SK12542002A3 - Orally administered controlled delivery system for once daily administration of ciprofloxacin - 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

A controlled drug delivery system for oral ciprofloxacin once daily administration

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 composition, a blowing agent and comprises either a viscolyzing composition or a gelling agent. The blowing agents belong to the group of compounds with high absorption, commonly referred to as superdisintegrants. This class of compounds includes, for example, the cross-linked polyvinylpyrrolidone and the 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 composition comprises, for example, a carbohydrate gum, for example xanthan gum, or a cellulose ether, for example hydroxypropylmethylcellulose (metocell). 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 digestive tract (spatial control). An improved controlled drug delivery system prevents under-utilization of the dose by the body and ensures the best therapeutic benefit of administering ciprofloxacin to the subject.

BACKGROUND OF THE INVENTION

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. As soon as the blood level of the drug is within this range, the drug is removed from the body at a certain rate. A 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 the uncontrolled fluctuations observed when administering multiple doses of a conventional rapid release dosage form 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 pharmaceutical functional and therapeutically effective drug delivery systems. Attention has been paid in particular to orally administered controlled drug delivery systems for ease of administration by the oral route as well as for ease 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 orally controlled drug delivery systems are based on different functional principles and have different names such as solvent driven systems, diffusion controlled systems, ion-exchange resins, osmotically controlled systems, decomposable matrix systems, pH independent formulations, swelling controlled systems and theirs Similarly.

An orally administered controlled drug delivery system encounters a wide variety of very different conditions in the gastrointestinal process, such as pH, mixing intensity, and gastric and intestinal fluid 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 may not be absorbed with the same intensity over the entire length of the gastrointestinal tract, and that absorption of the drug in the colon is usually uncertain and ineffective. Some medicines are only absorbed in the stomach or upper parts of the small intestine. Another important factor that can adversely affect the function of an orally administered controlled drug delivery system is that the dosage form can be rapidly transported from the more absorbing upper regions of the intestine to the lower regions where the drug is less well absorbed. Thus, in cases where the drug is not absorbed uniformly along the gastrointestinal tract, the rate of drug absorption may not be constant even though the drug delivery system delivers the drug.

-3 constant speed to 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 small intestine, they 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. 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 having an acid number between 100 and 1200 mg KOH / g solid polymeric substance. Optionally, the composition may also comprise a gas-forming additive. The composition absorbs an amount of acidic water which is several times greater than its weight and forms a highly swollen gel with high mechanical and bulk stability. The gelling agent should be sufficient to swell upon administration to a size that prevents passage through the porter for a relatively long time. At least 30% 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.

In the field of controlled drug delivery systems, it is generally known 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, making a once-per-day formulation from a particular excipient in specific relative amounts may work for a particular active ingredient or medicament, but is unlikely to work for another medicament.

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

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

4. Summary 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. forms and captures gas in the hydrated matrix until contact with an aqueous medium or gastric juice and retains a substantially homogeneous form in the stomach,

b. it stays longer in the stomach, and the drug delivery system also stays in the digestive tract for a long time,

c. delivers the drug at a controlled rate such 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 digestive tract; and

d. provides, in comparison with other oral controlled systems, drug delivery by increased drug absorption while being strongly absorbed in the upper parts of the gastrointestinal tract.

It is also an object of the present invention to provide a once-daily controlled release formulation of ciprofloxacin that maintains physical integrity, i. it remains intact or takes on substantially homogeneous forms in contact with the aqueous medium, although the amount of drug is large and where the amount of polymers is small compared to the 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, the system having an acceptable size for oral administration.

The invention provides a novel pharmaceutical composition in the form of tablets or capsules that form a once daily oral administration formulation for the controlled release of ciprofloxacin. The pharmaceutical composition comprises ciprofloxacin, a gas generating agent, bulking agent (e.g., cross-linked polyvinylpyrrolidone or cross-saturated sodium carboxymethylcellulose), further comprising either a viscolyzing agent (e.g., a carbohydrate gum such as xanthan gum or cellulose ether, such as hydroxypropyl cellulose, such as hydroxypropyl cellulose) (e.g., 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 wt. % of a viscolyzing composition or a gelling composition, or both, from about 5% to about 15% by weight. and about 3 to 15 wt. % blowing agent.

More preferably, the amount of viscolyzing composition or gelling composition, or both, is about 0.2 to 5% and the amount of blowing agent is in the range of 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 and 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-saturated 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 unless it breaks down immediately. It is noteworthy that in the presence of an immediately reacting viscolyzing agent and / or a gelling agent, the forming gas is trapped and the super-disintegrant behaves as a blowing agent which swells preferably to twice its original volume. Therefore, the combination of a gas-forming composition, a blowing agent that is virtually a superdisintegrant and a viscolyzing composition or a gelling composition allows the formulation to act as a controlled drug delivery system. In addition, over time, the gelling agent and / or viscolyzing agent forms a transversely saturated three-dimensional molecular network that results in a hydrodynamically balanced system that enters the stomach and releases the drug over a longer period of time.

Surprisingly, it has been found that a tablet or capsule formed from the formulation of the invention is retained for a longer period in the stomach (local control) than previously known hydrophilic matrix tablets, buoyant capsules and bioadhesive tablets when

-6these systems serve with food. The formulation of the invention results in the release of the drug into better absorbing areas of the gastrointestinal tract, i. rather in the stomach and small intestine than in the large intestine, where absorption of the drug is weak or uncertain. Therefore, 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 (ie from the stomach down to the cervix), such as ciprofloxacin, the formulation of the invention provides the desired absorption at a rate that effective plasma levels are maintained for longer especially 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 approximately equal to or less than the tablet retention time at the site of absorption. Thus, the tablet or capsule will not pass the "absorption window" until all the drug has been released, 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 composition such that the gas (usually CO 2, but in some cases SO 2) is formed in a controlled manner and entrapped in a hydrated gel matrix. The blowing agent, which belongs to a group of compounds called superdisintegrants, absorbs large amounts of fluid and causes considerable swelling of the matrix. The gas formed by the gas generating agent also causes the matrix to expand. Nevertheless, the swelling of the matrix according to the invention is governed by a viscolyzing agent and / or a gelling agent, which behave in the same way as swelling control agents and also as drug release controlling agents.

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 supply 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 the gas trapped in the matrix may influence the length of the drug diffusion pathway and thereby control release;

b. the presence of gas trapped in the matrix may 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. increasing pressure and the 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 trapped gas and its increasing pressure affect the flow of acidic gastric juices through the pores of the matrix and thus control release.

It will be appreciated that the gas formed in the small volume of the matrix can create high pressure. When this pressure exceeds the capillary pressure formed by the surface tension of the aqueous liquid, the aqueous liquid is expelled from the pores and the gas expands 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, this will also affect the development of the gel structure.

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

The drug

The pharmaceutical composition of the invention is in the form of tablets or capsules that allow the rate of delivery (i.e., the specific 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 only absorbed in the upper parts of the gastrointestinal tract with a specific absorption window (i.e., local control), i. ciprofloxacin (which is only absorbed from the stomach to the sphincter). The pharmaceutical composition is particularly suitable for ciprofloxacin since the absorption of the drug is dependent on the characteristics

-8rozpúšťania. 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 drugs such as ciprofloxacin, the tablet does not miss 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 when administered for a given period of time. The pharmaceutical composition of the invention may contain a large dose of the drug. Therefore, the amount of ciprofloxacin used in the invention is usually from about 0.5 mg to about 1200 mg.

Gaseous preparation

The gas-forming composition comprises a substance which produces gas upon 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 gas generating composition interacts with the acid source upon acceleration by contact with water or gastric juice to form carbon dioxide, which is trapped in the hydrated gel matrix of the swelling composition. Gaseous formulations, 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, 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 may be used in the present invention as an acid source include a monoalkalic organic acid salt having more than one carboxylic function, an organic acid bi-alkaline metal salt containing more than two acidic carboxylic acid functionalities, and the like. The acid source may be present in an amount of from about 0.5%

-9 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 a cross-linked polyvinylpyrrolidone; other blowing agents include cross-saturated carboxymethylcellulose sodium 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 composition which, upon contact with the digestive juice, immediately viscolyses and captures the gas formed by the gas generating composition. The viscolyzing composition preferably comprises a carbohydrate gum such as xanthan gum. Other examples of carbohydrate gums include tragacanth, karaya gum, guar gum, acacia, and the like. Medium to high viscosity cellulose esters 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 composition or a gelling composition, or both. The gelling agent is preferably sodium alginate. Over time, the gelatin preparation cross-sieves and forms a stable structure that captures the generated gas. Therefore, over time, the gelling composition becomes a hydrodynamic balanced system so that the matrix retains in the stomach for a longer period of time. The simultaneous use of a viscolyzing agent and a gelling agent provides an indirect diffusion pathway for the drug, resulting in controlled drug release.

Preferably, the solubilizer and / or gelling agent is 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 composition and / or the gelling composition 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 composition and / or a gelling composition 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 ingredients can cause rapid disintegration of tablets. 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 a breakdown may lead to a 'dose dumping' effect, i. to rapidly release 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 granules resulting from disintegration will also be released from the stomach in less time than intact tablets. The invention prevents such disintegration by the use of small amounts of a viscolyzing composition such as a heteropolysaccharide gum so that tablets or capsules containing a high dose of the 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 high molecular weight biosynthetic polysaccharide gum (ca. 2x10 ⁶ ) produced by aerobic fermentation of a pure sugar culture with Xantomonas campestris. It is particularly enzymatic 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, the xanthan gum has a particle size such that they all pass through a 44 µm mesh screen (Sieve No. 325, ASTM).

The viscolyzing composition 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 viscolysis composition is present in an amount of from about 0.2% to about 5% by weight of the total weight of the composition.

- 11Additional aids

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.

Method of preparation

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. Alternatively, the pharmaceutical composition is prepared by mixing the preceding ingredients with only half of the lubricants. The mixture is compressed between rolls and then screened 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 other described examples:

Particle size distribution - ciprofloxacin base

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- 13Pack

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 here.

Examples of water-soluble pharmaceutical excipients include film-forming agents such as cellulose ethers polymers or soluble pharmaceutical solvents such as lactose, sucrose, dextrose, mannitol, xylitol and the like. In an exemplary 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 flavor associated with the drug.

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

Image overview

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

Fig. 2 and 3 are graphs illustrating the mean concentration of ciprofloxacin with a free base in blood plasma over time when placed in an oral controlled drug delivery system compared to Cipro ™ immediate-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.

- 14Table 1

component mass (Mg / tablet) Materials. % ciprofloxacin hydrochloride monohydrate 598,47 55.16 xanthan gum 20.00 1.84 sodium alginate (Kelton LVCR) 15,00 1.38 cross-saturated 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-saturated polyacrylic acid (Carbopol 971 P) 10,0 0.93 talc 10.00 0.93 Magnesium stearate 20.00 1.84 Aerosil 10.00 0.93 Pretty 1085,00 100%

Ciprofloxacin, xanthan gum, sodium alginate, cross-linked carboxymethylcellulose, sodium bicarbonate, microcrystalline cellulose, sodium chloride, citric acid and half of the lubricants are blended and sieved (British Standard Sieve (BSS) No. 44). The mixture is compressed between rollers and the compact is sieved through a sieve (BSS No. 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 are 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.

- 15Table 2

Time (hrs) release percent in cumulative 1 21.16 2 33.22 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) materials. % tablets materials. % 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 transversely saturated 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 pretty 1400,00 100 -

Ciprofloxacin is sieved through British Standard Sieve (BSS) no. 22. Xanthan gum, sodium alginate, sodium bicarbonate, crospovidone and half of the amount of lubricants, namely magnesium stearate and talc, are sieved (BSS No. 44). All of the above screened components were blended uniformly, pressed on a roller press, and the pressed pieces were sieved through a sieve (BSS No. 18) to obtain granules. The remaining magnesium stearate and talc were sieved through a sieve (BSS No. 60) and

- 16 mixed with granules and a limited portion of 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 white until a weight increase of 1% to 1.5%.

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 when the active ingredient is ciprofloxacin hydrochloride. The pharmaceutical composition is shown in Table 5.

Table 5

component mass (Mg / tablet) materials. % ciprofloxacin hydrochloride monohydrate 600.00 61,54 xanthan gum (Keltrol TF) 10.00 1.02 sodium alginate (Kelton LVCR) 25.00 2.57 cross-saturated 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 pretty 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.

Table 6

time (hours) release in percent cumulative 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 the tablets prepared according to the invention are retained in the stomach for a longer period.

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 the table

8th

Table 7

component weight (mg / tablet) ciprofloxacin hydrochloride monohydrate 599.99 hydroxypropyl cellulose-L 20.00 medium sodium phosphate 25.00 citric acid 25.00 talc 7.00 magnesium stearate 15,00 Aerosil 200 10.00 pretty 701.99

- 18Table 8

component weight (mg / tablet) hydroxypropyl methylcellulose (Metocel K4M) 215.00 cross-saturated polyacrylic acid (Carbopol 934 P) 75,00 Middle calcium phosphate 145.00 Sodium benzoate 8.00 talc 2.00 Aerosil-200 2.50 Sunset Yellow 2.50 Pretty 405.00

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

2.5 hours to 3.5 hours.

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

Table 9

component weight (mg / tablet) ciprofloxacin hydrochloride monohydrate 599.9 hydroxypropyl methylcellulose (Metocel K4M) 20.00 hydroxypropyl cellulose-L 40.00 citric acid 25.00 medium sodium phosphate 25.00 talc 10.00 magnesium stearate 10 00 pretty 729,99

70 mg of barium sulfate was also added to the above composition. Tablets were prepared by conventional methods of blending, rolling, crosslinking, blending with lubricants, and compressing 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 (Metocel K4M) 30.00 hydroxypropyl cellulose-L 30.00 citric acid 5.00 Medium sodium phosphate 5.00 talc 4.00 Magnesium stearate 6.00 Pretty 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. Hydrophilic matrix tablets were retained for 2 hours to 2.5 hours and buoyant capsules for 3.5 hours to 4.5 hours.

Gastric retention studies were also performed for a ciprofloxacin base formulation with a similar composition to that shown in Example 2. Two tablets were administered to the 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, bioavailability pilot study was conducted for formulation A (two 500 mg ciprofloxacin hydrochloride once daily tablets, prepared according to Example 1), for formulation B (1000 mg free tablets). ciprofloxacin base

-20 for once-daily administration, prepared according to Example 2) and for Reference Formulation R (Ciprofloxacin ™ (Bayer Corp.) containing 500 mg as immediate-release tablets administered twice daily). The tablets are administered 30 minutes after regular breakfast. The profile of the mean serum concentration-time profile is shown in FIG.

Figure 1 is based on the following values, which are shown in the table below

II.

Table 11

Chad (hours) average concentration (mcg / ml) A B C 0 0.0000 0.0000 0.0000 0.5 * * 0,30000 1 0.0489 .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 .7638 6 1.7944 1.3594 .5404 8 1.2467 0.9494 .3579 10 .9367 .7855 .2323 12 .6503 .8714 0.1687 12.5 * .1594 13 * * .3916 13.5 ★ * .8982 14 .4171 .6831 1.0993 14.5 * * 1.1432 15 ★ ★ 1.3889 16 .2753 .4826 1.1187 17 * ★ 0.9377 18 .1901 0.3812 .7633 20 * * .4864 22 * ★ .3766 24 .1039 .1778 .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 have not been investigated)

Both the once daily formulations (A and B) exhibit an increase in absorption compared to immediate release (R) tablets. 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 a once-daily formulation, since the maximum serum concentration was comparable to the maximum concentration for the immediate release drug and was maintained for a longer period with the effective drug concentration in the serum.

Example 5

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

An improved once-daily formulation of 1,000 mg of free ciprofloxacin base ("OD" formulation), the composition of which is shown in Table 12, was developed. In the OD formulation, the amount of gelatin preparation (sodium alginate) 0.49% versus 1.0%).

Table 12

ingredients weight (mg / tablet) weight. % drug ciprofloxacin base 1000.0 69.9 sodium alginate 5.0 0.34 xanthan gum 15.0 1.03 sodium bicarbonate 200.0 13.74 cross-saturated polyvinylpyrrolidone (Kollidon CL-M) 176.8 12.15 magnesium stearate 33.0 2.26 talc 10,0 0.68 pretty 1440 100

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

13th

Table 13

time (hours) release percent in cumulative 1 35.49 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 with three periods in 12 healthy adult male subjects between 18-45 years of age receiving a single dose of OD 1000 mg ciprofloxacin tablets 30 minutes after regular high fat breakfast. Immediate release of Cipro ™ tablets was tested under both saturated and unsaturated conditions.

Under oral 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).

Two oral doses of 500 mg Cipro ™ immediate release tablets were administered under fasting conditions. The first oral dose was administered fasting 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 FIG. 2 and 3, wherein FIG. 2 shows the plasma concentration of OD tablets (saturation) versus Cipro ™ (saturation); and FIG. 3 shows the plasma concentration of OD tablets (saturation) versus Cipro ™ (fasting). Fig. 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) A B 0 0.0000 0.0000 0.5 0.2190 ★ 1 1.0964 .3430 1.5 1.9702 ★ 2 2.0397 .9751 2.5 1.8232 * 3 1.5617 1.6335 4 1.2265 2.6216 5 1.0123 2.9162 6 .7777 2.0336 8 .5291 1.4256 10 .3527 1,3841 12 .2608 .9790 12.5 .3159 ★ 13 .4176 * 13.5 .8401 * 14 1.9238 .5942 14.5 1.8384 * 15 1.6543 ★ 16 1.2336 .4393

17 0.9689 * 18 .8258 .3357 20 0.5962 * 22 0.4366 ★ 24 .3653 .1843

Α: 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 .3430 1.5 2.7413 * 2 2.3684 .9751 2.5 2.0204 * 3 1.5997 1.6335 4 1.1985 2.6216 5 .9429 2.9162 6 .7298 2.0336 8 .5172 1.4256 10 .3575 1,3841 12 .2709 .9790 12.5 0.9855 ★ 13 2.5113 * 13.5 2.7718 * 14 2.4376 .5942 14.5 1.9856 * 15 1.7173 *

16 1.1702 .4393 17 0.8631 * 18 .7360 .3357 20 .5095 * 22 .4207 * 24 0,3431 .1843

500: 500 mg b.l.d. Fed (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 by making the maximum plasma concentration (C max) comparable to an immediate release drug exhibiting a similar rate of drug absorption. The overall bioavailability of AUC (o-x) (area under the curve) was also comparable to immediate release tablets, indicating that all drug is released from the formulation during its presence in the stomach. See Table 16.

Table 16

study C max (µg / 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 µg / 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 the immediate and controlled release form after a meal. Therapeutic efficacy of OD

The -26 tablets at saturation were comparable to the therapeutic efficacy of Cipro ™ immediate-release tablets used in the fasting state.

Based on the above results in FIG. 1, 2 and 3, it is contemplated that the sustained release solid dosage form of ciprofloxacin should exhibit pharmacokinetic efficacy as measured at the average serum concentration, using the area under the concentration-time curve above the minimum inhibitory concentration and the treatment time above the minimum inhibitory concentrations in ciprofloxacin. serum / plasma not less than 70% compared to divided doses of an equivalent amount of a conventional solid-dose immediate release ciprofloxacin dosage form. While both results were specifically identified for a 1000 mg tablet, it is believed that 100-1000 mg tablets with ciprofloxacin administered orally to humans at saturation would provide a serum / plasma concentration-time curve from zero to zero. infinity) ranging from 3.5 pg / ml.h to about 30 pg / ml.h. Similarly, it is contemplated that 100 mg-1000 mg tablets would provide a maximum serum / plasma concentration in the range of about 0.5 pg / ml to about 4 pg / ml. Further, it is contemplated that 100 mg -1000 mg tablets would provide a serum / plasma drug concentration-time curve curve (above the minimum inhibitory concentration of 0.1 pg / ml) ranging from about 3 to about 26 pg / ml . It is also contemplated that a 100 mg-1000 mg tablet would provide a serum / plasma drug concentration time curve with an area under the curve (above a minimum inhibitory concentration of 0.25 µg / ml) ranging from about 2 µg / ml.h to about 22 µg / ml.h. pg / ml per hour. Finally, it is envisaged that 100 mg -1000 mg tablets would provide a serum / plasma drug concentration-time curve (above the minimum inhibitory concentration of 0.5 pg / ml) ranging from about 1 pg / ml.h to about 18 pg / ml.h.

Table 17

Treatment 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 ™ 2 x 500mg bid (Fasted) 21.5 ± 3.7 18.0 ± 3.8 13.4 ± 4.0 Cipro ™ 2 x 500mg bid (Fed) 17.68 ± 3.9 14.2 ± 3.9 9.7 ± 3.4

Also a small change in the percentage of hydrophilic polymer (sodium alginate) from 0.71 wt. % of the composition up to 0.34 wt. % of the composition resulted in 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) materials. % ciprofloxacin 1,012.10 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 Pretty 1,476.92 100

The tablets were prepared as described in Example 2. The tablets were examined for dissolution as described in Example 1. The dissolution results are shown in the table below.

19th

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:

-28Table 20

component Weight (mg / tablet) % by weight ciprofloxacin 1,012.10 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 pretty 1,456.92 100.02

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.

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) materials. % ciprofloxacin 1,012.10 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 Metocel K15M 30 2.04

Pretty 1,466.92 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 the table below.

23rd

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) materials. % ciprofloxacin 1,015.18 75,15 sodium alginate 5.0 0.37 xanthan gum 15 1.11 sodium bicarbonate 200 14.8 crospovidone 72.75 5.39 magnesium stearate 33 2.44 talc 10 0.74 pretty 1,350.93 100

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

-30Table 25

time (hours) release percent in cumulative 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 1,015.18 67.35 sodium alginate 5.0 0.33 xanthan gum 15 1.0 crospovidone 176,82 11.73 magnesium stearate 33 2.19 talc 10 0.66 sodium carbonate 252.32 16.74 pretty 1,507.32 100

Tablets were prepared as described in Example 2. 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

-31 Example 11

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

Table 28

component weight (mg / tablet) materials. % ciprofloxacin 1,015.18 69.66 sodium alginate 7.28 0.5 xanthan gum 15 1.03 sodium bicarbonate 200 13.72 crospovidone 176,82 12,13 magnesium stearate 33 2.26 talc ¹⁰ 0.69 pretty 1,457.28 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) release percent in cumulative 1 40,06 2 59,26 3 86.19 4 96.39 6 100.2

Example 12

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

Table 30

component weight (mg / tablet) materials. % ciprofloxacin 1,015.18 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 I talc 10 0.69 pretty 1,441.46 100

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) materials. % ciprofloxacin 1,015.18 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 pretty 1,461.83 100

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 the table.

33rd

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) materials. % ciprofloxacin 1,016.19 72.51 sodium alginate 5.0 0.36 xanthan gum 15 1.07 sodium bicarbonate 145.5 10.38 crospovidone 176,82 12.61 magnesium stearate 33 2.35 talc 10 0.71 pretty 1,401.51. 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 the table below.

35th

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.

Table 36

72.15 1.07 0.36 12.61 10.38 2.97: 1 4.46 CD WHAT* 5.91 4.19 9.31 8.49 68 T LO CD r- 00 cn • n- τ -r- in- what cn * LO WHAT cm " what" CD 00 6.95 WHAT -r- about 'T- t CN cn what r- what about 35 n- r *. cri CD what cn T " CN CM * what cn WHAT T " WHAT* CN h- about about T " about '' Φ T WHAT cn T cn l · » CD WHAT about WHAT CN what * 03 CD * what* LO * CD cn * LO CN what about about WHAT LO L'- 00 cn τ- CD about t CN 90 ‘ , 26 cn cn CN what about* m WHAT about cn CD (L * about 0.33 WHAT TJ- LO WHAT cn WHAT r- ' CD r-. WITH- ο about_ nothing CD ' about what CD WHAT what cn CD cn what LO LO cn * LO * about* cn what WHAT WHAT LO r- cn cn cn what" T ~ WHAT xt * cn CN cn b- about io in- WHAT about CN CN m · cn about* LO WHAT cn Ν ' CN • Ν ' about ε. what LO 00 about about CD xT (D what cn CD nothing WHAT about" CN what about CN ON THE ABOUT u. ω Q_ CD WHAT about LO 0.2 .c WHAT K- yt n. r- about 73 about xt LO r- what cn γ- • 'T CM C > - cn * CD nothing ^ 1 - CN what T " < FROM ative cd_ 2.0 N * 00 9.5 N " CN 5.7 φ = j E WHAT LO what r- cn cn Ό ro what b- D IN LO what what" WHAT about > About en 3.5 < > 4.0 'Lf about cn * 4.8 about* about Q. ω CD WHAT C from Φ WHAT LO CD cn > C CD ο ^ * t > about LO > c cn T what CN ο cn WHAT Ν ' in- WHAT N CD what r- Ε cn about_ WHAT CN what ABOUT > LO * WHAT* CN 00 -C m CD about what Σ3 WHAT LO WHAT cn in- in- 'N LO ro CN T about • 20 ABOUT about CN * I •> s · - · and beyond I LO -0.9 Ión 5 UPOS : alginate n -Π3 ABOUT ro 1 CM about about an xacínov; E D cn • ro > Sodium 0 a vinyl énuhličit n sodium LO xanthan >; C TJ component ciproflo xantánc alginate XL poly cn about l_ TJ >. sz carbonate Methocel [ratio time (him IN" CN what xr CD WHAT

-36Example 15

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

Table 37

component weight (mg / tablet) materials. % ciprofloxacin 1,015.18 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 Pretty 1,493.27 98.637

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) materials. % ciprofloxacin 1,015.18 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 pretty 1,464.55 97.32

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 1,015.18 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 pretty 1,512.75 99,019

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, it was found that one of them, i. no. the dissolution profile or buoyancy characteristic is unsatisfactory compared to the previous examples.

Table 43

component Example 18 Example 19 ciprofoxacin 1,015.18 1,015.18 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 Pretty 1450,00 1,440.0 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

ingredients Example 20 Example 21 Example 22 Example 23 Example 24 ciprofloxacin 1,016.19 1,016.19 1012,1 1,016.19 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 Metocel K15M 15.0 - - - - gellan gum - 15.0 30.0 - - Carrageenan - - - 15.0 45.0 Pretty 1,456.01 1,456.01 1,466.92 1,456.01 1,481.92 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

ingredients example 25 example 26 example 27 example 28 example 29 example 30 ciprofloxacin 1,015.18 1012,1 1,015.18 1012,1 1,015.18 1012,1 xanthan gum 15.0 15.0 15.0 15.0 15.0 15.0 sodium 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 Pretty 1,455.0 1,446.92 1,455.0 1,456.92 1,455.0 1,466.92 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 1,015.18 1012,1 1,015.18 1012,1 1,015.18 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 sodium 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 Pretty 1,455.0 1,375.1 1,455.0 1400.1 1,455.0 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 1,015.18 1,015.18 1,015.18 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 pretty 1,278.18 1,540.08 1,641.93 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

ingredients Example 40 Example 41 Example 42 ciprofloxacin 1,016.19 1,016.19 1,016.19 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 Metocel K15M 15.0 - - gellan gum - 15.0 - carrageenan - - 15.0 pretty 1,456.01 1,456.01 1,456.01 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

ingredients Example 46 Example 47 Example 48 ciprofloxacin 1,015.18 1,015.18 1,015.18 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 1 10,0 10,0 10,0 Ac-di-sol 176,82 - - sodium starch glycolate - 176,82 - MCC (Avicel pH 101) - 176,82 - pretty 1,455.0 1,455.0 1,455.0 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

ingredients Example 49 ciprofloxacin 1,015.18 sodium alginate 5.0 xanthan gum 15.0 crospovidone 176,82 magnesium stearate 33.0 talc 10,0 potassium bicarbonate 238.34 pretty 1,493.34 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 1,015.18 1,015.18 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 pretty 1450,00 1,451.46 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 1,015.18 sodium alginate 5.0 sodium bicarbonate 200.0 crospovidone 176,82 magnesium stearate 33.0 talc 10,0 pretty 1,440.0 dissolution time (hours) cumulative percent release 1 52.5 2 68.94 3 90.39 4 100.8 6 104.79

-45Table 54

component Example 53 Example 54 Example 55 Example 56 ciprofloxacin 1,015.18 1,016.19 1,015.18 1,015.18 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 pretty 1,255.0 1,328.76 1,546.0 1,691.5 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 (38)

PATENT CLAIMS A formulation in the form of a tablet for oral administration once daily to humans for the controlled release of ciprofloxacin, comprising a pharmaceutically effective amount of ciprofloxacin, from 0.1 to 8.0 wt. % of a viscolyzing agent and / or a gelling agent, from 5.0% to 15% by weight. % gaseous agent and 3.0 wt. % to 15 wt. % by weight of the blowing agent, the weight percent being based on the total weight composition. A formulation in the form of a tablet for oral administration once daily 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, from 5.0% to 15% by weight. % gaseous agent and 5.0 wt. % to 15 wt. % by weight of the blowing agent, the weight percent being based on the total weight of the composition. The formulation of claim 1 or 2, wherein the viscolyzing composition 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. The formulation according to claim 1 or 2, wherein the gelling agent is sodium alginate. A formulation according to claim 1 or 2, characterized in that it contains either a viscolyzing agent or a gelling agent or both. The formulation of claim 6, wherein the viscolyzing agent is xanthan gum. The formulation according to claim 3, wherein the gas generating agent is selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, and mixtures thereof. -479. The formulation according to claim 3, characterized in that the blowing agent is a cross-saturated polyvinylpyrrolidone. A formulation intended 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% by weight. % 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. % by weight of the cross-linked poly vinylpyrrolidone, 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 according to claim 10, characterized in that it comprises 69.9% by weight. % 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. The formulation according to claim 10, characterized in that it 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 small intestine containing a pharmaceutically effective amount of ciprofloxacin, from 0.2 to 0.5 materials. % sodium alginate, from 0.5 to 2.0 wt. % xanthan gum, from 10.0 to 25 wt. % sodium bicarbonate and 5.0 to 20 wt. % by weight of the 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 in the range of 1: 1 to 1:10. A formulation according to claim 13, characterized in that it comprises 69.9% by weight. % 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. -4815. Tablet formulation for once-daily oral administration to humans for the controlled release of ciprofloxacin in the stomach or upper parts of the small intestine, comprising a pharmaceutically effective amount of ciprofloxacin, from 0.2 to 0.5% by weight. % sodium alginate, from 0.5 to 2.0 wt. % xanthan gum, from 10.0 to 25 wt. and from 5.0 to 20 wt. % by weight of cross-linked polyvinylpyrrolidone and optionally other pharmaceutical excipients, wherein the weight percentages are 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% by weight. % 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. A formulation according to claim 15, in the form of tablets. A tablet formulation for once daily oral administration to humans, characterized in that the controlled release of ciprofloxacin occurs in the stomach or upper parts of the small intestine, comprising a pharmaceutically effective amount of ciprofloxacin, from 0.2 to 0.5% by weight. % sodium alginate, from 0.5 to 2.0 wt. % xanthan gum, from 10.0 to 25 wt. % sodium bicarbonate, and from 5.0 to 20 wt. % by weight of the 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 in the range of 1: 1 to 1:10. 19. A formulation according to claim 18, comprising 69.9% by weight. % 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. A formulation according to claim 18, characterized in that it is in the form of tablets. -4921. 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 within 2-4 hours and releasing more than 60% of the drug within 4-8 hours. A formulation according to claim 22, characterized in that it is suitable for a once daily administration profile. 24. The formulation of claim 23, wherein the formulation is in the form of a tablet or capsule. 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. Formulation according to claim 26, characterized in that the pharmaceutically acceptable excipients comprise a viscolyzing agent and / or a gelling agent, a gas-forming agent and a blowing agent. A formulation according to claim 27, characterized in that it comprises from 0.1 to 8.0 wt. % viscolysis and / or gelling agent, 5.0 to 15 wt. and 5.0 to 15 wt. % by weight of the blowing agent, the weight percent being based on the total weight of the composition. A formulation according to claim 28, characterized in that it comprises from 0.2 to 5.0 wt. % viscolysis and / or gelling agent, 5.0 to 15 wt. % of the gaseous agent and 5.0% to 15 wt. % by weight of the blowing agent, the weight percent being based on the total weight of the composition. -5030. The formulation of claim 29, wherein the viscolyzing composition is either xanthan gum or hydroxypropyl methylcellulose (methocell) and the gelling composition is sodium alginate. A formulation according to claim 30, characterized in that it contains both a viscolysis preparation and sodium alginate. 32. 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 according to claim 28, wherein the blowing agent is a cross-saturated polyvinyl pyrrolidone. A formulation according to claim 26, characterized in that it is suitable for once daily administration profile. The formulation of claim 26, which is in the form of a tablet or capsule. The formulation of claim 26, which is in the form of a tablet that is coated with a pharmaceutically acceptable excipient. 38. A sustained release solid dosage form of ciprofloxacin, characterized in that, when administered orally in humans at saturation, it provides a mean serum / plasma concentration, an area below the serum / plasma concentration time dependency above the minimum inhibitory concentrations, and a duration of action above the minimal inhibitory serum / plasma. concentrations not less than 70% compared to divided doses of an equivalent amount of a conventional solid immediate release ciprofloxacin dosage form. -5139. 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 from zero to infinity ranging from 3.5 to 30 µg / ml. .h. The solid sustained release 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, it provides a time dependence of serum / plasma drug concentration 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, it provides a time dependence of serum / plasma drug concentration 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. The solid sustained release 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 above a minimum inhibitory concentration of 0.5 µg / ml in the range of 1 to 18 μρ / ΙηΙ.ίι. 1/3 FIG. 1 A linear graph of serum ciprofloxacin concentration versus time in healthy men