figure 1 is based on the following values, which are shown in Table 11 below.

· * ···· *

Table 11

Chad (hours) average concentration (mcg / ml) AND (B) C 0 0.0000 0.0000 0.0000 0.5 ★ ♦ 0,30000 1 0,0489 0.3720 1,8379 1.5 * * 2,0779 2 0.1557 0.9940 1,8546 2.5 * * 1.6348 3 1,1806 1,5004 1,3731 4 2.7070 2,1164 1,0868 5 2,8478 1,8898 0.7638 6 1.7944 1,3594 0.5404 8 1,2467 0.9494 0.3579 10 0.9367 0.7855 0.2323 12 0.6503 0.8714 0.1687 12.5 * * 0.1594 13 * * 0.3916 13.5 ★ * 0.8982 14 0.4171 0.6831 1,0993 14.5 * ★ 1,1432 15 Dec * * 1,3889 16 0.2753 0.4826 1,1187 17 * * 0.9377 18 0.1901 0.3812 0.7633 20 May * * 0.4864 22nd * * 0.3766 24 0.1039 0.1778 0.2825

A: 500mg x 2 OD Fed (FDA Meal)

B: 1000 mg OD, FDA Meal

R: 500 mg b.l.d. Fed (FDA Meal) * for OD formulation, these sampling points were not investigated)

Both once daily formulations (A and B) show an increase in absorption compared to immediate release tablets (R). From this, it can be concluded that the time of drug release into the gastric fluid has been set such that the retention time of the tablets at the site of absorption is about equal to or less than the time of release. Furthermore, formulation B showed a serum concentration-time profile that would be suitable for the once-daily formulation, since the maximum serum concentration was comparable to the maximum concentration for the immediate release drug and the effective drug concentrations in the serum were maintained for a longer period of time.

4444

* 4 4 ·

4 45 • 4 4 ·

4 4 4 4

4

4 44

4>

• 44

4 4

4 4 4 4 '4 4 I

44

Example 5

In some respects, formulation B of the previous example did not show as good results as twice daily Cipro ™ 500 mg tablets. For example, the Area under the Curve Above the Minimum Inhibitor Concentration (AUC above MIC) for formulation B was smaller than for conventional Cipro ™ tablets.

An improved once-daily formulation with 1,000 mg of free ciprofloxacin base ("OD" formulation) has been developed, the composition of which is shown in Table 12. In OD formulations, the amount of gelling agent (sodium alginate) is about half higher than formulation B ( 0.49% versus 1.0%).

Table 12

folders weight (mg / tablet) wt. % drug ciprofloxacin bases 1000.0 69.9 sodium alginate 5.0 0.34 xanthan gum 15.0 1.03 sodium bicarbonate 200.0 13.74 cross-linked polyvinylpyrrolidone (Kollidon CL-M) 176.8 12.15 magnesium stearate 33.0 2.26 talc 10.0 0.68 total 1440 100 ALIGN!

Tablets were prepared from the ingredients listed in Table 12 and examined for solubility as previously reported. Surprisingly, it was observed that the in vitro dissolution profile of the OD formulation (Table 13) showed a much faster release than formulation B. Thus, more than 80% of the drug in OD tablets was released within 4 hours compared to 8 hours for formulation B. Compare Table 12 with Table 13.

Table 13

time (hours) cumulative percent release 1 35.49

«0« · 0000 • 0 · 0 • 4 4 * • 4 0 0 • ·· 0

00 • 4 4 00

000

2 53.61 4 82.33 6 98.72

The mean retention of OD tablets in the stomach was studied by magnetic resonance imaging and was found to be 5.33 hours, which correlates well with the 6 hour dissolution profile of these tablets.

To compare the pharmacokinetic and pharmacodynamic parameters of this once daily formulation, a randomized, balanced and crossover bioavailability study was conducted over three periods in 12 healthy adult male subjects between 18-45 years of age receiving a single OD dose of 1000 mg ciprofloxacin tablets 30 minutes after a regular high fat breakfast. The immediate release of Cipro ™ tablets was tested under both saturation and unsaturation conditions.

Under the saturation conditions, two oral doses of 500 mg Cipro ™ immediate release tablets were administered. The first oral dose was given within 30 minutes after the high fat breakfast and the second dose was given 12 hours after the high fat meal (main meal of the day).

Under fasting conditions, two oral doses of 500 mg Cipro ™ immediate release tablets were administered. The first oral dose was given on an empty stomach overnight and the second oral dose was given 12 hours later but at least four hours after a light meal.

The results of the study are shown in Figures 2 and 3, where Figure 2 shows the OD concentration of the tablets (saturation) versus Cipro ™ (saturation) and Figure 3 shows the OD concentration of the tablets (saturation) versus Cipro ™ (fasting) . Giant. 2 and 3 are based on the following values, which are further shown in Table 14 and Table 15, respectively.

Table 14

time (hours) average concentration (mcg / ml) AND (B) 0 0.0000 0.0000 0.5 0.2190 *

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · φ · · · ·

1 1,0964 0.3430 1.5 1,9702 * 2 2,0397 0.9751 2.5 1,8232 * 3 1.5617 1.6335 4 1,2265 2.6216 5 1,0123 2.9162 6 0.7777 2,0336 8 0.5291 1.4256 10 0.3527 1,3841 12 0.2608 0.9790 12.5 0.3159. ★ 13 0.4176 ★ 13.5 0.8401 ★ 14 1.9238 0.5942 14.5 1,8384 * 15 Dec 1,6543 ★ 16 1,2336 0.4393 17 0.9689 ★ 18 0.8258 0.3357 20 May 0.5962 * 22nd 0.4366 * 24 0.3653 0.1843

A: 500 mg b.l.d. Fed (FDA Meal)

C: 1000 mg OD Fed (FDA Meal) * For OD formulation, these sampling points were not investigated

Table 15

time (hours) average concentration (mcg / ml) (B) C 0 0.0000 0.0000 0.5 1.3580 *

1 2.4747 0.3430 1.5 2.7413 * 2 2,3684 0.9751 2.5 2,0204 * 3 1,5997 1.6335 4 1,1985 2.6216 5 0.9429 2.9162 6 0.7298 2,0336 8 0.5172 1.4256 10 0.3575 1,3841 12 0.2709 0.9790 12.5 0,9855, ★ 13 2,5113 * 13.5 2.7718 * 14 2,4376 0.5942 14.5 1,9856 * 15 Dec 1,7173 * 16 1,1702 0.4393 17 0.8631 * 18 0.7360 0.3357 20 May 0.5095 * 22nd 0.4207 * 24 0.3431 0.1843 B: 500 mg b.l.d. Fed i FDA Meal)

C: 1000 mg OD Fed (FDA Meal) * For OD formulation, these sampling points were not investigated

The OD formulation showed a plasma concentration-time profile required for the once-daily formulation, wherein the maximum plasma concentration (C max) was comparable to an immediate release drug exhibiting a similar rate of drug absorption. The overall bioavailability of AUC («) (area under the curve) was also comparable to tablets

immediate release indicating that all drug is released from the formulation during its presence in the stomach. See Table 16.

Table 16

studies C max ^ g / ml) AUC (g.h / ml) ciprofloxacin 1000 mg OD (Fed) 3.04 24.81 Cipro ™ 500mg Bid (Fasted) 3.17 26.28 Cipro ™ 500 Mg Bid 26.66 22.39

Table 17 shows the area under the curve above the minimum inhibitory concentration for three levels of 0.1 pg / ml, 0.25 pg / ml and 0.5 pg / ml for ciprofloxacin OD 1000 mg versus Cipro ™ 500 mg bid. These values for ciprofloxacin OD were better than for Cipro ™ immediate-release tablets administered twice daily at saturation, suggesting better therapeutic efficacy of the OD formulation when administered in both immediate-release and controlled-release form. The therapeutic efficacy of the OD tablets on saturation was comparable to the therapeutic efficacy of fast-release Cipro ™ tablets.

Based on the above results in Figures 1, 2 and 3, it is anticipated that the sustained release ciprofloxacin dosage form should exhibit pharmacokinetic efficacy, as measured at the mean serum concentration, using the area under the concentration-time curve above the minimum inhibitory concentration. and exposure times above the minimum inhibitory concentrations in serum / plasma of not less than 70% compared to divided doses of an equivalent amount of a conventional solid immediate release form of ciprofloxacin.

While both results were specifically identified for 1,000 mg tablets, it is believed that 100-1,000 mg tablets with ciprofloxacin administered orally to humans at saturation would provide a serum / plasma concentration-time curve from zero to infinity at from 3.5 gg / ml.h to about 30 µg / ml.h. Similarly, it is believed that 100mg-1000mg tablets would provide a maximum serum / plasma concentration ranging from about 0.5 µg / ml to about 4 gg / ml. Further, it is contemplated that 10mg-1000mg tablets would provide a serum / plasma drug concentration curve with time below the curve (above a minimum inhibitory concentration of 0.1 pg / ml) ranging from about 3 to about 26 pg / ml. . It is also contemplated that 100mg1000mg tablets would provide a serum / plasma drug concentration-time curve with an area under the curve (above a minimum inhibitory concentration of 0.25 gg / ml) ranging from about 2 µg / ml.h to about 22 µg. /ml.h. Finally, it is contemplated that 100mg-1000mg tablets would provide a serum / plasma-time drug concentration curve with an area under the curve (above the minimum inhibitory concentration of 0.5µg / ml) ranging from about 1µg / ml.h to about 18µg. pg / ml.h.

Table 17

healing 0.1 pg / ml.h 0.25 pg / ml.h 0.5 pg / ml.h ciprofloxacin base 1000 mg, OD (Fed) 20.7 ± 4.4 17.4 ± 4.3 13.2 + 4.1 Cipro ^{| M} 2 x 500 mg 21.5 ± 3.7 18.0 ± 3.8 13.4 ± 4.0 Cipro ^IM 2 x 500 mg misery (Fed) 17.68 ± 3.9 14.2 ± 3.9 9.7 ± 3.4

Thus, a small change in the percentage of hydrophilic polymer (sodium alginate) from 0.71% by weight of the composition to 0.34% by weight of the composition led to a dramatic and unexpected improvement in pharmacodynamic and pharmacokinetic parameters, which are important measures of therapeutic efficacy.

Example 6

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 18

component weight (mg / tablet) % by weight ciprofloxacin 1012.10 68.53 xanthan gum 45.0 3.05 sodium bicarbonate 200 13.54 crospovidone 176.82 11.97

magnesium stearate 33 2.23 talc 10 0.68 total 1476,92 100 ALIGN!

Tablets were prepared as described in Example 2. Dissolution was investigated as described in Example 1. The dissolution results are shown in Table 19.

Table 19

time (hours) cumulative percent release 1 34 2 51.4 4 69.0 6 94.8 8 100.5

Example 7

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 20

Component Weight (mg / tablet) % by weight Ciprofloxacin 1012.10 69.47 sodium alginate 25 1.72 sodium bicarbonate 200 13.73 crospovidone 176.82 12.14 magnesium stearate 33 2.27 talc 10 0.69 total 1456,92 100.02

The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are shown in Table 21.

»· · And ··« ·

Table 21

time (hours) cumulative percent release 1 34.6 2 52 3 68.4 4 79, '5 6 92.4 8 95.7

Example 8

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 22

component weight (mg / tablet) wt. % ciprofloxacin 1012.10 69 sodium alginate 5.0 0.34 sodium bicarbonate 200 13.63 crospovidone 176.82 12.05 magnesium stearate 33 2.25 talc 10 0.68 Methocel K15M 30 2.04 total 1466,92 99.99

The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are shown in Table 23.

Table 23

time (hours) cumulative percent release 1 43.6 2 57.6 3 74.4

* ·

4 87.0 6 97.5 8 100.2

Example 9

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 24

component weight (mg / tablet) wt. % ciprofloxacin 1015.18 75.15 sodium alginate 5.0 0.37 xanthan gum 15 Dec 1.11 sodium bicarbonate 200 14.8 crospovidone 72.75 5.39 magnesium stearate 33 2.44 talc 10 0.74 total 1350,93 100 ALIGN!

The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are shown in Table 25.

Table 25

time (hours) cumulative percent release 1 39.2 2 54.2 3 72.39 4 84.9 6 100.29

Example 10

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 26

component weight (mg / tablet) % by weight ciprofloxacin 1015.18 67.35 sodium alginate 5.0 0.33 xanthan gum 15 Dec 1.0 crospovidone 176.82 11.73 magnesium stearate 33 2.19 talc 10 0.66 sodium carbonate 252.32. 16.74 total 1507.32 100 ALIGN!

The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are shown in Table 27. Table 27

time (hours) cumulative percent release 1 31.34 2 59.86 3 75.3 4 81.69 6 90.39 8 91.5

They did

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 28

component weight (mg / tablet) % by weight ciprofloxacin 1015.18 69.66 sodium alginate 7.28 0.5 xanthan gum 15 Dec 1.03 sodium bicarbonate 200 13.72 crospovidone 176.82 12.13 magnesium stearate 33 2.26 talc 10 0.69 total 1457,28 99.99

The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are shown in Table 29.

Table 29

time (hours) cumulative percent release 1 40.06 2 59.26 3 86.19 4 96.39 6 100.2

φ φ

· Φ φ • ··

φ · φ · · φ · · φ · · · φ φ * ·

Example 12

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 30

component weight (mg / tablet) wt. % ciprofloxacin 1015.18 70.43 sodium alginate 5.0 0.35 xanthan gum 1.46 0.1 sodium bicarbonate 200 13.87 crospovidone 176.82 12.27 magnesium stearate 33 2.29 talc 10 0.69 total 1441,46 100 ALIGN!

The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are shown in Table 31.

Table 31

time (hours) cumulative percent release 1 33.34 2 58.94 3 76.11 4 83.91 6 95.7

Example 13

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 32

component weight (mg / tablet) wt. % ciprofloxacin 1015.18 69.44 sodium alginate 5.0 0.34

xanthan gum 21.83 1.5 sodium bicarbonate 200 13.68 crospovidone 176.82 12.1 magnesium stearate 33 2.26 talc 10 0.68 total 1461,83 100 ALIGN!

The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are shown in Table 33.

Table 33

time (hours) cumulative percent release 1 44.2 2 61.86 3 87.9 4 98.7 6 106.95

Example 14

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 34

component weight (mg / tablet) wt. % ciprofloxacin 1016.19 72.51 sodium alginate 5.0 0.36 xanthan gum 15s 1.07 sodium bicarbonate 145.5 10.38 crospovidone 176.82 12.61 magnesium stearate 33 2.35 talc 10 0.71 total 1401,51 99.99

The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are shown in Table 35.

Table 35

time (hours) cumulative percent release 1 44.46 2 56.8 3 65.91 4 74.19 6 89.31 8 98.49

Table 36 below summarizes the above Examples 5-14 with respect to their components and contains dissolution profiles for each formulation.

·· 0 »

00 cn 4A Ca) TO) time (hours) [xanthan: alginate ratio] 10: 1 to 1: 1 Methocel K 15 M sodium carbonate sodium bicarbonate 10-25 XL polyvinylpyrrolidone 5-20 sodium alginate 0.2 - 0.9 xanthan gum 0.5-2.0 ciprofloxacin base component <o 00 Ol Ca) C Ca) _X _TO O σι Oi 3 00 Γ4 Ca) Ol < Q O Ca) him Ca) O WHAT 3 -4 Ca) 0) The Ca) ^ 4 —X The Ca) WHAT O N) Ca) - * WHAT 3 « O The Ol r-K □ < Q> —X □ -AND WHAT 0) Ol Ca) of _-X □ Ca) σι O O _AND WHAT -AND. The < > ω O O oo Ό -in 00 O The O Ol what Ol čn Ol 3 The * 4 Ca) 0) Q. (D <0 -4 0) Ol Ca) C Fri -4 S‘6 8.4 ro O The 0) 0) 4A tivní ON Ca) S -s | nothing ‘69 -4 3- ^ 4 —X N> The WHAT 00 ~ 4 Ol The Ca) The -4 O ~ 4 -4 4A ~ 4 Ca) Ό O * ** AND* Ol O -řx 0) 0) O N) 0) 00 k> O of —X O -3 CD □ Φ O > O Ca) TO) W O p 00 - ~ 4 Ol Ca) The 0) Ca) O Ol The O O THE N) The WHAT O k> <o <0 The N) N) = r Ca) —X Ol O _AND * 4 WHAT The Ca) Ca) Ol O <o 00 -4 Ol Ca) -and. 00 WHAT -4 Ol —X O r ¹ · Ol WHAT Ol O it 0) C0 Ca) 00 0) THE Ca) _AND 3 _AND O _x 0) _and. O 0) O _x Ca) O j-4 O WHAT 00 Ol The ω - ^ i ~ 4 Ca) Ca) Ca) Ol O 0) 0) WHAT O 0.2 Ca) what '-AND , 26 , 06 WHAT N) 0) -X - «X CJ —X mX 3.72 2.13 9.66 what Oi 00 ω ~ 4 _0) Ol 00 33, 06: i Ol 03 / ~ 4 what what Ca) —Ϊ. The The O —X _X 0.3 O * 4 _AND N) Ca) ΓΌ —X O TO) _x what 00 0) 4A <0 oo -χ | * sj Ol The Ca) O 00 ~ 4 -AND The -Λ CD CD - «· 'at what 00 0) t \) The _AND _x O _AND 0) _AND Oi The Ca) _N) Ca) Ol WHAT Ca) —X 0) -X The The 98 89 -4 4A 65 56 44 —X 00 The The (0 ω —X WHAT 'it 00 The 0) ΓΌ 'what —X O _x 0.3 O -4 The -4 Ca) 0) 0) ~ 4 —X -AND 00 Ol

Table 36 ω

9ι 9 9 9

9 9 9 9 9 9

9 9 9 9 9

9 9 99 999 ·· · «··

Example 15

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 37

component weight (mg / tablet) wt. % ciprofloxacin 1015.18 67.98 sodium alginate 5.0 0.003 xanthan gum 15.0 0.01 crospovidone 176.82 11.84 magnesium stearate 33.0 2.21 talc 10.0 0.67 calcium carbonate 238.27 15.96 total 1493,27 98,637

The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are shown in Table 38.

Table 38

time (hours) cumulative percent release 1 44.4 2 62.4 3 73.11 4 78.0 6 84.09 8 87.0

Example 16

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 39

component weight (mg / tablet) wt. % ciprofloxacin 1015.18 69.32 sodium alginate 14.55 0.009 xanthan gum 15.0 0.01 sodium bicarbonate 200.0 13.66 crospovidone 176.82 12.07 magnesium stearate 33.0 2.25 talc 10.0 0.68 total 1464,55 97.32

The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are shown in Table 40.

Table 40

time (hours) cumulative percent release 1 37.9 2 45.06 3 65.91 4 71.1 6 78.81

** * * • • · · · · · · · · · · · · · · · · · · ·

Example 17

The example illustrates the invention when the active ingredient is ciprofloxacin base:

Table 41

component weight (mg / tablet) % by weight ciprofloxacin 1015.18 67.11 sodium alginate 5.0 0.003 xanthan gum 72.75 4.81 sodium bicarbonate 200.0 13.22 crospovidone 176.82 11.69 magnesium stearate 33.0 2.18 talc 10,0, 0.006 total 1512,75 99,019

The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are shown in Table 42.

Table 42

time (hours) cumulative percent release 1 32.26 2 47.2 3 63.3 4 74.01 6 94.2

In addition to the above experiments, the following tablet formulations were prepared as described above. Dissolution and buoyancy characteristics were also investigated for these formulations. For tablets according to the following formulations, one of them, i.e. the dissolution profile or buoyancy characteristics, was found to be unsatisfactory compared to the previous examples.

Φ Φ φ · · · φ φ φ φ «« «· · · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ ·

Table 43

component Example 18 Example 19 ciprofoxacin 1015.18 1015.18 sodium alginate 0 5.0 xanthan gum 15.0 0 sodium bicarbonate 200.0 200.0 crospovidone 176.82 176.82 magnesium stearate 33.0 33.0 talc 10.0 10.0 total 1450,00 1440.0 dissolution time (hours) cumulative percent release 1 68.8 52.5 2 93.2 68.94 3 104.1 90.39 4 - 100.8 6 - 104.79 8 - -

Table 44

folders Example 20 Example 21 Example 22 Example 23 Example 24 ciprofloxacin 1016.19 1016.19 1012.1 1016.19 1012.1 sodium alginate 5.0 5.0 5.0 5.0 5.0 sodium bicarbonate 200.0 200.0 200.0 200.0 200.0 crospovidone 176.82 176.82 176.82 176.82 176.82 magnesium stearate 33.0 33.0 33.0 33.0 33.0 talc 10.0 10.0 10.0 10.0 10.0 Methocel K15M 15.0 - - - - gellan gum - 15.0 30.0 - - Carrageenan - - - 15.0 45.0 total 1456,01 1456,01 1466,92 1456,01 1481,92 dissolution

• ·

time (hours) cumulative percent release 1 48.66 50.74 49.6 72.46 88.8 2 63.54 62.86 58.2 81.54 93.2 3 80.31 74.19 67.2 87.09 97.8 4 89.49 80.79 74.4 92.1 99.0 6 100.11 91.71 88.2 96.45 100.2 8 101.7 99.99 95.1 97.11 101.1

Table 45

folders example 25 example 26 example 27 Mar: example 28 example 29 example 30 ciprofloxacin 1015.18 1012.1 1015.18 1012.1 1015.18 1012.1 xanthan gum 15.0 15.0 15.0 15.0 15.0 15.0 bicarbonate sodium 200.0 200.0 200.0 200.0 200.0 200.0 crospovidone 176.82 176.82 176.82 176.82 176.82 176.82 magnesium stearate 33.0 33.0 33.0 33.0 33.0 33.0 talc 10.0 10.0 10.0 10.0 10.0 10.0 Carbopol 971 P 5.0 10.0 - - - - methylcellulose - - 5.0 20.0 - - Eudragit EPO - - - - 5.0 30.0 total 1455.0 1446,92 1455.0 1456,92 1455.0 1466,92 dissolution time (hours) cumulative percent release 1 45.2 56.8 74.26 68.2 94.26 101.4 2 59,34 ' 67.0 87.06 83.0 94.94 - 3 71.79 76.8 95.61 92.4 97.89 - 4 80.91 84.9. 97.71 95.4 98.79 - 6 92.01 95.1 99.21 99.0 - - 8 93.0 97.5 100.59 100.8 - -

Table 46

component example 31 example 32 example 33 example 34 example 35 example 36 ciprofloxacin 1015.18 1012.1 1015.18 1012.1 1015.18 1012.1 sodium alginate 5.0 5.0 5.0 5.0 5.0 5.0 xanthan gum 15.0 15.0 15.0 15.0 15.0 15.0 bicarbonate sodium 200.0 200.0 200.0 200.0 200.0 200.0 magnesium stearate 33.0 33.0 33.0 33.0 33.0 33.0 talc 10.0 10.0 10.0 10.0 10.0 10.0 Ac-di-sol 176.82 100.0 - - - - starch glycolan sodium 176.82 125.0 MCC (Avicel pH 101) - - - - 176.82 125.0 total 1455.0 1375.1 1455.0 1400.1 1455.0 1400.1 dissolution time (hours) cumulative percent release 1 42.86 47.6 57.46 53.8 67.4 62.6 2 51.4 55.8 65.6 62.4 79.26 74.4 3 60.21 62.4 72.81 70.8 86.7 84.9 4 66.81 67.5 77.19 75.6 91.5 88.2 6 81.09 76.2 84.69 82.4 95.49 94.8 8 87.6 83.1 92.31 88.2 98.79 97.2

Table 47

component Example 37 Example 38 Example 39 ciprofloxacin 1015.18 1015.18 1015.18 sodium alginate 5.0 5.0 5.0 xanthan gum 15.0 15.0 15.0 sodium bicarbonate 200.0 200.0 200.0 crospovidone 0 261.9 363.75 magnesium stearate 33.0 33.0 33.0 talc 10.0 10.0 10.0

total 1278.18 1540,08 1641,93 dissolution time (hours) cumulative percent release 1 66.66 49.2 57.26 2 79.8 75.66 77.74 3 91.2 96.99 106.2 4 94.71 100.71 - 6 97.59 - -

Table 48

folders Example 40 Example 41 Example 42 ciprofloxacin 1016.19 1016.19 1016.19 sodium alginate 5.0 5.0 5.0 sodium bicarbonate 200.0 200.0 200.0 crospovidone 176.82 176.82 176.82 magnesium stearate 33.0 33.0 33.0 talc 10.0 10.0 10.0 Methocel K15M 15.0 - - gellan gum - 15.0 - Carrageenan - - 15.0 total 1456,01 1456,01 1456,01 dissolution time (hours) cumulative percent release 1 48.66 50.74 72.46 2 63.54 62.86 81.54 3 80.31 74.19 87.09 4 89.49 80.79 92.1 6 100.11 91.71 96.45 8 101.7 99.99 97.11

Table 50

folders Example 46 Example 47 Example 48 ciprofloxacin 1015.18 1015.18 1015.18 sodium alginate 5.0 5.0 5.0 xanthan gum 15.0 15.0 15.0 sodium bicarbonate 200.0 200.0 200.0 magnesium stearate 33.0 33.0 33.0 talc 10.0 10.0 10.0 Ac-di-sol 176.82 - - sodium starch glycolate - 176.82 - MCC (Avicel pH 101) - 176.82 - total 1455.0 1455.0 1455.0 dissolution time (hours) cumulative percent release 1 42.86 57.46 67.4 2 51.4 65.6 79.26 3 60.21 72.81 86.7 4 66.81 77.19 91.5 6 81.09 84.69 95.49 8 87.6 92.31 98.79

Table 51

folders Example 49 ciprofloxacin 1015.18 sodium alginate 5.0 xanthan gum 15.0 crpspovidone 176.82 magnesium stearate 33.0 talc 10.0 · potassium bicarbonate 238.34 total 1493,34 dissolution time (hours) cumulative percent release

·· ···· * *

1 69.06 2 77.74 3 85.2 4 87.0 6 87.0 8 98.1

Table 52

component Example 50 Example 51 ciprofloxacin 1015.18 1015.18 sodium alginate 0 1.46 xanthan gum 15.0 15.0 sodium bicarbonate 200.0 200.0 crospovidone 176.82 176.82 magnesium stearate 33.0 33.0 talc 10.0 10.0 total 1450,00 1451,46 dissolution time (hours) cumulative percent release 1 68.8 51.46 2 93.2 65.34 3 104.1 84.36 4 - 92.79 6 - 97.41

Table 53

component Example 52 ciprofloxacin 1015.18 sodium alginate 5.0 sodium bicarbonate 200.0 crospovidone 176.82 magnesium stearate 33.0 talc 10.0

«·

total 1440.0 dissolution time (hours) cumulative percent release 1 52.5 2 68.94 3 90.39 4 100.8 6 104.79

Table 54

component Example 53 Example 54 Example 55 Example 56 ciprofloxacin 1015.18 1016.19 1015.18 1015.18 sodium alginate 5.0 5.0 5.0 5.0 xanthan gum 15.0 15.0 15.0 15.0 sodium bicarbonate 0 72.75 291.0 436.5 crospovidone 176.82 176.82 176.82 176.82 magnesium stearate 33.0 33.0 33.0 33.0 talc 10.0 10.0 10.0 10.0 total 1255.0 1328,76 1546.0 1691.5 dissolution time (hours) % release 1 73.06 50.86 49.0 42.46 2 73.7 63.6 72.14 74.66 3 - 73.89 96.3 96.6 4 94.8 83.7 103.8 104.1 6 87.9 93.51 - - 8 - 98.19 - -

Although the invention has been described by reference to specific examples, it was for illustrative purposes only. Many alternative embodiments will be apparent to those skilled in the art and are also within the scope of the invention.

Claims (43)

PATENT CLAIMS A tablet formulation for once-daily oral administration to humans for the controlled release of ciprofloxacin, comprising a pharmaceutically effective amount of ciprofloxacin, from 0.1 to 8.0 wt. from about 5.0% to about 15% by weight of the gaseous agent and from about 3.0% to about 15% by weight of the blowing agent, wherein the weight percentages are based on the total weight of the composition. 2. A tablet formulation for oral once daily administration to humans for the controlled release of ciprofloxacin, comprising a pharmaceutically effective amount of ciprofloxacin, from 0.2% to 5.0% by weight of a viscolyzing agent and / or a gelling agent; 5.0% to 15% by weight of the gaseous agent and 5.0% to 15% by weight of the blowing agent, the weight percentages being based on the total weight of the composition. The formulation of claim 1 or 2, wherein the viscolyzing agent is either a carbohydrate gum or cellulose ethers. The formulation of claim 3, wherein the carbohydrate gum is xanthan gum and the cellulose ether is hydroxypropyl methylcellulose (methocel). The formulation of claim 1 or 2, wherein the gelling agent is sodium aiginate. The formulation of claim 1 or 2, comprising either a viscolyzing agent or a gelling agent, or both. The formulation of claim 6, wherein the viscolyzing agent is xanthan gum. The formulation of claim 3, wherein the gas generating agent is selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, and mixtures thereof. The formulation of claim 3, wherein the blowing agent is a cross-linked polyvinylpyrrolidone. A formulation for oral once daily administration to humans for the controlled release of ciprofloxacin, comprising a pharmaceutically effective amount of ciprofloxacin, from 0.2 to 0.5 wt% sodium alginate, from 0.5 to 2.0 wt% % xanthan gum, from 10.0 to 25% sodium bicarbonate and 5.0 wt% to 20 wt% of cross-linked polyvinylpyrrolidone, wherein the weight percent is based on the total weight of the composition, the weight ratio of sodium alginate and xanthan gum is from 1 : 1 to 1:10. The formulation of claim 10 comprising 69.9 wt% ciprofloxacin base, 0.34 wt% sodium alginate, 1.03 wt% xanthan gum, 13.7 wt% sodium bicarbonate, 1% by weight of cross-linked polyvinylpyrrolidone and optionally other pharmaceutical excipients. 12. The formulation of claim 10, which is in the form of tablets. 13. A homogeneous oral once daily tablet formulation for humans comprising a single layer, wherein the controlled release of ciprofloxacin occurs in the stomach or upper intestine containing a pharmaceutically effective amount of ciprofloxacin from 0.2 to 0; 5% by weight of sodium alginate, from 0.5 to 2.0% by weight of xanthan gum, from 10.0 to 25% by weight of sodium bicarbonate, and 5.0 to 20% by weight of cross-linked polyvinylpyrrolidone, the weight percentages being based on to the total weight of the composition, the weight ratio of sodium alginate and xanthan gum ranges from 1: 1 to 1:10. 4 4 The formulation of claim 13 comprising 69.9 wt.% Ciprofloxacin base, 0.34 wt.% Sodium alginate, 1.03 wt.% Xanthan gum, 13.7 wt.% Sodium bicarbonate, 12.1 wt.%. % of cross-linked polyvinylpyrrolidone and optionally other pharmaceutical excipients. f · * ··· A tablet formulation for once-daily oral administration to humans for the controlled release of ciprofloxacin in the stomach or upper intestine, comprising a pharmaceutically effective amount of ciprofloxacin, from 0.2 to 0.5% by weight of sodium alginate, from 0, From 5 to 2.0 wt.% Xanthan gum, from 10.0 to 25 wt.% Sodium bicarbonate; and from 5.0 to 20 wt. % by weight of cross-linked polyvinylpyrrolidone and optionally other pharmaceutical excipients, wherein the weight percent is based on the total weight of the composition, the weight ratio of sodium alginate and xanthan gum being between 1: 1 and 1:10, wherein said components present in relative amounts are present . A formulation according to claim 15, characterized in that it comprises 69.9 wt% ciprofloxacin base, 0.34 wt% sodium alginate, 1.03 wt% xanthan gum, 13.7 wt% sodium bicarbonate, 12.1 wt%. % of cross-linked polyvinylpyrrolidone and optionally other pharmaceutical excipients. 17. The formulation of claim 15 which is in the form of tablets. 18. A tablet formulation for once daily oral administration to humans, characterized in that the controlled release of ciprofloxacin occurs in the stomach or upper intestine and comprises a pharmaceutically effective amount of ciprofloxacin, from 0.2 to 0.5% by weight of sodium alginate, from 0.5 to 2.0% by weight of xanthan gum, from 10.0 to 25% by weight of sodium bicarbonate, and from 5.0 to 20% by weight of cross-linked polyvinylpyrrolidone, the weight percent based on the total weight of the composition, the weight ratio of sodium alginate and xanthan gum ranges from 1: 1 to 1:10. • » 19. A formulation according to claim 18 comprising 69.9 wt. % ciprofloxacin base, 0.34 wt% sodium alginate, 1.03 wt% xanthan gum, 13.7 wt% sodium bicarbonate, 12.1 wt% cross-linked polyvinylpyrrolidone, and optionally other pharmaceutical excipients. The formulation of claim 18, which is in the form of tablets. 21. A sustained release formulation comprising ciprofloxacin, characterized in that it releases more than 50% of the drug in less than 4 hours and releases more than 60% of the drug in less than 8 hours. 22. A sustained release formulation comprising ciprofloxacin, releasing more than 50% of the drug in 2 to 4 hours and releasing more than 60% of the drug in 4 to 8 hours. 23. The formulation of claim 22, which is suitable for a once daily administration profile. 24. The formulation of claim 23, which is in the form of a tablet or capsule. 25. The formulation of claim 24, which is in the form of a tablet that is coated with a pharmaceutically acceptable excipient. 26. A sustained release formulation comprising 100 to 1000 mg of ciprofloxacin and pharmaceutically acceptable excipients, wherein the total weight of the unit dose is less than 2000 mg. The formulation of claim 26, wherein the pharmaceutically acceptable excipients comprise a viscolyzing agent and / or a gelling agent, a gas generating agent, and a blowing agent. A formulation according to claim 27, characterized in that it comprises from 0.1 to 8.0% by weight of a viscolyzing and / or gelling agent, 5.0 to 15% by weight of a gas generating agent, and 0 to 15% by weight of the blowing agent, wherein the weight percent is based on the total weight of the composition. Formulation according to claim 28, characterized in that it comprises from 0.2 to 5.0% by weight of a viscolyzing and / or gelling agent, 5.0 to 15% by weight of a gas generating agent and 5.0% to 15% by weight of a gelling agent. % by weight of the blowing agent, the weight percent being based on the total weight of the composition. The formulation of claim 29, wherein the viscolyzing agent is either xanthan gum or hydroxypropyl methylcellulose (methocel) and the gelling agent is sodium alginate. 31. The formulation of claim 30 comprising both a viscolyzing agent and sodium alginate. The formulation of claim 31, wherein the viscolyzing agent is xanthan gum. The formulation according to claim 28, wherein the gas generating agent is selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, and mixtures thereof. The formulation of claim 28, wherein the blowing agent is a cross-linked polyvinylpyrrolidone. The formulation of claim 26, which is suitable for a once daily administration profile. 36. A formulation according to claim 26, which is in the form of a tablet or capsule. 37. The formulation of claim 26, which is in the form of a tablet that is coated with a pharmaceutically acceptable excipient. • 9 ·· · * ·· 51 ......... 38. A sustained release solid dosage form of ciprofloxacin which, when administered orally in humans at saturation, provides a mean serum / plasma concentration, an area below the serum / plasma concentration-time dependence above the minimum inhibitory concentrations, and a duration of action above the minimum inhibitory serum / plasma. concentrations not less than 70% compared to divided doses of an equivalent amount of a conventional solid immediate release form of ciprofloxacin. The sustained release solid dosage form of claim 38, wherein, when administered orally to humans at saturation, it provides a time-dependency of serum / plasma drug concentration with an area under the curve, ranging from zero to infinity, ranging from 3.5 up to 30 gg / ml.h. The sustained release solid dosage form of claim 38, wherein, when administered orally to humans at saturation, it provides a mean serum / plasma concentration ranging from 0.5 to 4 µg / ml. 41. The sustained release solid dosage form of claim 38, wherein, when administered orally to humans at saturation, provides a serum / plasma drug concentration time dependency with an area under the curve above a minimum inhibitory concentration of 0.1 pg / ml ranging from 3 to 26 pg / ml.h. 42. The sustained release solid dosage form of claim 38, wherein, when administered orally to humans at saturation, provides a serum / plasma drug concentration time dependency with an area under the curve above a minimum inhibitory concentration of 0.25 pg / ml in the range of 2 to 22. pg / ml.h. 43. The sustained release solid dosage form of claim 38, wherein, when administered orally to humans at saturation, provides a serum / plasma drug concentration time dependency with an area under the curve above a minimum inhibitory concentration of 0.5 pg / ml ranging from 1 to 18 pg / ml.h. time (hours)