HRP20020715A2 - Orally adminestered controlled delivery system for once daily administration of ciprofloxacin - Google Patents

Description

Background of the invention

The present invention relates to a pharmaceutical preparation in the form of tablets or capsules that provide a combination of spatial and temporal control of drug release, specific to the drug ciprofloxacin, for effective therapeutic results in the patient. The pharmaceutical composition contains ciprofloxacin, a gas-evolving component, a swelling agent, and at least one of a viscosity agent and a gelling agent. The swelling agent belongs to a class of highly absorbent compounds commonly referred to as superdisintegrants. This class of compounds includes, for example, cross-linked polyvinyl pyrrolidone and cross-linked sodium carboxymethylcellulose. A viscosifier is a highly viscous material that, upon contact with gastric fluid, traps the gas produced by the gas developing component. The viscosity agent comprises, for example, a carbohydrate resin, for example, xanthan gum, or a cellulose ether, eg, hydroxypropyl methylcellulose (methocel). The gelling agent is preferably a crosslinkable gelling agent, such as a water soluble salt of one of the polyuronic acids, eg sodium alginate.

The improved controlled drug release system of the present invention is designed to efficiently deliver ciprofloxacin to the patient over a specific period of time (temporal control) and in a specific portion of the patient's gastrointestinal tract (spatial control). The improved controlled drug release system avoids dose hopping and results in the best therapeutic administration of ciprofloxacin to the individual.

It is well known to those skilled in the art that for diseases requiring multiple doses of a particular drug, the blood level of the drug must be maintained above its minimum effective level and below its minimum toxic level to achieve desired therapeutic effects, avoid unwanted toxic effects, and minimize side effects. When the drug level in the blood is within this range, the drug is eliminated from the body at a certain rate. A controlled drug release system is usually designed to release the drug at that particular rate; a safe and effective level of the drug in the blood is maintained for as long as the system releases the drug at that rate. Controlled drug release usually results in a very constant blood level of the active ingredient compared to the uncontrolled fluctuations seen when multiple doses of conventional rapid release dosage forms are administered to a patient. Controlled drug release 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 basic concepts of controlled drug release are well known to those skilled in the art. In the last decades, significant efforts have been made to develop new, pharmaceutically cost-effective and therapeutically effective systems for controlled drug release. Attention is particularly focused on controlled drug release systems for oral administration due to the ease of oral administration, as well as the ease and economy of production of oral dosage forms, such as tablets and capsules. A number of different controlled-release oral systems have been developed, based on different release mechanisms. These oral systems for controlled drug release are based on different models of action and are variously named, for example, as dissolution-controlled systems, diffusion-controlled systems, ion-exchange resins, osmotically controlled systems, erosion matrix systems, pH-independent preparations, controlled systems which swells, and the like.

An orally administered controlled drug release system encounters many highly variable conditions, such as pH, intensity of agitation, and composition of gastrointestinal fluids, as it passes through the gastrointestinal tract. Ideally, an oral controlled release system will release the drug at a constant and reproducible rate, despite changing conditions. Accordingly, significant efforts have been made to develop controlled constant rate oral drug release systems that overcome these difficulties and release the drug at a constant rate as it passes through the gastrointestinal tract.

It is well known to those skilled in the art that a drug may not be absorbed uniformly throughout the length of the gastrointestinal tract, and that absorption of a drug from the colon is usually unpredictable and inefficient. Also, certain drugs are absorbed only from the stomach or upper parts of the small intestine. Furthermore, an important factor that can adversely affect the properties of an oral controlled release drug system is that the dosage form must be rapidly transported from the more absorptive upper regions of the intestine to the lower regions of the intestine where the drug is less absorbed. Therefore, in cases where the drug is not absorbed uniformly along the gastrointestinal tract, the rate of drug absorption may not be constant despite the drug release system releasing the drug at a constant rate into the gastrointestinal fluids. More specifically, in cases where the drug has a well-defined "absorption window", i.e., the drug is absorbed only from certain areas of the stomach or upper small intestine, it may be incompletely absorbed when administered in the form of a typical oral controlled-release system. It is obvious that for a drug having such an "absorption window", an effective oral controlled release system should be designed not only to release the drug at a controlled rate, but also to maintain the drug in the upper gastrointestinal tract for a longer period of time.

LOUSE. Patent no. 5,651,985, assigned to Bayer AG, discloses a composition comprising a pharmacologically active compound, a pharmaceutically acceptable excipient, polyvinylpyrrolidone, and a methacrylic acid polymer having an acid number between 100 and 1200 mg KOH/g polymer solids. Optionally, the composition also contains a gas-generating additive. The preparation absorbs acidic water in an amount many times greater than its mass and forms a highly swollen gel with great mechanical and dimensional stability. The gel forming agent should be sufficient so that after application it can swell to a size that prevents passage through the duodenum for a relatively long period of time. At least 30% of the mass and up to 90% of the mass of the preparation are polymers, and thus a dosage form containing a large dose of the drug would be large and unsuitable for oral administration.

In general, in the field of controlled drug release systems, it is known that in order to make a particular drug available as a once-daily tablet or capsule, it is necessary to experiment and invent a particular drug, along with specific excipients. Thus, those particular excipients and in those particular relative amounts that may work for a particular active ingredient or drug, to enable its once-daily administration, are unlikely to work for another drug.

Nishioka et al. (JP 06024959) is a Japanese patent publication in which an attempt was made to prolong the release of ciprofloxacin for a longer period of time, in such a way that the tablet containing ciprofloxacin remains suspended in the stomach. The release period achieved by the Nishioka tablet is so slow, that only 46% of the Nishioka tablet dissolves after 24 hours (see drawing). A practical and significant effect of this slow release is that the Nishioka formulation would not be as effective as a "once daily" formulation of ciprofloxacin.

Accordingly, none of the oral controlled drug release systems described so far are completely satisfactory for the purpose of providing a once daily release formulation of ciprofloxacin.

Objects of the present invention

The object of the present invention is to provide a pharmaceutical composition in the form of tablets or capsules which is a once-daily controlled-release preparation of ciprofloxacin, which:

evolves and traps gas in a hydrated matrix after contact with an aqueous medium or gastric fluids, and which remains in a mostly monolithic form in the stomach,

enables a prolonged stay in the stomach and, accordingly, a prolonged stay of the drug release system in the gastrointestinal tract,

releases the drug at a controlled rate, so that the drug is released for a period of time equal to or shorter than the retention period of the release system in the absorptive regions of the gastrointestinal tract, and

allows, in comparison with other oral systems for the controlled release of the drug, increased absorption of the drug, which is absorbed mainly from the upper parts of the gastrointestinal tract.

It is also an object of the present invention to provide a once-a-day formulation for controlled release of ciprofloxacin that maintains its physical integrity, i.e., remains intact or largely retains its monolithic form when in contact with an aqueous medium, even when the amount of drugs is high and the polymer ratio is low. compared to other system components. It is a further object of the present invention to provide a once-a-day formulation for the controlled release of ciprofloxacin, which incorporates a large dose of the drug without losing any of its desirable attributes, which are enumerated above, such that the system is of an acceptable size for oral administration.

The essence of invention

The present invention provides a novel pharmaceutical composition in the form of tablets or capsules, which composition is a once-daily oral formulation for the controlled release of ciprofloxacin. The pharmaceutical composition contains ciprofloxacin, a gas-evolving component, a swelling agent (eg, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethylcellulose), at least one of a viscosity agent (eg, a carbohydrate resin such as xanthan gum or a cellulose ether such as hydroxy -propyl methylcellulose), and gelling agents (eg, sodium alginate).

Preferably, the inventive oral controlled drug release system, which is a pharmaceutical formulation in tablet or capsule form, contains a pharmaceutically effective amount of ciprofloxacin, about 0.1% to about 8% by weight of at least one of the viscous agent and the gelling agent, about 5% up to about 15% by weight of the gas developing component, and about 3% to about 15% by weight of the swelling agent.

More preferably, the amount of at least one of the viscosity agent and the gelling agent ranges from about 0.2% to about 5% and the amount of the swelling agent ranges from about 3% to about 15%.

Even more preferably, the present invention relates to a once-daily tablet formulation for oral administration in humans for the controlled release of ciprofloxacin, comprising a pharmaceutically effective amount of ciprofloxacin, about 0.2% to about 0.5% sodium alginate, about 0, 5 to about 2.0% xanthan gum, about 10.0% to about 25% sodium bicarbonate, and about 5.0% to about 20% cross-linked polyvinylpyrrolidone, said percentages being expressed as mass ratios of the composition, wherein the mass ratio is sodium of alginate to xanthan gum between about 1:1 to about 1:10.

The swelling agents used herein (crosslinked polyvinylpyrrolidone or crosslinked sodium carboxymethylcellulose) belong to a class of compounds known as super-disintegrants, which typically function to promote tablet disintegration by absorbing large amounts of water and resulting swelling. This expansion, as well as hydrostatic pressure, causes the tablet to burst. In a tablet that also contains a gas-evolving component (which may actually be a gas-evolving combination), the tablet would be expected to disintegrate immediately upon contact with an aqueous liquid, if not explode. Significantly, it has been found that in the presence of a fast-acting viscous agent and/or gelling agent, the evolved gas is trapped and the super-disintegrant acts as a swelling agent which swells to, preferably, at least twice its initial volume. Thus, the combination of a gas-evolving component, a swelling agent which is effectively a super-disintegrant, and a viscous or gelling agent allows the formulation to act as a controlled drug release system. Additionally, over time, the gelling agent and/or viscous agent produces a cross-linked three-dimensional molecular network, resulting in a hydrodynamically balanced system that retains the drug in 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 composition of the present invention is retained for a longer period of time in the stomach (time control) than previously known hydrophilic matrix tablets, floating capsules and bioadhesive tablets when these systems are administered with food. The composition of the present invention results in drug release in the more absorptive regions of the gastrointestinal tract, ie, the stomach and small intestine instead of the large intestine, where drug absorption is poor and unpredictable. Therefore, if a drug is released at a constant and controlled rate, it can be expected that it will also be absorbed at a more or less constant rate.

Even more surprisingly, it was found that even for a drug that is absorbed only from the upper gastrointestinal tract (ie, from the stomach to the jejunum), such as cirpofloxacin, the present formulation provides the desired absorption at such a rate that an effective plasma level is maintained in an extended duration and the preparation is particularly suitable for application once a day (time control). Further, the formulation provides increased drug absorption compared to other oral controlled drug release systems, such as hydrophilic matrix tablets and floating capsules. This is achieved by adjusting the drug release time period so that it is approximately equal to or shorter than the tablet's retention time at the site of absorption. Therefore, the tablet or capsule is not transported outside the "absorption window" before the entire amount of drug is released, and maximum bioavailability is achieved.

Short description of the pictures

Figure 1 is a graph showing the mean serum concentration versus time for ciprofloxacin free base and ciprofloxacin HCl when incorporated into an oral controlled release system compared to the currently marketed formulation, Cipro™ (Bayer Corp.), immediate release tablets .

Figures 2 and 3 are graphs showing the mean plasma concentration versus time for ciprofloxacin free base when incorporated into the oral controlled release system of the present invention compared to Cipro™ immediate release tablets under fed and fasted conditions.

Detailed description of the invention

According to the present invention, the composition of the present invention includes ciprofloxacin, a swelling agent, and at least one of a viscosity agent and a gelling agent. Together, these components form a hydrated gel matrix. The composition further contains a gas-evolving component so that the gas (generally CO 2 , but in some cases SO 2 ) is evolved in a controlled manner and remains trapped in the hydrated gel matrix. A swelling agent belonging to a class of compounds known as super-disintegrants, absorbs large amounts of liquid and causes the matrix to swell instantly. The gas developed by the gas developing component also causes the matrix to expand. However, in the present invention, the swelling of the matrix is controlled by a viscous agent and/or a gelling agent, both of which act as both a swelling agent and a drug release control agent.

The characteristics of the hydrated gel matrix can be modified by varying the proportions and amounts of the swelling agent, viscosity and/or gelling agent, and gas-evolving component, without losing the physical integrity of the hydrated gel system. The preparation can, therefore, be formulated in such a way as to achieve the optimal rate of release of ciprofloxacin. It was also established that such a preparation, when administered with food, remains for a longer period in the stomach, and therefore in the gastrointestinal tract, without losing its physical integrity.

The evolved gas affects the release of the drug from tablets or capsules in ways that have not yet been fully elucidated. For example, factors that can affect drug release include:

the presence of trapped gas inside the matrix can affect the length of the drug's diffusion path and thus have an effect on controlling the release;

the presence of trapped gas within the matrix can affect the rate of surface erosion of the hydrated gel matrix and thus express both the hydrodynamic and release control effects;

expansion pressure and the presence of gas affects the internal structure of the hydrated gel and thus exhibits both hydrodynamic and release control effects; and

the presence of trapped gas and its expansion pressure influence the influx of acidic gastric fluid through the matrix pores and thus exert an effect on release control.

It should be understood that the gas evolved in a small volume within the matrix can reach a high pressure. If it exceeds the capillary pressure due to the surface tension of the aqueous fluid, then it will cause the aqueous fluid in the pore to be displaced by the gas, allowing the gas to expand until the internal pressure of the gas equals the capillary pressure. This phenomenon would therefore affect the rate of hydration of the matrix and play a role in determining the rate of drug release. In cross-linking systems, this will also have an impact on the structuring of the developing gel.

The various components of the new preparation will now be described in more detail.

DRUG

According to the present invention, the pharmaceutical composition is in the form of tablets or capsules that allow a controlled release rate (ie, time control, specifically) of ciprofloxacin. The present invention is particularly suitable for controlled rate release of a drug such as ciprofloxacin, which does not exhibit uniform dissolution and absorption characteristics along the gastrointestinal tract.

The new pharmaceutical formulation is best suited for the controlled release of drugs that are absorbed only from the upper gastrointestinal tract with a specific absorption window (ie, time control), ie, ciprofloxacin (absorbed only in the region extending from the stomach to the jejunum). The pharmaceutical preparation is particularly suitable for ciprofloxacin because the absorption of the drug depends on its solubility characteristics. Ciprofloxacin dissolves at lower pH values and therefore the "absorption window" is predominantly in the stomach or upper small intestine. In the case of drugs such as ciprofloxacin, the tablet is not transported outside the "absorption window" before the entire amount of drug is released, so that maximum bioavailability can be achieved.

Ciprofloxacin alone, or a pharmaceutically acceptable salt or ester thereof, may be used in the present invention. The amount of ciprofloxacin to be used in the preparation is that which is typically administered over a given period of time. According to the present invention, the pharmaceutical composition may include a large dose of the drug. Accordingly, the amount of ciprofloxacin to be used in the present invention typically ranges from about 0.5 mg to about 1200 mg.

COMPONENT FOR GAS DEVELOPMENT

The gas developing component contains a substance known to produce gas upon contact with gastric fluid. Examples of the gas-evolving component that can be used in the present invention include carbonates, such as calcium carbonate, potassium carbonate, or sodium carbonate, and bicarbonates, such as sodium hydrogen carbonate.

The gas-evolving component reacts with an acid source, triggered by contact with water or simply with gastric fluid, to evolve carbon dioxide that remains trapped within the hydrated gel matrix of the swelling formulation. The gas-evolving component, such as carbonates and 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 source of the acid can be one or more edible organic acids, a salt of an edible organic acid, or a mixture thereof. Examples of organic acids that can be used as an acid source in the present invention include, for example: citric acid or salts thereof, such as sodium citrate or calcium citrate; malic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, or their salts; ascorbic acid or its salts, such as sodium or calcium ascorbate; glycine, sarcosine, alanine, taurine, glutamic acid, and the like. Organic acid salts that can be used as an acid source in the present invention include, for example, mono-alkali salts of an organic acid having more than one carboxylic acid functional group, bialkali metal salts of an organic acid having more than two carboxylic acid functional groups, and similar to. 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, in in relation to the total mass of the preparation.

AGENT FOR SWELLING

According to the present invention, the pharmaceutical composition contains a swelling agent that is capable of swelling to a volume greater than its initial volume when in contact with an aqueous fluid, such as gastrointestinal fluid. A preferred swelling agent is cross-linked polyvinylpyrrolidone; other swelling agents include cross-linked sodium carboxymethylcellulose and the like. These compounds belong to a class of compounds known as super-disintegrants. A swelling agent, which normally swells to several times its original volume in water, exhibits controlled swelling in the presence of a viscous and/or gelling agent. The swelling agent may be present in an amount of about 3% to about 15% by weight, of the total weight of the composition. More preferably, the swelling agent may be present in an amount of about 5% to about 15% by weight, of the total weight of the composition.

VISCOUS AGENT AND GELLING AGENT

According to the present invention, the pharmaceutical composition contains a viscous agent which, upon contact with gastrointestinal fluid, instantly becomes viscous to trap the gas evolved by the gas-evolving component. Preferably, the viscous agent comprises a carbohydrate resin, such as xanthan gum. Other examples of carbohydrate resins include tragacanth resin, karaya resin, guar resin, acacia, and the like. Cellulose ethers of moderate to high viscosity may also be used, such as hydroxypropyl methylcellulose. In the present invention, it has been found that xanthan gum aids in maintaining the integrity of the tablet when mixed in an aqueous medium, and in sustaining drug release.

According to the present invention, the pharmaceutical composition contains either said viscous agent or gelling agent or both. The gelling agent is preferably sodium alginate. The gelling agent cross-links over time to form a stable structure that traps the evolved gas. Thus, over time, the gelling agent will result in a hydrodynamically balanced system whereby the matrix is retained in the stomach for an extended period of time. Simultaneously, the viscous agent and the gelling agent provide a tortuous diffusion path for the drug, thus resulting in controlled drug release.

Preferably, the viscous agent and/or gelling agent is present in an amount of about 0.1% to about 8% by weight, of the total weight of the composition. Even more preferably, the viscous and/or gelling agent is present in an amount of about 0.2% to about 5% by weight, of the total weight of the composition.

The successful use of even small amounts of a viscous agent and/or gelling agent, such as xanthan gum, to enable tablet integrity is indeed surprising in view of the fact that the pharmaceutical composition of the present invention contains a gas-evolving component and a swelling agent which are commonly used as a decomposition agent. Experts can easily conclude that both components can result in rapid disintegration of the tablet. Tablets containing hydroxypropylcellulose in amounts approximately equal to the amount of carbohydrate resin in the present invention disintegrate after 10 to 15 minutes when mixed in an acidic medium. Such disintegration can result in a dose-hopping effect, i.e., rapid release of a large amount of drug from the system, and is undesirable especially because controlled drug release systems contain several times more drug than a conventional preparation. Granules formed as a result of disintegration are also emptied from the stomach in a shorter time than intact tablets. The present invention avoids such disintegration by using small amounts of a viscous agent, such as a heteropolysaccharide resin, so that tablets or capsules containing a large dose of drug are acceptable amounts for oral administration.

In preferred embodiments of the present invention, the viscous agent is xanthan gum. Xanthan gum, also known as corn sugar gum, is a biosynthetic polysaccharide resin of high molecular weight (ca. 2 × 106), produced by aerobic fermentation of carbohydrates from a pure culture of Xanthomonas campestris. It is extremely resistant to enzymes.

In preferred embodiments of the present invention, the xanthan gum has a particle size such that at least 50% of the mass passes through a sieve with a mesh size of 44 µm (Sieve No. 325, ASTM). In even more preferred embodiments, the xanthan gum has a particle size such that all particles pass through a sieve with a mesh size of 44 µm (Sieve No. 325, ASTM).

Preferably, the viscous agent is present in an amount of about 0.1% to about 8% by weight, of the total weight of the composition. Even more preferably, the viscous agent is present in an amount of about 0.2% to about 5% by weight, of the total weight of the composition.

OTHER AUXILIARY MEANS

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

PREPARATION PROCEDURE

According to the present invention, the pharmaceutical composition is prepared by mixing the drug with a gas-evolving component, a swelling agent, and one or both of a viscous agent and a gelling agent, and with other excipients and lubricants. The mixture is directly compressed into tablets or can be filled into capsules. Alternatively, the pharmaceutical preparation is obtained by mixing the aforementioned ingredients with half the amount of lubricant. The mixture is compressed with a roller and then sieved to obtain granules. The granules are then mixed with the remaining amount of lubricant, and filled into capsules or compressed into tablets.

The following table sets out the various particle sizes for ciprofloxacin base (determined using the Malvern Master Sizer) used in the examples described below:

PARTICLE SIZE DISTRIBUTION - CIPROFLOXACIN BASE

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* This material is obtained as coarsely ground. It is ground to obtain the desired size range.

ENVELOPE

According to the present invention, when the pharmaceutical preparation is in tablet form, it can be coated with a thin layer of a water-soluble pharmaceutical excipient that dissolves quickly. A water-soluble excipient envelope results in faster hydration and gas formation than a water-soluble polymer envelope and is the preferred envelope.

Examples of water-soluble pharmaceutical excipients include film-forming agents such as polymers of cellulose ethers, or water-soluble pharmaceutical diluents such as lactose, sucrose, dextrose, mannitol, xylitol, and the like. In a preferred embodiment of the present invention, the water-soluble excipient used as a coating is lactose.

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

The present invention is illustrated, but is in no way limited, by the following examples:

EXAMPLE 1

This example illustrates the present invention when the active ingredient is cirpofloxacin hydrochloride. Ciprofloxacin is an example of a drug that is absorbed only from the upper intestine. The pharmaceutical preparation is given in table 1.

TABLE 1

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Ciprofloxacin, xanthan gum, sodium alginate, cross-linked carboxymethylcellulose, sodium bicarbonate, microcrystalline cellulose, sodium chloride, citric acid, and half of the lubricants are mixed together and sieved through a sieve (British Standard Sieve (BSS, British Standard Sieve) No. 44). The mixture is compacted on a roller compactor and the compact is sieved through a screen (BSS No. 22) to obtain granules. The granules are mixed with the remaining lubricants and Carbopol and then compressed into tablets. Tablets are spray-coated with an aqueous coating composition containing 15.8% w/w lactose, 3.18% w/w talc, and 1.587% w/w titanium dioxide to a mass concentration of 1% to 1.5%.

Tablets are tested for dissolution in 0.1N HCl using USP apparatus 1 with a basket speed of 100 rpm. The dissolution results are shown in Table 2.

TABLE 2

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EXAMPLE 2

This example illustrates the present invention when the active ingredient is cirpofloxacin base. The pharmaceutical preparation is given in Table 3.

TABLE 3

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Ciprofloxacin is sieved through British Standard Sieve (BSS) no. 22. Xanthan gum, sodium alginate, sodium bicarbonate, crospovidone and half the amount of lubricants, namely magnesium stearate and talc, are sieved (BSS No. 44). All the above sieved ingredients are uniformly mixed, compacted on a roller compactor and the compact sieved through a sieve (BSS No. 18) to obtain granules. The remaining magnesium stearate and talc are sieved (BSS No. 60) and mixed with the upper granules and a limited proportion of fine granules (finer than BSS No. 60) and then compressed into tablets. If necessary, the tablets are coated by spraying with an aqueous coating composition containing 15.8% w/w lactose, 3.18% w/w talc, and 1.587% w/w titanium dioxide to a mass layer of 1% to 1.5%.

The dissolution results are shown in Table 4.

TABLE 4

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EXAMPLE 3

This example illustrates the present invention when the active ingredient is cirpofloxacin hydrochloride. The pharmaceutical preparation is given in table 5.

TABLE 5

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Tablets are made as described in Example 1, except that Ac-Di-Sol is included extragranularly. The tablets are tested for dissolution as described in Example 1. The dissolution results are shown in Table 6.

TABLE 6

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EXAMPLE 4

Gastric retention and bioavailability studies

This example shows that the tablets prepared according to the present invention are retained in the stomach for a prolonged period.

The bioadhesive tablet is made as a two-layer tablet. The formulation of the drug layer is shown in Table 7 and the formulation of the bioadhesive layer is shown in Table 8.

TABLE 7

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TABLE 8

[image] Tablets are made by the usual steps of mixing, roller compacting, screening, mixing with lubricants and compressing into two-layer tablets. 70 mg of barium sulfate is included in the bioadhesive layer to serve as an x-ray contrast medium. Gastric retention studies of bioadhesive bilayer tablets were performed on healthy male volunteers who were given two tablets after a standard breakfast. X-ray images were taken periodically. Bioadhesive tablets remained in the stomach for 2.5 to 3.5 hours.

Hydrophilic matrix tablets with the formulation shown in Table 9 were also made.

TABLE 9

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70 g of barium sulfate is also included in the above preparation. The tablets are made by the usual steps of mixing, roller compacting, screening, mixing with lubricants and compressing into tablets.

Floating capsules were also made with the composition shown in Table 10.

TABLE 10

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50 mg of barium sulfate is included in the above preparation. Gastric retention studies of bioadhesive bilayer tablets were performed on healthy male volunteers who were given two tablets/capsules after a standard breakfast. Hydrophilic matrix tablets were retained for 2 to 2.5 hours, and floating capsules for 3.5 to 4.5 hours.

Gastric retention studies were also performed with a ciprofloxacin base preparation of similar composition to Example 2. Volunteers were given two tablets after a standard breakfast. Magnetic resonance imaging confirmed that the tablets according to the present invention remained in the stomach for a period of 5 to 7 hours.

In a second trial, a randomized, three-treatment, three-period crossover pilot study of bioavailability was conducted for preparation A (two tablets of ciprofloxacin hydrochloride 500 mg, once daily administration, made according to example 1), preparation B (tablets of ciprofloxacin free base 1000 mg, once-daily application, made according to example 2), and reference preparation R (Cipro™ (Bayer Corp.) 500 gm rapid release, twice-daily application). The tablets were administered 30 minutes after a standard breakfast. The mean serum concentration-time profile is shown in Figure 1. Figure 1 is based on the following data shown in Table 11, below.

TABLE 11

[image] A: 500 mg × 2 OD (once daily), after food (FDA meal)

B: 1000 mg OD, after meal (FDA meal)

R: 500 mg BID (twice daily), after meals (FDA meal)

* for the one-day preparation, these sampling points are not included

Both OD formulations (A and B) gave an extent of absorption comparable to immediate-release tablets (R). Therefore, it can be concluded that the time period of release of the drug into the gastric fluid is adjusted so that it is approximately equal to or shorter than the retention time of the tablet at the absorption site. Further, formulation B provided a serum concentration-time profile that would be desirable for a once-daily formulation in that the peak serum concentration is comparable to that of an immediate-release drug, and the effective serum concentration of the drug is maintained over a longer period.

EXAMPLE 5

In some respects, formulation B of the previous example did not perform as well as twice-daily Cipro™ 500 mg tablets. For example, the area under the curve above the minimum inhibitory concentration (AUC above MIC) for formulation B was less than that of conventional Cipro™ tablets.

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

TABLE 12

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Tablets were made from the components of Table 12 and tested for dissolution as described earlier. Notably, it was observed that the in vitro dissolution profile of formulation OD (Table 13) had a faster release than formulation B. According to Tomma, 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

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The mean gastric retention of the OD tablets was studied by magnetic resonance imaging and 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 preparation, a randomized, three-period, balanced cross-over bioavailability study was conducted in 12 healthy, adult male human subjects, between 18-45 years of age, where a single dose of ciprofloxacin 1000 mg OD tablet administered 30 minutes after a standard high-fat breakfast. The immediate release of Cipro™ tablets was tested under fed and fasted conditions.

Under fed conditions, two oral doses of 500 mg Cipro™ immediate-release tablets were given. The first oral dose was given within 30 minutes of a fatty breakfast and the second dose was given 12 hours later after a fatty meal (dinner).

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

The results of the study are shown in Figures 2 and 3, with Figure 2 showing the plasma concentration over time of OD tablets (postprandial) versus Cipro™ (postprandial), and Figure 3 showing the plasma concentration of OD tablets (postprandial) versus Cipro™ ( fast). Figures 2 and 3 are based on the following data listed in Table 14 and Table 15, respectively, below.

TABLE 14

[image] [image] A: 500 mg BID, after meal (FDA meal)

B: 1000 mg OD, after meal (FDA meal)

* for OD preparation these sampling points are not included

TABLE 15

[image] [image] B: 500 mg BID, fasting

C: 1000 mg OD, after meal (FDA meal)

* for OD preparation these sampling points are not included

The OD formulation provided a plasma concentration-time profile desirable for a once-daily dosage form in that the peak plasma concentration (Cmax) was comparable to that of the immediate-release drug, indicating a similar rate of drug absorption. The total drug bioavailability AUC(0-∞) (area under the curve) was also comparable to that of the immediate-release tablet, indicating that all the drug is released from the formulation during its residence in the stomach. See table 16.

TABLE 16

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Table 17 gives the AUC above the MIC at three levels of 0.1 µg/ml, 0.25 µg/ml and 0.5 µg/ml for ciprofloxacin OD 1000 mg versus Cipro™ 500 mh BID. These values for ciprofloxacin OD were better than those for Cipro™ immediate-release tablets administered twice daily under fed conditions, indicating better therapeutic efficacy of the OD preparation when both immediate and controlled dosage forms are administered after food. The therapeutic efficacy of OD tablets under fed conditions was comparable to the therapeutic efficacy of Cipro™ immediate-release tablets administered under fasting conditions.

Based on the above results shown in Figures 1, 2, and 3, it is hypothesized that the solid form of ciprofloxacin extended release should have pharmacokinetic characteristics, according to the measured mean serum concentration, the area under the serum/plasma concentration-time curve above the minimum inhibitory concentrations and duration above the minimal inhibitory serum/plasma concentrations, of at least 70% compared to treatment with a divided dose of the immediate release preparation. Although the above results are specifically identified for 1,000 mg tablets, it is assumed that 100-1,000 mg ciprofloxacin tablets, administered orally to humans under fed conditions, would provide a serum/plasma drug concentration-time curve with an area under the curve (time zero to infinity) , which ranges from 3.5 to about 30 µg-hours/ml. Similarly, it is assumed that 100 mg-1000 mg tablets would provide a mean peak serum/plasma concentration ranging from about 0.5 to about 4 µg/ml. Further, it is hypothesized that 100 mg-1,000 mg tablets would provide a serum/plasma drug concentration-time curve with an area under the curve (above the minimum inhibitory concentration of 0.1 µg/ml), ranging from about 3 to about 26 µg- hours/ml. It is also hypothesized that 100 mg-1,000 mg tablets would provide a serum/plasma drug concentration-time curve with an area under the curve (above the minimum inhibitory concentration of 0.25 µg/ml), ranging from about 2 to about 22 µg-hours / ml. Finally, it is hypothesized that 100 mg-1,000 mg tablets would provide a serum/plasma drug concentration-time curve with an area under the curve (above the minimum inhibitory concentration of 0.5 µg/ml), ranging from about 1 to about 18 µg- hours/ml.

TABLE 17

AUC above MIC

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Thus, a minor change in the percentage of hydrophilic polymer (sodium alginate) from 0.71% w/w of the preparation to 0.34% w/w of the preparation resulted in a dramatic and unexpected improvement in pharmacodynamic and pharmacokinetic parameters, which are important measures of therapeutic efficacy.

EXAMPLE 6

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 18

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Tablets are prepared as described in Example 2. Tablets are tested for dissolution as described in Example 1. Dissolution results are given in Table 19.

TABLE 19

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EXAMPLE 7

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 20

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Tablets are prepared as described in Example 2. Tablets are tested for dissolution as described in Example 1. Dissolution results are given in Table 21.

TABLE 21

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EXAMPLE 8

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 22

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Tablets are prepared as described in Example 2. Tablets are tested for dissolution as described in Example 1. The dissolution results are given in Table 23.

TABLE 23

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EXAMPLE 9

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 24

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

TABLE 25

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EXAMPLE 10

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 26

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Tablets are prepared as described in Example 2. Tablets are tested for dissolution as described in Example 1. The dissolution results are given in Table 27.

TABLE 27

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EXAMPLE 11

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 28

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Tablets are prepared as described in Example 2. Tablets are tested for dissolution as described in Example 1. Dissolution results are given in Table 29.

TABLE 29

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EXAMPLE 12

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 30

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Tablets are prepared as described in Example 2. Tablets are tested for dissolution as described in Example 1. Dissolution results are given in Table 31.

TABLE 31

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EXAMPLE 13

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 32

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Tablets are prepared as described in Example 2. Tablets are tested for dissolution as described in Example 1. Dissolution results are given in Table 33.

TABLE 33

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EXAMPLE 14

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 34

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Tablets are prepared as described in Example 2. Tablets are tested for dissolution as described in Example 1. Dissolution results are given in Table 35.

TABLE 35

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Table 36 below summarizes Examples 5-14 above with respect to their ingredients and includes the dissolution profile of each formulation.

TABLE 36

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EXAMPLE 15

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 37

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Tablets are prepared as described in Example 2. Tablets are tested for dissolution as described in Example 1. Dissolution results are given in Table 38.

TABLE 38

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EXAMPLE 16

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 39

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Tablets are prepared as described in Example 2. Tablets are tested for dissolution as described in Example 1. Dissolution results are given in Table 40.

TABLE 40

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EXAMPLE 17

This example illustrates the present invention when the active ingredient is ciprofloxacin base:

TABLE 41

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Tablets are prepared as described in Example 2. Tablets are tested for dissolution as described in Example 1. Dissolution results are given in Table 42.

TABLE 42

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In addition to the above experiments, the following preparations were formulated into tablets as described above. Dissolution and flotation characteristics were also tested for the following preparations. For one or the other, i.e., the dissolution profile or the flotation characteristics, it was found that they were not satisfactory compared to the above examples, for tablets according to the following formulations:

TABLE 43

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TABLE 44

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TABLE 45

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TABLE 46

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TABLE 47

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TABLE 48

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TABLE 49

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TABLE 50

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TABLE 51

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TABLE 52

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TABLE 53

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TABLE 54

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Although the invention has been described with reference to specific examples, this has been for the purpose of illustration only. Numerous alternative embodiments will be apparent to those skilled in the art and are considered to be within the scope of the invention.

Claims (43)

1. A tablet preparation for once-daily oral administration in humans, for the controlled release of ciprofloxacin, characterized in that it contains a pharmaceutically effective amount of ciprofloxacin, from about 0.1% to about 8.0% of a viscous agent and/or gelling agent, about 5 .0% to about 15% of the gas-evolving agent, and about 3.0% to about 15% of the swelling agent, said percentages being expressed as w/w composition. 2. A tablet preparation for once-daily oral administration in humans, for the controlled release of ciprofloxacin, characterized in that it contains a pharmaceutically effective amount of ciprofloxacin, from about 0.2% to about 5.0% of a viscous agent and/or a gelling agent, about 5 .0% to about 15% of the gas-evolving agent, and about 5.0% to about 15% of the swelling agent, said percentages being expressed as a w/w composition. 3. Preparation according to claim 1 or 2, characterized in that the viscous agent is either a carbohydrate resin or cellulose ethers. 4. The preparation according to claim 3, characterized in that the carbohydrate resin is xanthan gum and the cellulose ether is hydroxypropyl methylcellulose (methocel). 5. Preparation according to claim 1 or 2, characterized in that the gelling agent is sodium alginate. 6. Preparation according to claim 1 or 2, characterized in that one or both of a viscous agent and a gelling agent are used. 7. Preparation according to claim 6, characterized in that the viscous agent is xanthan gum. 8. Preparation according to claim 3, characterized in that the component for developing gas is selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, and their mixtures. 9. The preparation according to claim 3, characterized in that the swelling agent is cross-linked polyvinylpyrrolidone. 10. A formulation for once-daily oral administration in humans, for the controlled release of ciprofloxacin, comprising a pharmaceutically effective amount of ciprofloxacin, from about 0.2% to about 0.5% sodium alginate, from about 0.5 to about 2.0 % xanthan gum, about 10.0% to about 25% sodium bicarbonate, and about 5.0% to about 20% cross-linked polyvinylpyrrolidone, said percentages are expressed as a mass/mass composition, while the mass ratio of sodium alginate to xanthan gum is between about 1:1 to about 1:10. 11. The preparation according to claim 10, characterized in that it contains 69.9% ciprofloxacin base, 0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium bicarbonate, 12.1% cross-linked polyvinylpyrrolidone, and other pharmaceutical aids if necessary. 12. The preparation according to claim 10, characterized in that it is in the form of a tablet. 13. A homogenous, single-layer, once-daily oral human tablet formulation for the controlled release of ciprofloxacin in the stomach or upper small intestine, characterized in that it contains a pharmaceutically effective amount of ciprofloxacin, about 0.2% to about 0.5 % sodium alginate, about 0.5 to about 2.0% xanthan gum, about 10.0% to about 25% sodium bicarbonate, and about 5.0% to about 20% cross-linked polyvinylpyrrolidone, said percentages being expressed as wt/ mass of the preparation, while the mass ratio of sodium alginate to xanthan gum is between about 1:1 and about 1:10. 14. The preparation according to claim 13, characterized in that it contains 69.9% ciprofloxacin base, 0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium bicarbonate, 12.1% cross-linked polyvinylpyrrolidone, and other pharmaceutical aids if necessary. 15. A preparation for once-daily oral administration in humans for the controlled release of ciprofloxacin in the stomach or upper small intestine, characterized in that it contains a pharmaceutically effective amount of ciprofloxacin, from about 0.2% to about 0.5% sodium alginate, about 0 .5 to about 2.0% xanthan gum, about 10.0% to about 25% sodium bicarbonate, and about 5.0% to about 20% cross-linked polyvinylpyrrolidone, said percentages being expressed as a w/w of the composition, wherein the mass a ratio of sodium alginate to xanthan gum between about 1:1 to about 1:10, said ingredients being present in said relative proportions in one layer. 16. The preparation according to claim 15, characterized in that it contains 69.9% ciprofloxacin base, 0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium bicarbonate, 12.1% cross-linked polyvinylpyrrolidone, and other pharmaceutical aids if necessary. 17. The preparation according to claim 15, characterized in that it is in the form of a tablet. 18. A preparation for once-daily oral administration in humans for the controlled release of ciprofloxacin in the stomach or upper small intestine, characterized in that it contains a pharmaceutically effective amount of ciprofloxacin, from about 0.2% to about 0.5% sodium alginate, about 0 .5 to about 2.0% xanthan gum, about 10.0% to about 25% sodium bicarbonate, and about 5.0% to about 20% cross-linked polyvinylpyrrolidone, said percentages being expressed as a w/w of the composition, wherein the mass the ratio of sodium alginate to xanthan gum is between about 1:1 to about 1:10. 19. The preparation according to claim 18, characterized in that it contains 69.9% ciprofloxacin base, 0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium bicarbonate, 12.1% cross-linked polyvinylpyrrolidone, and other pharmaceutical aids if necessary. 20. The preparation according to claim 18, characterized in that it is in the form of a tablet. 21. A sustained-release preparation containing 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, characterized in that it releases more than 50% of the drug within about 2-4 hours and releases more than 60% of the drug within about 4-8 hours. 23. Preparation according to claim 22, characterized in that it is suitable for a one-day profile. 24. The preparation according to claim 23, characterized in that it is in the form of a tablet or capsule. 25. The preparation according to claim 24, characterized in that it is in the form of a tablet coated with a pharmaceutically acceptable auxiliary agent. 26. Preparation for extended release containing 100-1000 mg of ciprofloxacin and pharmaceutically acceptable excipients, characterized in that the total mass of the dosage form is less than 2000 mg. 27. The composition according to claim 26, characterized in that the pharmaceutically acceptable excipients include a viscous and/or gelling agent, a gas-evolving component, and a swelling agent. 28. The composition according to claim 27, characterized in that it contains from about 0.1% to about 8.0% of a viscous and/or gelling agent, about 5.0% to about 15% of a gas-evolving agent, and about 3 .0% to about 15% swelling agent, the mentioned percentages are expressed as mass/mass of the preparation. 29. The composition according to claim 28, characterized in that it contains from about 0.2% to about 5.0% of a viscous agent and/or gelling agent, about 5.0% to about 15% of a gas-evolving agent, and about 5 .0% to about 15% swelling agent, the mentioned percentages are expressed as mass/mass of the preparation. 30. The preparation according to claim 29, characterized in that the viscous agent is xanthan gum or hydroxypropyl methylcellulose (methocel), and the gelling agent is sodium alginate. 31. Preparation according to claim 30, characterized in that both a viscous agent and sodium alginate are used. 32. The preparation according to claim 31, characterized in that the viscous agent is xanthan gum. 33. Preparation according to claim 28, characterized in that the means for developing gas is selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, and their mixtures. 34. The preparation according to claim 28, characterized in that the swelling agent is cross-linked polyvinylpyrrolidone. 35. Preparation according to claim 26, characterized in that it is suitable for a one-day profile. 36. The preparation according to claim 26, characterized in that it is in the form of a tablet or capsule. 37. The preparation according to claim 26, characterized in that it is in the form of a tablet coated with a pharmaceutically acceptable auxiliary agent. 38. A sustained-release solid dosage form, characterized in that, when administered orally in humans under postprandial conditions, it provides a mean peak serum/plasma concentration, an area under the serum/plasma concentration-time curve above the minimum inhibitory concentrations and a duration above the minimum inhibitory serum/plasma concentrations, not less than 70% compared to divided doses of an equivalent amount of the usual solid form of immediate release ciprofloxacin. 39. A solid dosage form according to claim 38, characterized in that, when administered orally in humans under postprandial conditions, it provides a serum/plasma drug concentration-time curve with an area under the curve, time zero to infinity, which ranges from about 3 .5 to about 30 µg-hours/ml. 40. The solid dosage form of claim 38, wherein when administered orally to humans under postprandial conditions, it provides a mean peak serum/plasma concentration ranging from about 0.5 to about 4 µg/ml. 41. A solid dosage form according to claim 38, characterized in that, when administered orally in humans under postprandial conditions, it provides a serum/plasma drug concentration-time curve with an area under the curve above the minimum inhibitory concentration of 0.1 µg/ml, which ranges from about 3 to about 26 µg-hours/ml. 42. A solid dosage form according to claim 38, characterized in that, when administered orally in humans under postprandial conditions, it provides a serum/plasma drug concentration-time curve with an area under the curve above the minimum inhibitory concentration of 0.25 µg/ml, which ranges from about 2 to about 22 µg-hours/ml. 43. A solid dosage form according to claim 38, characterized in that, when administered orally in humans under postprandial conditions, it provides a serum/plasma drug concentration-time curve with an area under the curve above the minimum inhibitory concentration of 0.5 µg/ml, which ranges from about 1 to about 18 µg-hours/ml.