MXPA02008568A - 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

SYSTEM. OF CONTROLLED SUPPLY ORALLY ADMINISTERED FOR ADMINISTRATION ONCE A DAY OF CIPROFLOXACIN DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition in the form of tablets or capsules that provides a combination of spatial and temporal control of drug delivery, specifically for drug ciprofloxacin, to a patient for effective therapeutic results. The pharmaceutical composition comprises ciprofloxacin, a gas generating component, a swelling agent, and at least one viscolizing agent and a gelling agent. The swelling agent belongs to a class of highly absorbent compounds commonly referred to as superintegrators. This class of compounds includes, for example, cross-linked polyvinylpyrrolidone and crosslinked sodium carboxymethylcellulose. The viscolizing agent is a highly viscous material that, when making contact with the gastric fluid traps the gas produced by the gas generating component. The viscolizing agent comprises, for example, a carbohydrate gum, for example, xanthan gum or a cellulose ether for example, hydroxypropylmethylcellulose (methocel). The gelling agent is preferably a crosslinkable 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 present invention is designed to deliver ciprofloxacin effectively to a patient for a specific period of time (temporal control) and from a particular portion of the patient's gastrointestinal tract (spatial control). The improved controlled drug delivery system prevents the discharge of doses and results in more therapeutic administration of ciprofloxacin to a person. It is well known to those skilled in the art that for foods that require multiple doses of a particular drug, the blood levels of a drug need to be maintained above its minimum effective level and below its minimum toxic level in order to obtain therapeutic effects. desired to avoid unwanted toxic effects, and to reduce side effects. When blood levels of a drug are in this range, the drug is removed from the body at a particular rate. A controlled drug delivery system is typically designed to deliver the drug at this particular rate; safe and effective blood levels are maintained for a period as long as the system continues to deliver the drug at this rate. Controlled drug delivery usually results in substantially constant blood levels of the Active ingredients when compared to uncontrolled fluctuations observed when multiple doses of conventional rapid release dosage forms are administered to a patient. Controlled drug delivery results in optimal therapy, and not only reduces the frequency of dosing, but also reduces the severity and frequency of side effects. The above basic concepts of controlled drug delivery are well known to those skilled in the art. Considerable efforts have been made in recent decades to develop novel and therapeutically effective pharmaceutically viable drug delivery systems. Attention has been focused particularly on orally administered controlled drug delivery systems due to the ease of administration by the oral route as well as the ease and economy of manufacture of oral dosage forms such as tablets and capsules. A number of different oral controlled drug delivery systems based on different release mechanisms have been developed. These oral controlled drug delivery systems are based on different modes of operation and have been variously named, for example, as systems controlled by dissolution, diffusion controlled systems, ion exchange resins, osmotically controlled systems, erodible matrix systems, independent pH formulations, controlled swelling systems, and the like. A controlled orally administered drug delivery system finds a wide range of highly variable conditions, such as pH, agitation intensity, and composition of gastrointestinal fluids as it passes into the gastrointestinal tract. Ideally, an orally controlled drug delivery system will deliver the drug at a constant and reproducible rate despite varying conditions. Considerable efforts have therefore been made to design oral controlled drug delivery systems that overcome these disadvantages and deliver the drug at a constant rate as it passes into the gastrointestinal tract. It is well known to those skilled in the art that a drug can not be absorbed uniformly throughout the gastrointestinal tract, and that the absorption of drugs from the colon is usually erratic and ineffective. Also, certain drugs are only absorbed from the stomach or upper parts of the small intestine. In addition, an important factor that can adversely affect the performance of an oral controlled drug delivery system is that the dosage form can be transported rapidly from the higher regions further. absorbents of the intestine to the lower regions where the drug is absorbed less well. Therefore, in cases where the drug is not uniformly absorbed over the gastrointestinal tract, the rate of drug absorption can not be constant despite the drug delivery system that delivers the drug at a constant rate in gastrointestinal fluids. More particularly, in cases where a drug has a well-defined "window of absorption," that is, the drug is absorbed only from the specific regions of the stomach or upper parts of the small intestine, it can not be completely absorbed when administered in the form of a typical oral controlled drug delivery system. It is apparent that for a drug that has an "absorption window", an effective oral controlled drug delivery system must be designed not only to deliver the drug at a controlled rate, but also to retain the drug in the upper parts of the gastrointestinal tract. for a long period of time. U.S. Patent No. 5,651,985, assigned to Bayer AG discloses a composition comprising a pharmacologically active compound, a pharmaceutically acceptable auxiliary, polyvinylpyrrolidone, and a methacrylic acid polymer having an acid number between 100 and 1200 mg KOH / g of the polymeric solid substance. Optionally, the The composition also comprises a gas-forming additive. The composition absorbs many times its weight of acidic water and forms a highly dilated gel of high mechanical and dimensional stability. The gel-forming agent should be sufficient so that after administration it can swell to a size that prevents passage through the pylorus for a relatively long time. At least 30% by weight and up to 90% by weight of the composition comprises the polymers, and thus the dosage forms containing a highly dosing medicament can be large and inconvenient for oral administration. Generally, in the field of controlled drug delivery systems, it is known that in order to make a particular drug available as a tablet or capsule once a day, it is necessary to experiment and invent with the particular drug together with the specific excipients. Thus, what particular excipients and in what particular relative amounts can work for a particular active ingredient or drug, makes it available on a once a day basis, will probably not work for another drug. Nishioka et al. (JP 06024959) is a Japanese patent application wherein an attempt is made to cause the release of ciprofloxacin for a longer period of time by causing the tablet containing ciprofloxacin remain suspended in the stomach. The release period obtained by the Nishioka tablet is so slow that only 46% of the Nishioka tablet dissolves after 24 hours (see scheme). The practical and significant effect of this slow dissolution is that the Nishioka formulation can not be effective as a "once a day" ciprofloxacin formulation. Accordingly, none of the oral controlled drug delivery systems described thereby is completely satisfactory for the purpose of providing a once-a-day formulation for the controlled release of ciprofloxacin. It is an object of the present invention to provide a pharmaceutical composition in the form of tablets or capsules which constitutes a once-a-day formulation for the controlled release of ciprofloxacin which: a. generate and trap a gas in a hydrated matrix upon contact with an aqueous medium or gastric fluids, and retain a substantially monolithic shape in the stomach, b. provide increased gastric residence and with this a longer period of residence of the drug delivery system in the gastrointestinal tract, c. administer the drug at a controlled rate so that the drug is delivered during a a period of time that is the same as or less than the residence period of the supply system in the absorbing regions of the intestinal tract, and d. provide, when compared with other oral controlled drug delivery systems, increased absorption of a drug that is widely absorbed 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 the controlled release of ciprofloxacin that maintains its physical integrity, i.e., remains intact or substantially gains a monolithic form when contacted with an aqueous medium, even when the number of drugs is large, and where the proportion of polymers is small compared to other components of the system. It is another object of the present invention to provide a once-a-day formulation for the controlled release of ciprofloxacin that incorporates a high dosing medicament without the loss of any of its desirable attributes, as listed above, so that the system It is of an acceptable size for oral administration. The present invention provides a novel pharmaceutical composition in the form of tablets or capsules whose composition constitutes a once a day formulation. orally administered for the controlled release of ciprofloxacin. The pharmaceutical composition comprises ciprofloxacin, a gas generating component, a swelling agent (e.g., cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethylcellulose), at least one of a viscolizing agent (e.g., a carbohydrate gum such as a gum). xanthan or a cellulose ether such as hydroxypropylmethylcellulose), and a gelling agent (e.g., sodium alginate). Preferably, the inventive oral 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 about 8% by weight of at least one of a viscolizing agent and a gelling agent, about 5% to about 15% by weight of the gas generating component, and about 3% to about 15% by weight of the swelling agent. More preferably, the amount of at least one of the viscolizing 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-a-day 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% of sodium bicarbonate, and about 5.0% to about 20% cross-linked polyvinylpyrrolidone, the percentages are w / w of the composition, where the weight ratio of sodium alginate to xanthan gum is between about 1: 1 to about 1:10 The swelling agents used herein (cross-linked polyvinylpyrrolidone or crosslinked sodium carboxymethylcellulose) belong to a class of compounds known as super-integrators that normally function to promote the disintegration of a tablet by absorbing large amounts of water and thereby swelling. This expansion, as well as the hydrostatic pressure, cause the tablet to explode. In a tablet that also comprises a gas generating component (which can presently be a gas generating coupling), one can expect the tablet to instantly disintegrate upon contact with the accusation fluid, if not to burst separately. Notably, it has been found that in the presence of a viscolizing agent acting Instantly and / or gelling agent, the generated gas is trapped and the superintegrator acts as a swelling agent that swells, preferably, at least twice its original volume. In this way, the combination of the gas generating component, the swelling agent which is currently a super-disintegrant, and the viscolizing agent or a gelling agent allow the formulation to act as a controlled drug delivery system. Additionally, with the passage of time, the gelling agent and / or The viscolyzing agent produces a cross-linked three-dimensional molecular network that results in a hydrodynamically balanced system that is retained in the stomach and releases the drug for a sustained period of time. Surprisingly, it has been found that a tablet 15 or capsule formed of the formulation of the present invention is retained for long periods of time in the stomach (spatial control) than the previously known hydrophilic matrix tablets, floating capsules and bioadhesive tablets when these systems are administered with 20 foods. The formulation of the present invention results in the release of the drug in the more absorptive regions of the gastrointestinal tract, ie, within the stomach and small intestine rather than in the large intestine where absorption of the drug is deficient or erratic. In this way, 25 one can expect that if the drug is released at a speed ^ u ^ gtti ^ constant and controlled, it will also be absorbed at a more or less constant speed. Even more surprisingly, it has been found that even for a drug that is only absorbed from the upper gastrointestinal tract (ie, from the stomach into the jejunum) such as ciprofloxacin, the present formulation provides the desired absorption at a rate such that the levels of effective plasma are maintained for a prolonged duration and the formulation is especially suitable for once-a-day administration (temporary control). In addition, the formulation provides increased absorption of the drug when compared to other oral controlled drug delivery systems such as hydrophilic matrix tablets and floating capsules. This is achieved by adjusting the release time period for the drug so that it is approximately the same as or less than the retention time of the tablets at the absorption site. In this way the tablet or capsule is not transported past the "absorption window" before releasing all the drug, and the maximum bioavailability is obtained. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph illustrating an average serum concentration against time for the ciprofloxacin drug-free base and ciprofloxacin HCl when incorporated into the drug delivery system orally controlled when compared to the currently marketed Cipro ™ immediate release tablets (Bayer Corp.). Figures 2 and 3 are graphs illustrating the average plasma concentration versus time for the ciprofloxacin-free base when incorporated into the oral controlled drug delivery system of the present invention when compared to the Cipro immediate release tablets. ™ under feeding and fasting conditions. According to the present inver-- > n, the formulation of the present invention includes cipro ioxacin, a swelling agent, and at least one of a viscolizing agent and a gelling agent. Together these components form a hydrated gel matrix. The formulation further comprises a gas generating component such that a gas (generally C02 but in some cases S02) is generated in a controlled manner and entrapped in the hydrated gel matrix. The swelling agent, which belongs to the class of compounds known as superintegrators, absorbs large amounts of fluid and causes the matrix to swell significantly. The gas generated by the gas generating component also causes the expansion of the matrix. However, in the present invention, the swelling of the matrix is controlled by the t ^ »- ^ u-.

Viscolyzing agent and / or the gelling agent, which acts as a swelling and a drug release control agent. The characteristics of the hydrated gel matrix can be modified by altering the ratios and amounts of the swelling agent, the viscolizing agent and / or the gelling agent, and the gas generating component without loss of physical integrity of the hydrated gel system. The composition in this way can be designated to obtain the optimum release rate of ciprofloxacin. It has also been found that such a composition when administered with food is retained for long periods in the stomach, and with this in the gastrointestinal tract without loss of physical integrity. The gas generated influences the drug supply of the tablets or capsules in ways that are currently not well understood. For example, factors that can influence drug delivery include: a. the presence of gas trapped within the matrix can affect the diffusion path length of the drug and thereby exert a release control effect; b. the presence of trapped gas within the matrix can affect the surface erosion rate of the hydrated gel matrix and thus exerts an effect of hydrodynamic and release control; c. the expansion pressure and the presence of gas affects the internal structure of the hydrated gel and thus exerts a hydrodynamic control and release effect; and d. the presence of trapped gas and its expansion pressure affects the influx of acidic gastric fluid through the pores of the matrix and thus exerts a release control effect. It should be understood that gas generated at low volume within the matrix can exert a high pressure. If it exceeds the capillary pressure due to the surface tension of the aqueous fluid, it will then cause the aqueous fluid in a pore to be pushed by the gas that allows the gas to extend until the pressure of the internal gas equals the capillary pressure. In this way, this phenomenon can affect the rate of hydration of the matrix and have a role in determining the rate of drug release. In systems that crosslink, they will also have an influence on the structuring of the developing gel. The various components of the novel formulation 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 provide a controlled rate of supply (ie, temporary control, specifically) of ciprofloxacin. The present invention is particularly suitable for the controlled rate of delivery of a drug such as ciprofloxacin which does not show uniform dissolution and absorption characteristics throughout the length of the gastrointestinal tract. The novel pharmaceutical composition is more suitable for the controlled delivery of drugs that are absorbed only from the upper parts of the gastrointestinal tract with a specific absorption window (i.e., spatial control), that is, ciprofloxacin (which is absorbed only from the region that extends from the stomach to the jejunum). The pharmaceutical composition is particularly suitable for ciprofloxacin since the absorption of the drug is dependent on its solubility characteristics. Ciprofloxacin dissolves at lower pH values and therefore the "absorption window" is predominantly in the stomach or upper parts of the small intestine. In the case of drugs such as ciprofloxacin, the tablet is not transported past the "absorption window" before releasing all the drug so that maximum bioavailability can be obtained. Ciprofloxacin itself or its pharmaceutically acceptable salt or ester can be used in the present invention. The amount of ciprofloxacin a used in the composition is that which is typically administered for a given period of time. According to the present invention, the pharmaceutical composition can incorporate a high dosage medicament. Accordingly, the amount of ciprofloxacin to be used in the present invention typically ranges from about 0.5 mg to about 1200 mg. GAS GENERATOR COMPONENT The gas generator component comprises a substance known to produce gas when making contact with gastric fluid. Examples of gas generating components that can be used in the present invention include carbonates, such as calcium carbonate, potassium carbonate or sodium carbonate, and bicarbonates such as sodium acid carbonate. The gas generating component interacts with an acidic source triggered by contact with water or simply with the gastric fluid to generate carbon dioxide that is trapped within the hydrated gel matrix of the swelling composition. The gas generating component such as carbonates and bicarbonates may be present in amounts of about 5% to about 15% by weight of the composition. These salts can be used alone or in combination with an acidic source as a coupling. The m-.J¿, A ^ - "_" _._. _. _. »__. _. . "___ Acidic source can be one or more of an edible organic acid, a salt of an edible organic acid, or mixtures thereof. Examples of organic acids that can be used as the acidic source in the present invention include, for example: citric acid or its salts such as sodium citrate or calcium citrate; malic acid, tartaric acid, succinic acid, fumaric acid, maleic acid or its salts; ascorbic acid or its salts such as sodium or calcium ascorbate; glycine, sarcosine, alanine, taurine, glutamic acid, and the like. The organic acid salts that can be used as the acidic source in the present invention include, for example, a monoalkali salt of an organic acid having more than one carboxylic acid functional group, a biálcali metal salt of an organic acid which it has more than two carboxylic acid functional groups, and the like. The acidic source can be present in an amount of from about 0.5% to 15% by weight, preferably from about 0.5% to about 10% by weight, and more preferably from about 0.5% to about 5% by weight, of the total weight of the composition. TUMPING AGENT In accordance with the present invention, the pharmaceutical composition comprises a swelling agent that is capable of swelling to more than its original volume when it comes in contact with an aqueous fluid, such as the fluid gastrointestinal. The preferred swelling agent is crosslinked polyvinylpyrrolidone; Other swelling agents include cross-linked sodium carboxymethyl cellulose and the like. These compounds belong to the class of compounds known as superintegrators. The swelling agent, which normally swells to several times its original volume in water, shows a controlled swelling in the presence of the viscolizing 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. VISCOLIZING AGEN AND GELANT AGENT According to the present invention, the pharmaceutical composition comprises a viscolizing agent which, upon contact with the gastrointestinal fluid, instantly viscolizes to trap the gas generated by the gas generating component. Preferably, the viscolizing agent comprises a carbohydrate gum, such as a xanthan gum. Other examples of carbohydrate gums include gum tragacanth, karaya gum, guar gum, acacia and the like. Cellulose ethers of moderate to high viscosity, such as hydroxypropylmethylcellulose, can also be be used. In the present invention, it has been found that xanthan gum helps maintain the integrity of the tablet when agitated in an aqueous medium, and to sustain the release of the drug. In accordance with the present invention, the pharmaceutical composition comprises either the viscolyzing agent or a gelling agent or both. The gelling agent preferably is sodium alginate. The gelling agent reticles with time to form a stable structure that traps the generated gas. Thus, with the passage of time, the gelling agent results in a hydrodynamically balanced system with which the matrix is retained in the stomach for a prolonged period of time. Simultaneously, the viscolizing agent and the gelling agent provide a tortuous diffusion path for the drug, thereby resulting in controlled drug release. Preferably, the viscolizing agent and / or the gelling agent are present in an amount of about 0.1% to about 8% by weight of the total weight of the composition. More preferably, the viscolizing agent and / or the gelling agent are present in an amount of about 0.2% to about 5% by weight of the total weight of the composition. The successful use of still low amounts of a viscolizing agent and / or gelling agent such as xanthan gum for Providing tablet integrity is truly surprising in view of the fact that the pharmaceutical composition of the present invention comprises a gas generating component and a swelling agent which is most often used as a disintegrator. Those skilled in the art can well recognize that both components can result in the rapid disintegration of tablets. Tablets containing hydroxypropylcellulose in amounts of approximately the same as the amounts of the carbohydrate gum in the present invention disintegrate in 10 to 15 minutes when agitated in an acidic medium. Disintegration can result in a dose-discharging effect, i.e., rapid release of a large amount of drug from the system, and is particularly undesirable since controlled drug delivery systems contain several times the amount of drug in a conventional formulation . The granules formed as a result of disintegration are also emptied of the stomach in a shorter time than the intact tablets. The present invention prevents disintegration with the use of small amounts of a viscolizing agent, such as a heteropolysaccharide gum, so that tablets or capsules containing a high dosage medicament are of an acceptable size to be taken orally. In preferred embodiments of the present invention, the viscolizing agent is xanthan gum. Xanthan gum, also known as corn sugar gum, is a high molecular weight biosynthetic polysaccharide gum (ca. 2 X10?) Produced by an aerobic fermentation of a pure carbohydrate culture with Xanthomonas campestris. It is enzymatically resistant in an extraordinary way. In preferred embodiments of the present invention, the xanthan gum has a particle size such that at least 50% by weight passes through a sieve with a mesh size of 44 μm (Sieve No. 325, ASTM). In more preferred embodiments, the xanthan gum has such a particle size that everything passes through a 44 μm mesh aperture (Sieve No. 325, ASTM). Preferably, the viscolizing agent is present in an amount of about 0.1% to about 8% by weight of the total weight of the composition. More preferably, the viscolizing agent is present in an amount from about 0.2% to about 5% by weight of the total weight of the composition. OTHER EXCIPIENTS 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, cellulose «Á a *, a * * powder and the like; or lubricants such as talc, stearic acid or its salt, magnesium stearate, and the like. PROCESS FOR PREPARATION In accordance with the present invention, the pharmaceutical composition is prepared by mixing the drug with the gas generating component, the swelling agent, and one or both of the viscolyzing agent and the gelling agent, plus other excipients and lubricants. The mixture is compressed directly into tablets or can be filled into capsules. Alternatively, the pharmaceutical composition is prepared by mixing the above ingredients with only half the lubricants. The mixture is compacted by roller and then passed through the screen to obtain granules. The granules are then mixed with the remaining lubricants, and filled into the capsules or compressed into tablets. The following table establishes the various particle size margins for the ciprofloxacin base (determined using a Malvern Master Sizer) using the 'examples described in the following: DISTRIBUTION OF SIZE OR PARTICLE - BASE OF CYPRUSION * This material is supplied as in the ordinary state. It was ground to obtain the desired size margin.

COATING In accordance with the present invention, when the pharmaceutical composition is in the form of tablets, it can be coated with a thin layer of a rapidly dissolving water-soluble pharmaceutical excipient. A coating of a water-soluble excipient results in faster hydration and gas formation than a water-soluble polymer coating and is the preferred coating. Examples of water soluble pharmaceutical excipients include film formers such as ether cellulose polymers, or 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 accumulation of about 1% to about 4%, preferably, about 1% to about 2%. The coating also helps to mask any bitter taste associated with the drug. The present invention is illustrated by, but not limited to, the following examples: EXAMPLE 1 This example illustrates the present invention when the active ingredient is ciprofloxacin hydrochloride. Ciprofloxacin is an example of a drug that is absorbed only from the upper part of the intestine. The pharmaceutical composition is given in Table 1. TABLE 1 Ciprofloxacin, xanthan gum, sodium alginate, crosslinked carboxymethylcellulose, sodium bicarbonate, microcrystalline cellulose, sodium chloride, citric acid and half of the lubricants were mixed together and passed through a sieve (British Standard Sieve (BSS) No. 44). The mixture was compacted in a roller compactor and the compact was passed through a screen (BSS No. 22) to obtain granules. The granules were mixed with the remaining lubricants and Carbopol and then compressed into tablets. The tablets were coated with an aqueous spray composition containing 15.8% w / w of lactose, 3.18% w / w of talc, and 1587% w / w of titanium dioxide at a weight accumulation of 1% to 1.5%. The tablets were tested for dissolution in 0.1 N HCl using the USP 1 Apparatus with a basket speed at 100 rpm. The results of the dissolution are given in Table 2. TABLE 2 EXAMPLE 2 This example illustrates the present invention when The active ingredient is ciprofloxacin base. The pharmaceutical composition is given in Table 3. TABLE 3 Ciprofloxacin was filtered through a British Standard Sieve (BSS) No. 22 filter. Xanthan gum, sodium alginate, sodium bicarbonate, crospovidone and half the amounts of lubricants, particularly magnesium stearate and talc, they were filtered through the sieve (BSS No. 44). All the aforementioned filtered ingredients were uniformly mixed, compacted in a roller compactor and the compacts were filtered through a sieve (BSS No. 18 to obtain granules. *. .: iSRs * 4.r of remaining magnesium and talc were filtered through the screen (BSS No. 60) and mixed with the above granules and a limited portion of fine granules (finer than BSS No. 60) and then compressed into tablets. The tablets were optionally spray coated with an aqueous coating composition containing 15.8% w / w of lactose, 3.18% w / w of talc, and 1587% w / w of titanium dioxide at a weight accumulation of 1% by weight. 1.5% The results of the dissolution are given in Table 4. TABLE 4 EXAMPLE 3 This example illustrates the present invention when the active Ingredient is ciprofloxacin hydrochloride. The pharmaceutical composition is given in Table 5. i-J-ÁJiM ,, ..,.

TABLE 5 The tablets were prepared as described in Example 1 except that Ac-Di-Sol was incorporated extragranularly. The tablets were tested for dissolution as described in Example 1. The results of the dissolution are given in Table 6. TABLE 6 EXAMPLE 4 Gastric Retention and Bioavailability Studies This example demonstrates that the tablets prepared according to the present invention are retained for prolonged periods in the stomach. The bioadhesive tablet was prepared as a double layer tablet. The drug layer composition is given in Table 7, and the bioadhesive layer composition is given in Table 8. TABLE 7 TABLE 8 The tablets were prepared by the conventional stages of mixing, roller compaction, sifting, mixing with the lubricants and compression into double layer tablets. 70 mg of barium sulfate was incorporated into the bioadhesive layer to function as an X-ray contrast medium. The gastric retention study of the bioadhesive double-layer tablets was done in healthy volunteers who were given two tablets after breakfast standard. X-ray images were recorded periodically. The bioadhesive tablets were retained in the stomach for 2.5 to 3.5 hours. The hydrophilic matrix tablets with the composition given in Table 9 were also prepared. tt iAAJ fc TABLE 9 70 mg of barium sulfate was also incorporated in the above composition. The tablets were prepared by conventional mixing steps, roller compaction, sifting, mixing with the lubricants and tablet compression. The floating capsules with the composition given in Table 10 were also prepared. TABLE 10 50 mg of barium sulfate was incorporated in the above composition. Gastric retention studies were done in healthy volunteers who were given two tablets / capsules after a standard breakfast. X-ray images were recorded periodically. The hydrophilic matrix tablets were retained for 2 to 2.5 hours, and the capsules floated for 3.5 to 4.5 hours. Gastric retention studies were also done in the ciprofloxacin base formulation of a similar composition as given in Example 2. The volunteers were given two tablets after a standard breakfast. Magnetic resonance imaging confirmed that the tablets according to the present invention were retained in the stomach for a period of 5 to 7 hours. In another experiment, a pilot bioavailability study of three-period crossover, three randomized treatments was conducted for formulation A (two 500 mg tablets of ciprofloxacin hydrochloride, for administration once a day, prepared in accordance with Example 1), formulation B (tablets of 1000 mg of free base of ciprofloxacin, for administration once a day, prepared according to Example 2), and reference formulation R (Cipro ™ (Bayer Corp.) Tablets of liberation immediate 500 mg given twice a day). The tablets were administered 30 minutes after a standard breakfast. The average serum concentration-time profile is given in Figure 1. Figure 1 is based on the following data listed in Table 11, below. TABLE 11 A: 500 mg X 2 Administered OD (Food FDA) B: 1000 mg Administered OD (Food FDA) C: 500 mg Administered bld (Food FDA) * For the formulation OD these sampling points were not included For both formulations once a day (A and B) provided an absorption degree comparable with the immediate release tablets (R). Thus, it can be inferred that the time period of drug release in the gastric fluid was adjusted so that it was approximately the same as or less than the retention time of the tablets at the absorption site. In addition, formulation B gave a time profile of serum concentration that would be desirable for a once a day formulation in which the peak serum concentration was comparable to that of the immediate release drug, and the effective serum concentrations of the drug. they were kept for periods Longer EXAMPLE 5 In some respects, formulation B of the previous Example did not provide as good results as the 500 mg tablets of Cipro ™ twice a day. For example, the Area Under the Curve above the Minimum Inhibitory Concentration (AUC above MIC) for formulation B was lower than that of conventional Cipro ™ tablets. A ciprofloxacin-free formulation of 1000 mg once daily improved was developed (the "OD" formulation), the composition of which is given in Table 12. In the OD formulation, the amount of gelling agent (alginate) sodium) is approximately half that of Formulation B (0.49% vs. 1.0%). TABLE 12 Me * The tablets were prepared from the components in Table 12 and tested for dissolution as previously described. Notably, it was observed that the dissolution profile in vi of the OD formulation (Table 13) was much faster than the release of formulation B. Thus, more than 80% of the drug in the OD tablets was released within of 4 hours when compared with 8 hours for formulation B. Compare Table 12 with Table 13. TABLE 13 The average stomach retention of the OD tablets was studied by magnetic resonance imaging and found to be 5.33 hours which correlated well with the six hour dissolution profile of these tablets. In order to compare the pharmacokinetic and pharmacodynamic parameters of this formulation once a day, a bioavailability study of balanced cross-over of Three randomized periods were conducted in twelve healthy adult human male individuals, between 18-45 years of age where the dose of 1000 mg of ciprofloxacin OD tablets was administered 30 minutes after a standard high-fat breakfast. Immediate-release Cipro ™ tablets were tested under feeding and fasting conditions. Under feeding conditions, two oral doses of 500 mg immediate release Cipro ™ tablets were provided. The first oral dose was given within 30 minutes of a high-fat breakfast and the second dose was provided 12 hours later after a high-fat meal (dinner). Under fasting conditions, two oral doses of 500 mg tablets of the Cipro ™ immediate release tablets were administered. The first oral dose was given after a night meal, 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 the Figures 2 and 3, wherein Figure 2 shows the plasma concentration over time of the OD (feeding) tablets against Cipro ™ (feeding), and Figure 3 shows the plasma concentration of the DO tablets (feeding). ) against Cipro ™ (fasting). Figures 2 and 3 are based on the following data listed in Table 14 and Table 15, respectively, below. TABLE 14 A: 500 mg Administered from b.l.d. (Food FDA) C: 1000 mg Administered OD (Food FDA) * For the formulation OD these sampling points they included TABLE 15 B: 500 mg In fasting from b.l.d. C: 1000 mg Administered OD (FDA Food) * For OD formulation these sampling points were included The OD formulation provided a desirable plasma concentration time profile for the once-a-day dosage form in which the peak plasma concentration (Cmax) was comparable to that of the immediate release drug indicating a similar rate of absorption of the drug The total bioavailability of the drug AUC (o-oo) (Area Under the Curve) was also comparable to that of the immediate release tablets indicating that all the drug is released from the formulation during its residence time in the stomach. See Table 16. TABLE 16 Table 17 provides the AUC above MIC at the three levels of 0.1 μg / ml, 0.25 μg / ml and 0.5 μg / ml for 1000 mg of ciprofloxacin OD against 500 mg of Cipro ™ of bid. These values for ciprofloxacin OD were better than those for Cipro ™ immediate release tablets administered twice daily under feeding conditions, indicating better therapeutic efficacy of the DO formulation when both immediate and controlled dosage forms were administered after feeding. The therapeutic efficacy of the DO tablets under feeding conditions were comparable with the therapeutic efficacy of the Cipro ™ immediate-release tablets administered under fasting conditions. Based on the above results seen in Figures 1, 2, and 3, it is anticipated that a sustained release solid dosage form of ciprofloxacin may have to provide pharmacokinetic performance when measured by the average serum concentration, area under the curve of Serum / plasma concentration-time above minimum inhibitory concentrations and durations above minimum inhibitory serum / plasma concentrations of at least 70% when compared to the immediate release divided dosing treatment. While the above results have been specifically identified for 1,000 mg tablets, it is anticipated that 100-1,000 mg ciprofloxacin tablets, orally administered to humans under feeding conditions, may provide a serum concentration / time curve of drug with an area under the curve (time zero to infinity), which varies from 3.5 to approximately 30 μg-hours / ml. Similarly, it is anticipated that 100 mg-1,000 mg tablets may provide an average peak serum / plasma concentration ranging from about 0.5 to about 4 μg / ml. In addition, it is anticipated that 100 mg-1,000 mg tablets may provide a serum-plasma concentration-time curve of medicament with an area under the curve (above a minimum inhibitory concentration of 0.1 μg / ml), which varies from about 3 to about 26 μg-hours / ml. It is also anticipated that 100 mg-1,000 mg tablets may provide a serum-plasma concentration-time curve of medicament with an area under the curve (above a minimum inhibitory concentration of 0.25 μg / ml), which varies from about 2 to about 22 μg-hours / ml. Finally, it is anticipated that 100 mg-1,000 mg tablets may provide a serum-plasma concentration-time curve of medicament with an area under the curve (above a minimum inhibitory concentration of 0.5 μm / ml), which varies from about 1 to about 18 μg-hours / ml. TABLE 17 AUC above MIC Treatment 0.1 μg / ml .h 0.25 μg / ml.h 0.5 μg / ml .h lOOOg Base 20.7 ± 4.4 17.4 ± 4.3 13.2 ± 4.1 Ciprofloxacin OD (Food) Thus, a minor change in the percentage of the hydrophilic polymer (sodium alginate) from 0.71% w / w of the composition to 0.34% w / w of the composition resulted in a dramatic and unexpected improvement in the 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 The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 19. TABLE 19 EXAMPLE 7 This example illustrates the present invention when the active Ingredient is ciprofloxacin base: TABLE 20 The tablets were prepared as described in tttáaJAAA ... .¿ > ^ a i Example 2. The tablets were tested for dissolution as described in Example 1. The results of the dissolution are given in Table 21. TABLE 21 EXAMPLE 8 This example illustrates the present invention when the active ingredient is ciprofloxacin base: TABLE 22 The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The results of the dissolution are given in Table 23. TABLE 23 EXAMPLE 9 This example illustrates the present invention when the active Ingredient is ciprofloxacin base: TABLE 24 The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The results of the solution are given in Table 25. TABLE 25 EXAMPLE 10 This example illustrates the present invention when the active Ingredient is ciprofloxacin base: TABLE 26 The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The results of the solution are given in Table 27. TABLE 27 EXAMPLE 11 This example illustrates the present invention when the active Ingredient is ciprofloxacin base: TABLE 28 The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The results of the dissolution are given in Table 29. TABLE 29 EXAMPLE 12 This example illustrates the present invention when the active Ingredient is ciprofloxacin base: TABLE 30 The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The results of the dissolution are given in Table 31. TABLE 31 EXAMPLE 13 This example illustrates the present invention when the active Ingredient is ciprofloxacin base: TABLE 32 ta_l? .___ b < Í__ifc ___ i .. » The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The results of the dissolution are given in Table 33. TABLE 33 EXAMPLE 14 This example illustrates the present invention when the active Ingredient is ciprofloxacin base: TABLE 34 The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The results of the dissolution are given in Table 35. TABLE 35 Table 36 below summarizes Examples 5-14 above with respect to its Ingredients and includes the dissolution profile of each formulation.

TABLE 36 EXAMPLE 15 This example illustrates the present invention when the active Ingredient is ciprofloxacin base: TABLE 37 The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The results of the dissolution are given in Table 38. TABLE 38 4. .Í ..? .i.rl¡. ¿¿¿*.

EXAMPLE 16 This example illustrates the present invention when the active Ingredient is ciprofloxacin base: TABLE 39 The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The results of the dissolution are given in Table 40. TABLE 40 j ^ mg & EXAMPLE 17 This example illustrates the present invention when the active ingredient is ciprofloxacin base: TABLE 41 The tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The results of the solution are given in Table 42. TABLE 42 j? á ~ *.,.? to i, 4L, t i.

Unlike the previous experiments, the following formulations were made into tablets as described above. The dissolution and floating characteristics were also made for the following formulations. One or the other, that is, the dissolution profile or the floating characteristics, were found to be satisfactory in comparison with the previous examples, for tablets according to the following formulations: TABLE 43 TABLE 44 ~ - «*. to . &L £ ito * jkx & * ^ TABLE 45 - "~ fi-" •• TABLE 46 tiiAAá -., TABLE 47 t .... t_a, á J ....

TABLE 48 TABLE 49 TABLE 50 I ^ k iiiiíÉ TABLE 51 TABLE 52 TABLE 53 TABLE 54 While the invention has been described by reference to the specific examples, this was for purposes 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 (1)

1. CLAIMS 1. A once-daily tablet formulation for oral administration in humans for controlled release of ciprofloxacin, characterized in that it comprises a pharmaceutically effective amount of ciprofloxacin, from about 0.1% to about 8.0% of a viscolizing 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, the percentages are w / w of the composition. 2. A once-a-day tablet formulation for oral administration in humans for the controlled release of ciprofloxacin, characterized in that it comprises a pharmaceutically effective amount of ciprofloxacin, from about 0.2% to about 5.0% of a viscolizing agent and / or a gelling agent, about 5.0% to about 15% of a gas generating agent, and about 5.0% to about 15% of a swelling agent, the percentages are w / w of the composition. 3. The formulation according to claim 1 or 2, characterized in that the viscolizing agent is either a carbohydrate gum or cellulose ethers. 4. The formulation according to claim 3, characterized in that the rubber of .. ~ «j.j ni.j The carbohydrate is xanthan gum and the cellulose ether is hydroxypropylmethylcellulose (methocel). 5. The formulation according to claim 1 or 2, characterized in that the gelling agent is sodium alginate. The formulation according to claim 1 or 2, characterized in that either or both of the viscolizing agent and the gelling agent are used. The formulation according to claim 6, characterized in that the viscolizing agent is xanthan gum. The formulation according to claim 3, characterized in that the gas generating agent is selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, and mixtures thereof. 9. The formulation according to claim 3, characterized in that the swelling agent is cross-linked polyvinylpyrrolidone. 10. A once-a-day formulation for oral administration in humans for the controlled release of ciprofloxacin, characterized in that it comprises a pharmaceutically effective amount of ciprofloxacin, about 0.2% to about 0.5% sodium alginate, about 0.5 to about 2.0% rubber xanthan, about 10.0% to about 25% sodium bicarbonate, and about 5.0% to about 20% crosslinked polyvinylpyrrolidone, the percentages are in w / w of the composition, wherein the weight ratio of sodium alginate to rubber Xanthan is between about 1: 1 to about 1:10. The formulation according to claim 10, characterized in that it comprises 69.9% of the ciprofloxacin base, 0.34% of sodium alginate, 1.03% of xanthan gum, 13.7% of sodium bicarbonate, 12.1% of crosslinked polyvinylpyrrolidone, and optionally other pharmaceutical excipients. 12. The formulation according to claim 10, characterized in that it is in the form of a tablet. 13. A once-daily homogenous single layer tablet formulation for oral administration in humans for the controlled release of ciprofloxacin in the stomach or upper part of the small intestine, characterized in that it comprises a pharmaceutically effective amount of ciprofloxacin, approximately 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% crosslinked polyvinylpyrrolidone, the percentages are w / w of the composition, wherein the weight ratio of sodium alginate to xanthan gum is between about 1: 1 to about 1:10. 1 . The formulation according to claim 13, characterized in that it comprises 69.9% of ciprofloxacin base, 0.34% of sodium alginate, 1.03% of xanthan gum, 13.7% of sodium bicarbonate, 12.1% of cross-linked polyvinylpyrrolidone, and optionally other pharmaceutical excipients. 15. A once-a-day tablet formulation for oral administration in humans for the controlled release of ciprofloxacin in the stomach or upper part of the small intestine, characterized in that it comprises a pharmaceutically effective amount of ciprofloxacin, from about 0.2% to about 0.5% of sodium alginate, about 0.5 to about 2.0% of xanthan gum, about 10.0% to about 25% of sodium bicarbonate, and about 5.0% to about 20% of crosslinked polyvinylpyrro] ± dona, the percentages are in p / p of the composition, wherein the weight ratio of sodium alginate to xanthan gum is between about 1: 1 to about 1:10, ingredients present in the relative proportions in a single layer. í.i._j_i .__._ l ¿«. .... 16. The formulation according to claim 15, characterized in that it comprises 69.9% of ciprofloxacin base, 0.34% of sodium alginate, 1.03% of xanthan gum, 13.7% of sodium bicarbonate, 12.1% of crosslinked polyvinylpyrrolidone, and optionally other excipients pharmacists 17. The formulation according to claim 15, characterized in that it is in the form of a tablet. 18. A once-daily tablet formulation for oral administration in humans for the controlled release of ciprofloxacin in the stomach or upper part of the small intestine, characterized in that it comprises a pharmaceutically effective amount of ciprofloxacin, from about 0.2% to about 0.5% of sodium alginate, about 0.5 to about 2.0% of xanthan gum, about 10.0% to about 25% of sodium bicarbonate, and about 5.0% to about 20% of crosslinked polyvinylpyrrolidone, the percentages are in w / w of the composition , wherein the weight ratio of sodium alginate to xanthan gum is between about 1: 1 to about 1:10. 19. The formulation according to claim 18, characterized in that it comprises 69.9% of ciprofloxacin base, 0.34% of sodium alginate, 1.03% of ,, lAltáÁi .4 .... 4 i .., aj ?? »'ti ?? ?? i i xanthan gum, 13.7% sodium bicarbonate, 12.1% cross-linked polyvinylpyrrolidone, and optionally other pharmaceutical excipients. 20. The formulation according to claim 18, characterized in that it is in the form of a tablet. 21. A sustained release formulation, characterized in that it comprises ciprofloxacin that 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 2-4 hours and releases more than 60% of the drug within about 4-8 hours. 23. The formulation according to claim 22, characterized in that it is suitable for a profile once a day. 2 . The formulation according to claim 23, characterized in that it is in the form of a tablet or a capsule. 25. The formulation according to claim 24, characterized in that it is in the form of a tablet that is coated with a pharmaceutically acceptable excipient. 26. A quick release formulation, characterized in that it comprises 100-1000 mg of ciprofloxacin and the pharmaceutically acceptable excipient, wherein the total weight of the dosage unit is less than 2000 mg. 27. The formulation according to claim 26, characterized in that the pharmaceutically acceptable excipients comprise a viscolizing agent and / or a gelling agent, a gas generating component, and a swelling agent. 28. The formulation according to claim 27, characterized in that it comprises from about 0.1% to about 8.0 or the 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, the percentages are in w / w of the composition. 29. The formulation according to claim 28, characterized in that it comprises about 0.2% to about 5.0% of the viscolizing agent and / or a gelling agent, about 5.0% a 20 about 15% of a gas generating agent, and about 5.0% to about 15% of a swelling agent, the percentages are w / w of the composition. 30. The formulation according to claim 29, characterized in that the agent 25 viscolizante or either a xanthan gum or g j ^ jjg ^ hydroxypropylmethylcellulose (methocel) and the gelling agent is sodium alginate. The formulation according to claim 30, characterized in that both the viscolizing agent and the sodium alginate are used. 32. The formulation according to claim 31, characterized in that the viscolizing agent is xanthan gum. 33. The formulation according to claim 28, characterized in that the gas generating agent is selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate and mixtures thereof. 34. The formulation according to claim 28, characterized in that the swelling agent is cross-linked polyvinylpyrrolidone. 35. The formulation according to claim 26, characterized in that it is suitable for a profile once a day. 36. The formulation according to claim 26, characterized in that it is in the form of a tablet or a capsule. 37. The formulation according to claim 26, characterized in that it is in the form of a tablet that is coated with an excipient pharmaceutically acceptable. 38. A sustained release solid dosage form of ciprofloxacin, characterized in that when administered orally in humans under feeding conditions, it provides average peak serum / plasma concentration, area under the serum / plasma concentration-time curve above the minimum inhibitory concentrations and durations above the minimum serum / plasma inhibitory concentrations, of not less than 70% when compared to the divided doses of equivalent amount of conventional immediate release ciprofloxacin solid dosage forms. 39. The sustained release solid dosage form according to claim 38, characterized in that when administered orally in humans under feeding conditions, it provides a serum-plasma concentration-time curve of medicament with an area under the curve, time zero to infinity, which varies from about 3.5 to about 30 μg-hours / ml. 40. The sustained release solid dosage form according to claim 38, characterized in that when administered orally in humans under feeding conditions, it provides an average peak serum / plasma concentration that varies from about 0.5 to about 4 μg / ml. 41. The sustained release solid dosage form according to claim 38, characterized in that when administered orally in humans under feeding conditions, it provides a serum-plasma concentration-time curve of medicament with an area under the curve above. of a minimum inhibitory concentration of 0.1 μg / ml, ranging from about 3 to about 26 μg-hours / ml. 42. The sustained release solid dosage form according to claim 38, characterized in that when administered orally in humans under feeding conditions, it provides a serum-plasma concentration-time curve of medicament with an area under the curve above. of a minimum inhibitory concentration of 0.25 μg / ml, ranging from about 2 to about 22 μg-hours / ml. 43. The sustained release solid dosage form according to claim 38, characterized in that when administered orally in humans under feeding conditions, it provides a serum-plasma concentration-time curve of medicament with an area under the curve above. of a minimum inhibitory concentration of 0.5 μg / ml, which varies from approximately about 18 μg-hours / ml.