OA12381A - Orally administered controlled delivery system foronce 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

012381

ORALLY ADMINISTERED CONTROLLED DELIVERYSYSTEM FOR ONCE DAILY ADMINISTRATION OF CIPROFLOXACIN

BACKGROUND OF THE INVENTION

The présent invention relates to a pharmaceutical composition in the formof tablets or capsules which provides a combination of spatial and temporalcontrol of drug delivery, specifically for the drug ciprofloxacin, to a patient foreffective therapeutic résulte. The pharmaceutical composition comprisesciprofloxacin, a gas generating component, a sweliing agent, and at least oneof either a viscolyzing agent and a gelling agent. The sweliing agent belongs toa class of highly absorbent compounds commonly referred to as superdisinte-grants. This class of compounds includes, for example, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose. The viscolyzingagent is a highly viscous material which upon contact with gastric fluid entrapsthe gas produced by the gas generating component. The viscolyzing agentcomprises, for example, a carbohydrate gum, e.g., xanthan gum or a celluloseether, e.g., hydroxypropyl methylceliulose (methocel). The gelling agent ispreferably a cross-linkable gelling agent, such as a water soluble sait of one ormore polyuronic acids, e.g., sodium alginate.

The improved controlled drug delivery System of the présent invention isdesigned to deliver effectively ciprofloxacin to a patient over a spécifie timeperiod (temporal control) and from a particular portion of the patientsgastrointestinal tract (spatial control). The improved controlled drug deliverySystem avoids dose dumping and résulte in the most therapeutic administrationof ciprofloxacin to a person. -1 - 012381

It is well known to those skilled in the art that for aiiments requiringmultiple doses of a particular drug, the blood levels of a drug need to bemaintained above its minimum effective level and below its minimum toxic levelin order to obtain the desired therapeutic effects, to avoid undesired toxic effects, 5 and to minimize side effects. When the blood levels of a drug are in this range,the drug is eliminated from the body at a particular rate. A controlled drugdelivery system is usually designed to deliver the drug at this particular rate; safeand effective blood levels are maintained for a period as long as the systemcontinues to deliver the drug at this rate. Controlled drug delivery usually résulte 10 in substantially constant blood levels of the active ingrédient as compared to theuncontrolled fluctuations observed when multiple doses of quick releasingconventional dosage forms are administered to a patient. Controlled drugdelivery results in optimum therapy, and not only reduces the frequency ofdosing, but may also reduce the severity and frequency of side effects. 15 The above basic concepts of controlled drug delivery are well known to those skilled in the art. Considérable efforts hâve been made in the last décadesto develop new pharmaceutically viable and therapeutically effective controlleddrug delivery Systems. Attention has been focused particularly on orallyadministered controlled drug delivery Systems because of the ease of 20 administration via the oral route as well as the ease and economy ofmanufacture of oral dosage forms such as tablets and capsules. A number ofdifferent oral controlled drug delivery Systems based on different releasemechanisms hâve been developed. These oral controlled drug delivery Systemsare based on different modes of operation and hâve been variously named, for -2- 01238 1 example, as dissolution controlled Systems, diffusion controlled Systems, ion-exchange resins, osmotically controlled Systems, erodible matrix Systems, pH-independent formulations, swelling controlled Systems, and the like.

An orally administered controlled drug delivery System encounters a wide 5 range of highly variable conditions, such as pH, agitation intensity, andcomposition of the gastrointestinal fluids as it passes down the gastrointestinaltract. Ideally, an oral controlled drug delivery System will deliver the drug at aconstant and reproducible rate in spite of the varying conditions. Considérableefforts hâve therefore been made to design oral controlled drug delivery Systems 10 that overcome these drawbacks and deliver the drug at a constant rate as itpasses down the gastrointestinal tract.

It is well known to those skilled in the art that a drug may not be absorbeduniformly over the length of the gastrointestinal tract, and that drug absorptionfrom the colon is usually erratic and inefficient. Also, certain drugs are absorbed 15 only from the stomach or the upper parts of the small intestine. Furthermore, animportant factor which may adversely affect the performance of an oralcontrolled drug delivery System is that the dosage form may be rapidlytransported from more absorptive upper régions of the intestine to lower régionswhere the drug is less well absorbed. Therefore, in instances where the drug is 20 not absorbed uniformly over the gastrointestinal tract, the rate of drug absorptionmay not be constant in spite of the drug delivery System delivering the drug ata constant rate into the gastrointestinal fluids. More particularly, in instanceswhere a drug has a clear eut "absorption window," i.e., the drug is absorbed onlyfrom spécifie régions of the stomach or upper parts of the small intestine, it may -3- 012381 not be completely absorbed when administered in the form of a typical oralcontrolled drug delivery System. It is apparent that for a drug having such an"absorption window," an effective oral controlled drug delivery System should bedesigned not only to deliver the drug at a controlled rate, but also to retain the 5 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 acomposition comprising · a pharmacologically active compound, apharmaceutically acceptable auxiliary, polyvinylpyrrolidone, and a methacrylicacid polymer having an acidic number between 100 and 1200 mg of KOH/g of 10 polymer solid substance. Optionally, the composition also comprises a gasforming additive. The composition absorbs many times its weight of acidic waterand forms a highly swollen gel of high mechanical and dimensional stability. Thegel forming agent should be suffirent so that after administration it can swell upto a size which prevents passage through the pylorous for a relatively long time.

I 15 At least 30% by weight and up to 90% by weight of the composition comprisesthe polymers, and thus dosage forms containing a high dose médicament wouldbe large and inconvénient for oral administration.

Generally, in the field of controlled drug delivery Systems, it is known thatin orderto make a particular drug available as a once-daily tablet or capsule, it 20 is necessary to experiment and invent with the particular drug together withspécifie excipients. Thus, what particular excipients and in what particularrelative amounts may work for a particular active ingrédient or drug, to make itavailable on a once-daily basis, will likely not work for another drug. -4- 012381

Nishioka et al. (JP 06024959) is a Japanese patent publication whereinan attempt is made to cause the release of ciprofloxacin over a longer period oftime by causing the tablet containing ciprofloxacin to remain suspended in thestomach. The release period obtained by the Nishioka tablet is so slow that only 5 46% of the Nishioka tablet is dissolved after 24 hours (see plot). The practical and significant effect of this slow dissolution is that the Nishioka formulationwould not be effective as a "once daily” ciprofloxacin formulation.

Accordingly, none of the oral controlled drug delivery Systems heretoforedescribed is completely satisfactory for the purpose of providing a once daily 10 formulation for the controlled release of ciprofloxacin.

OBJECTS OF THE PRESENT INVENTION

It is an object of the présent invention to provide a pharmaceuticalcomposition in the form of tablets or capsules which constitutes a once dailyformulation for the controlled release of ciprofloxacin that: 15 a. generates and entraps a gas in a hydrated matrix upon contact with an aqueous medium or gastric fluids, and which retains asubstantially monolithic form in the stomach, b. provides increased gastric résidence and thereby a longer periodof résidence of the drug delivery System in the gastrointestinal 20 tract, c. delivers the drug at a controlled rate such that the drug is deliveredover a period of time which is the same as or less than the period -5- 012381 of résidence of the delivery System in the absorptive régions of thegastrointestinai tract, and d. provides, as compared to other oral controlled drug deliverySystems, increased absorption of a drug that is absorbed largely 5 from the upper parts of the gastrointestinai tract.

It is also an object of the présent invention to provide a once dailyformulation for the controlled release of ciprofloxacin that maintains its physicalintegrity, i.e., remains intact or substantially gains a monolithic form whencontacted with an aqueous medium, even when the quantity of médicaments is 10 large, and wherein the proportion of polymers is small compared to othercomponents of the System. It is a further object of the présent invention toprovide a once daily formulation for the controlled release of ciprofloxacin thatincorporâtes a high dose médicament without the loss of any of its désirableattributes, as listed above, such that the System is of an acceptable size for oral 15 administration.

SUMMARY OF THE INVENTION

The présent invention provides a novel pharmaceutical composition in theform of tablets or capsules which composition constitutes an orally administeredonce daily formulation for the controlled release of ciprofloxacin. The pharma- 20 ceutical composition comprises ciprofloxacin, a gas generating component, aswelling agent (e.g., cross-linked polyvinylpyrrolidone or cross-linked sodiumcarboxymethylcellulose), at least one of either a viscolyzing agent (e.g., acarbohydrate gum such as xanthan gum or a cellulose ether such as hydroxy-propyl methylcellulose), and a gelling .agent (e.g., sodium alginate). -6- 012381

Preferably, the inventive oral controlled drug delivery System which is apharmaceutical composition in the form of tablets or capsules comprises apharmaceutically effective amount of ciprofloxacin, about 0.1% to about 8% byweight of at least one of a viscolyzing agent and a gelling agent, about 5% to 5 about 15% by weight of the gas generating component, and about 3% to about15% by weight of the swelling agent.

More preferably, the amount of at least one of the viscolyzing agent andthe gelling agent ranges from about 0.2% to about 5% and the amount of theswelling agent ranges from about 3% to about 15%. 10 Even more preferably, the présent invention is related to a once-daily tablet formulation for oral administration in humans for the controlled release ofciprofloxacin comprising a pharmaceutically effective amount of ciprofloxacin,about 0.2% to about 0.5% sodium alginate, about 0.5 to about 2.0% xanthangum, about 10.0% to about 25% sodium bicarbonate, and about 5.0% to about 15 20% cross-linked polyvinylpyrrolidone, said percentages being w/w of the composition, wherein 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 orcross-linked sodium carboxymethylcellulose) belong to a class of compounds 20 known as super-disintegrants which usually function to promote disintegrationof a tablet by absorbing large amounts of water and thereby swelling. Thisexpansion, as well as hydrostatic pressure, cause the tablet to burst. In a tabletwhich also comprises a gas generating component (which may actually be a gas -7- 012381 -'F. t. .. generating couple), one would expert the tablet to disintegrate instantly uponcontact with aqueous fluid, if not blow apart. Remarkably, it has been found thatin the presence of an instantly acting viscolyzing agent and/or a gelling agent,the generated gas is entrapped and the super-disintegrant acts as a swellingagent which swells to, preferably, at least twice its original volume. Thus, thecombination of the gas generating component, the swelling agent which isactually a super-disintegrant, and the viscolyzing agent or a gelling agent permitthe formulation to act as a controlled drug delivery System. Additionally, with thepassage of time, the gelling agent and/or the viscolyzing agent produces across-linked three-dimensional molecular network resulting in a hydrodynam-ically balanced System that is retained in the stomach and releases the drug overa sustained period of time.

Surprisingly, it has been found that a tablet or capsule formed from theformulation of the présent invention is retained for longer periods of time in thestomach (spatial control) than previously known hydrophilic matrix tablets,floating capsules and bioadhesive tablets when these Systems are administeredwith food. The formulation of the présent invention résulte in release of the druginto the more absorptive régions of the gastrointestinal tract, i.e., into thestomach and the small intestine rather than into the large intestine where drugabsorption is poor or erratic. Thus, one may expect that if the drug is releasedat a constant and controlled rate, it will also be absorbed at a more or less constant rate.

Even more surprisingly, it has been found that even for a drug that isabsorbed only from the upper gastrointestinal tract (i.e., from the stomach down -8- 012381 to the jéjunum), such as ciprofloxacin, the présent formulation provides thedesired absorption at a rate such that effective plasma leveis are maintained fora prolonged duration and the formulation is especially suitable for once-dailyadministration (temporal control). Moreover, the formulation provides increased 5 absorption of the drug as compared to other oral controlled drug deliverySystems such as hydrophilic matrix tablets and floating capsules. This isachieved by adjusting the tinte period of release for the drug so that it is aboutthe same as or less than the rétention time of the tablets at the site ofabsorption. Thus, the tablet or capsule is not transported past the "absorption 10 window" prior to releasing ail of the drug, and maximum bioavailability is attained.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graph illustrating mean sérum concentration vs. time for thedrug ciprofloxacin free base and ciprofloxacin HCl when incorporated in the oral 15 controlled drug delivery System as compared to the presently marketed Cipro™(Bayer Corp.) immédiate release tablets.

Figs. 2 and 3 are graphs illustrating mean plasma concentration vs. timefor ciprofloxacin free base when incorporated in the oral controlled drug deliverySystem of the présent invention as compared to Cipro™ immédiate release 20 tablets under fed and fasting conditions.

DETAILED DESCRIPTION OF THE INVENTION

According to the présent invention, the formulation of the présent inven-tion includes ciprofloxacin, a swelling agent, and at least one of either a -9- 012381 ,ι viscolyzing agent and a gelling agent. Together these components form ahydrated gel matrix. The formulation further comprises a gas generatingcomponent such that a gas (generally CO2 but in some cases SO2) is generatedin a controlled mannerand is entrapped in the hydrated gel matrix. The swelling 5 agent which belongs to the class ot compounds known as superdisintegrants,absorbs large amounts of fluid and causes the matrix to swell significantly. Thegas generated by the gas generating component also causes matrix expansion.However, in the présent invention, swelling of the matrix is controlled by theviscolyzing agent and/or the gelling agent, which acts both as a swelling and a 10 drug release controlling agent.

The characteristics of the hydrated gel matrix can be modified by alteringthe ratios and amounts of the swelling agent, the viscolyzing agent and/or thegelling agent, and the gas generating component without loss of physicalintegrity of the hydrated gel System. The composition can thus be designed to 15 obtain the optimal rate of release of the ciprofloxacin. It has also been foundthat such a composition when administered with food is retained for longerperiods in the stomach, and thereby in the gastrointestinal tract without loss ofits physical integrity.

The generated gas influences the drug delivery from the tablets or 20 capsules in ways that are currently not well understood. For example, factorsthat may influence drug delivery include: -10- «'23βι * ν*κ 1 10 a. the presence of entrapped gas within the matrix can affect thediffusion path length of the drug and thus exerts a release-controlling effect; b. the presence of entrapped gas within the matrix can affect the rateof surface érosion of the hydrated gel matrix and thus exerts botha hydrodynamic and a release controlling effect; c. the expanding pressure and the presence of the gas affects theinternai structure of the hydrated gel and thus exerts both ahydrodynamic and a release controlling effect; and, d. the presence of entrapped gas and its expanding pressure affectsthe influx of the acidic gastric fluid through the pores of the matrixand thus exerts a release-controlling effect.

It should be realized that gas generated in a small volume within thematrix can exert a high pressure. If this exceeds the capillary pressure due to 15 the surface tension of the aqueous fluid, then it will cause the aqueous fluid ina pore to be pushed by the gas allowing the gas to expand until the internai gaspressure equals the capillary pressure. This phenomenon thus would affect therate of hydration of the matrix and hâve a rôle in determining the rate of releaseof the drug. In Systems which cross-link, it will also hâve an influence on the 20 developing gel structurization.

The various components of the novel formulation will now be described in more detail. -11 - ·' 012381

DRUG

According to the présent invention, the pharmaceutical composition is inthe form of tablets or capsules that 'provide a controlled rate of delivery (z'.e.,temporal control, specifically) of ciprofloxacin. The présent invention is partic- 5 ularly suitable for controlled rate of delivery of a drug such as ciprofloxacin thatdoes not show uniform dissolution and absorption characteristics throughout thelength of the gastrointestinal tract.

The novel pharmaceutical composition is most suited for controlleddelivery of drugs that are absorbed only from the upper parts of the gastro- 10 intestinal tract with a spécifie absorption window (i.e., spatial control), Le.,ciprofloxacin (which is absorbed only from the région extending from thestomach to the jéjunum). The pharmaceutical composition is particulariy suitablefor ciprofloxacin because the absorption of the drug is dépendent on its solubilitycharacteristics. Ciprofloxacin dissolves at lower pH values and therefore the 15 “absorption window” is predominantly in the stomach or upper parts of the smallintestine. In the case of drugs such as ciprofloxacin, the tablet is not transportedpast the "absorption window" prior to releasing ail the drug so that maximumbioavailability can be attained.

Ciprofloxacin itself or its pharmaceuticaliy acceptable sait or ester may be 20 used in the présent invention. The amount of ciprofloxacin to be used in thecomposition is that which is typically administered for a given period of time.According to the présent invention, the pharmaceutical composition canincorporate a high dose médicament. Accordingly, the amount of ciprofloxacin -12- 01238 1 l : to be used in the présent invention typically ranges from about 0.5 mg up toabout 1200 mg.

GAS GENERATING COMPONENT

The gas generating component comprises a substance known to produce 5 gas upon contact with gastric fiuîd. Examples of the gas generating componentthat may be used in the présent invention include carbonates, such as calciumcarbonate, potassium carbonate or sodium carbonate, and bicarbonates suchas sodium hydrogen carbonate.

The gas generating component interacts with an acid source triggered by 10 contact with water or simply with gastric fluid to generate carbon dioxide thatgets entrapped within the hydrated gel matrix of the swelling composition. Thegas generating component such as carbonates and bicarbonates may beprésent in amounts 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 15 a couple. The acid source may be one or more of an edible organic acid, a saitof an edible organic acid, or mixtures thereof. Examples of organic acids thatmay be used as the acid source in the présent invention include, for example: t citric acid or its salts such as sodium citrate or calcium citrate; malic acid, ta rtaric acid, succinic acid, fumaric acid, maleic acid, or their salts; ascorbic acid or its 20 salts such as sodium or calcium ascorbate; glycine, sarcosine, alanine, taurine,glutamic acid, and the like. The organic acid salts that may be used as the acidsource in the présent invention include, for example, a mono-alkali sait of anorganic acid having more than one carboxylic acid functional group, a bialkali -13- 012381 métal sait of an organic acid having more than two carboxylic acid functionalgroups, and the like. The acid source may be présent in an amount from about0.5% to 15% by weight, preferably from about 0.5% to about 10% by weight, andmore preferably from about 0,5 % to about 5% by weight, of the total weight of 5 the composition.

SWELLING AGENT

According to the présent invention, the pharmaceutical compositioncomprises a swelling agent which is capable of swelling to greater than itsoriginal volume when coming into contact with an aqueous fluid, such a 10 gastrointestinal fluid. The preferred swelling agent is cross-linked polyvinyl-pyrrolidone; other swelling agents include cross-linked carboxymethylcellulosesodium and the iike. These compounds belong to the class of compoundsknown as super-disintegrants. The swelling agent, which normally swells toseveral times its original volume in water, exhibits a controlled swelling in the 15 presence of the viscolyzing and/or gelling agent. The swelling agent may beprésent in an amount from about 3% to about 15% by weight of the total weightof the composition. More preferably, the swelling agent may be présent in anamount from about 5% to about 15% by weight of the total weight of thecomposition.

20 VISCOLYZING AGENT AND GELLING AGENT

According to the présent invention, the pharmaceutical compositioncomprises a viscolyzing agent which, upon contact with gastrointestinal fluid,instantaneously viscolyzes to trap the gas generated by the gas generating -14- 012381 '/il· component. Preferably, the viscolyzing agent comprises of a carbohydrate gum,such as xanthan gum. Other examples of carbohydrate gums include tragacanthgum, gum karaya, guar gum, acacia, and the like. Cellulose ethers of moderateto high viscosity, like hydroxypropyl methylcellulose, can also be used. In the 5 présent invention, it has been found that xanthan gum helps in maintaining tabletintegrity when stirred in an aqueous medium, and in sustaining the release of thedrug. . —

According to the présent invention, the pharmaceutical compositioncomprises either said viscolyzing agent or a gelling agent or both. The gelling 10 agent is preferably sodium alginate. The gelling agent cross-links with time toform a stable structure which entraps the generated gas. Thus, with thepassage of time, the gelling agent results in a hydrodynamically balancedSystem whereby the matrix is retained in the stomach for an extended period oftime. Simultaneously, the viscolyzing agent and the gelling agent provide a 15 tortuous diffusion pathway for the drug, thereby resulting in controlled drug release.

Preferably, the viscolyzing agent and/or the gelling agent are présent inan amount from about 0.1% to about 8% by weight of the total weight of thecomposition. More preferably, the viscolyzing agent and/or the gelling agent are 20 présent in an amount from about 0.2% to about 5% by weight of the total weightof the composition.

The successful use of even low amounts of a viscolyzing agent and/orgelling agent such as xanthan gum in providing tablet integrity is indeed -15-

H 012381 surprising in view of the fact that the pharmaceuticai composition of the présentinvention comprises a gas generating component and a swelling agent which ismost frequently employed as a disintegrant. Those skilled in the art can wellrecognize that both components can resuit in rapid disintegration of tablets.Tablets containing hydroxypropylcellulose in amounts approximately the sameas the amounts of carbohydrate gum in the présent invention disintegrate in 10to 15 minutes when stirred in an acidic medium. Such disintegration can resuitin a dose dumping effect, i.e., rapid delivery of a large quantity of drug from theSystem, and is undesirable particularly because controlled drug delivery Systemscontain several times the amount of drug in a conventional formulation.Granules formed as a resuit of the disintegration are also emptied from thestomach in a shorter time than intact tablets. The présent invention avoids suchdisintegration with the use of small quantities of a viscolyzing agent, such as aheteropolysaccharide gum, so that tabiets or capsules containing a high dosemédicament are of an acceptable size to be taken orally.

In preferred embodiments of the présent invention, the viscolyzing agentis xanthan gum. Xanthan gum, also known as corn sugar gum, is a highmolecularweight (ca. 2 x 10θ) biosynthetic polysaccharide gum produced by apure-culture aérobic fermentation of a carbohydrate with Xanthomonascamoestris. It is extraordinarily enzymatically résistant.

In preferred embodiments of the présent invention, the xanthan gum hasa particle size such that at least 50% by weight passes through a sieve with 44μίτι mesh aperture (Sieve No. 325, ASTM). In more preferred embodiments, the -16- 01238 1 xanthan gum has a particle size such that ail of it passes through a 44 μΐη meshaperture (Sieve No. 325, ASTM).

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

OTHER EXCIPIENTS

The pharmaceutical composition may also contain other conventionalpharmaceutical excipients, for example, water soluble diiuents such as lactose, 10 dextrose, mannitol, sorbitol, and the iike; water insoluble diiuents such as starch,microcrystalline cellulose, powdered cellulose, and the like; or lubricants such astalc, stearic acid or its sait, magnésium stéarate, and the like.

PROCESS FOR PREPARATION

According to the présent invention, the pharmaceutical composition is 15 prepared by mixing the drug with the gas generating component, the swellingagent, and one or both of the viscolyzing agent and the gelling agent, plus otherexcipients and lubricants. The blend is directly compressed into tablets or maybe filled into capsules. Alternatively, the pharmaceutical composition is preparedby mixing the foregoing ingrédients with only one-half of the lubricants. The 20 mixture is roll compacted and then sieved to obtain granules. The granules arethen mixed with the remaining lubricants, and filled into capsules or compressed into tablets. -17-

V» V 01238 1

The following table sets forth the various particle size ranges for the cipro-floxacin base (determined using a Malvern Master Sizer) used in the examplesdescribed below: -18- 0 1238 1

P ARTICLE SIZE DISTRIBUTION - CIPROFLOXACIN BASE oo T" 3 E»- a. 05 « Ea. O T" ▼- oi E T- 3. « E Ό a. en V ” cο Ev a. CO «> Eco a. CO E a. E a. o o Ifi ci h- E a. E a. q o iri CM <0 cm _tn £ Tf a. CO <o Ev SL ui E a. o E a. o tri ci in E o a. H Ecm a. CO T“ «î Eo> a. « Ecm a. CM V O E 05 a. 2.24 pm * T" 22.38 pm ! CO T— g cri a. h No. Etn a. » CM les s 10 pm Batc 90% than C «L? « O r*ma:

This material was supplied as coarse. It was milled to obtain the desired size range. -19- 012381

COATING

According to the présent invention, when the pharmaceutical compositionis in the form of tablets, it may be coated with a thin layer of a rapidly dissolvingwater soluble pharmaceutical excipient. A coating of a water soluble excipientresults in faster hydration and gas formation than a coating of water solublepolymer and is the preferred coating.

Examples of water soluble pharmaceutical excipients include film formerslike cellulose ether polymers, or soluble pharmaceutical diluents like lactose,sucrose, dextrose, mannitol, xylitol, and the like. In a preferred embodiment ofthe présent invention, the water soluble excipient used as a coating is lactose.

The tablets may be coated to a weight build-up of about 1% to about 4%,preferably, about 1% to about 2%. The coating also helps in masking any bittertaste associated with the drug.

The présent invention is illustrated by, but is by no means limited to, thefollowing exemples: EXAMPLE 1

This example illustrâtes the présent invention when the active ingrédientis ciprofloxacin hydrochloride. Ciprofloxacin is an example of a drug which isabsorbed only from the upper part of the intestine. The pharmaceuticalcomposition is given in Table 1. -20- 012381 ?c · · TABLE 1

Ingrédient Weight (mg/tabfet) % w/w Ciprofloxacin hydrochloride monohydrate 598.47 55.16 Xanthan Gum (Keltrol TF) 20.00 1.84 Sodium alginate (Keltone LVCR) 15.00 1.38 Cross-iinked carboxymethylcellulose (Ac-Di-Sol) 110.00 10.14 Sodium bicarbonate 230.00 21.20 Microcrystalline cellulose (Avicel PH 101) 16.53 1.52 Sodium Chloride 25.0 2.30 Citric Acid 20.0 1.84 Cross-iinked polyacrylic acid (Carbopol 971 P) 10.0 0.93 Talc 10.00 0.93 Magnésium Stéarate 20.00 1.84 Aerosil 10.00 0.93 Total 1085.00 100%

Ciprofloxacin, xanthan gum, sodium alginate, cross-iinked carboxymethyl- 5 cellulose, sodium bicarbonate, microcrystalline cellulose, sodium chloride, citricacid, and half of the lubricants were mixed together and sieved through a sieve(British Standard Sieve (BSS) No. 44). The blend was compacted on a roll-compactor and the compact sieved through a sieve (BSS No. 22) to obtaingranules. The granules were mixed with the remaining lubricants and Carbopol 10 and then compressed into tablets. The tablets were spray coated with anaqueous coating composition containing 15.8% w/w lactose, 3.18% w/w taie, and1.587% w/w titanium dioxide to a weight build up of 1% to 1.5%.

The tablets were tested for dissolution in 0.1 N HCl using USP Apparatus1 with basket speed at 100 rpm. The dissolution results are given in Table 2. -21 - ••f · 012381 TABLE 2

Time (hrs) Cumulative Percent Release 1 21.16 2 33.22 4 58.72 6 74.6 8 85.83 10 93.58 EXAMPLE 2 5

This example illustrâtes the présent invention when the active ingrédientis ciprofloxacin base. The pharmaceutical composition is given in Table 3. TABLE 3

Ingrédient Weight (mg/tablet) % w/w oftablet % w/wof drug Ciprofloxacin base 1000.00 71.43 100.0 Xanthan Gum (Keltrol TF) 15.00 1.07 1.5 Sodium alginate (Keltone LVCR) 10.00 0.71 1.0 Cross-lin ked polyvinylpyrroiidone(Kollidon CL-M) 150.00 10.71 15.0 Sodium bicarbonate 200.00 14.28 20.0 Magnésium Stéarate 15.00 1.07 1.5 Talc 10.00 0.71 10.0 Total 1400.00 100 10

Ciprofloxacin was sifted through British Standard Sieve (BSS) No. 22.Xanthan gum, sodium alginate, sodium bicarbonate, crospovidone and half thequantities of lubricants, namely, magnésium stéarate and talc, were siftedthrough a sieve (BSS No. 44). Ail the above mentioned sifted ingrédients were 15 blended uniformly, compacted on a roil-compactor and the compacts sifted -22- 012381 through a sieve (BSS No. 18) to obtain granules. Remaining magnésiumstéarate and talc were sifted through a sieve (BSS No. 60) and blended withabove granules and limited proportion of granule fines (finer than BSS No. 60)and then compressed into tablets. The tablets were optionally spray coated with 5 an aqueous coating composition containing 15.8% w/w lactose, 3.18% w/w talcand 1.587% w/w titanium dioxide to a weight build up of 1 % to 1.5%.

The dissolution résulte are given in Table 4. TABLE 4

Time (hrs) Cumulative Percent Release 1 24.9 2 37.8 4 60.5 6 80.6 8 85.4 10 98.8 EXAMPLE 3

This example illustrâtes the présent invention when the active ingrédientis dprofloxacin hydrochioride. The pharmaceutical composition is given in Table5. -23- 01238 1 TABLE 5

Ingrédient Welght (mg/tablet) % w/w Ciprofloxacin hydrochloride monohydrate 600.00 61.54 Xanthan Gum (Keltrol TF) 10.00 1.02 Sodium alginate (Keltone LVCR) 25.00 2.57 Cross-linked carboxymethylcellulose (Ac-Di-Sol) 60.00 6.16 Sodium bicarbonate 250.00 25.64 Microcrystalline cellulose (Avicel PH 101) 15.00 1.54 Talc 5.00 0.52 Magnésium Stéarate 10.00 1.02 Total 975.00 100%

The tablets were prepared as described in Example 1 except that Ac-Di-Sol was incorporated extragranuiarly. Tablets were tested for dissolution as 5 described in Example 1. The dissolution results are given in Table 6. TABLE 6

Time (hrs) Cumulative Percent Release 1 28.16 2 38.32 4 52.37 6 64.03 8 74.23 10 82.80 EXAMPLE 4 10 Gastric Rétention and Bioavailability Studies

This example demonstrates that tablets prepared according to the présent invention are retained for extended periods in the stomach. -24- 012381

The bioadhesive tablet was prepared as a bilayertablet. The drug layercomposition is given in Table 7, and the bioadhesive layer composition is given in Table 8. TABLE 7

Ingrédient Weight (mg/tablet) Ciprofloxacin hydrochloride monohydrate 599.99 Hydroxypropylcellulose-L 20.00 Disodium hydrogen phosphate 25.00 Citric Acid 25.00 Talc 7.00 Magnésium Stéarate 15.00 Aerosil 200 10.00 Total 701.99 TABLE 8

Ingrédient Weight (mg/tablet) Hydroxypropyl methylcellulose (Methocel K4M) 215.00 Cross-linked polyacrylic acid (Carbopol 934 P) 75.00 Dicalcium phosphate 145.00 Sodium benzoate 8.00 Talc 2.00 Aerosil-200 2.50 Sunset Yellow 2.50 Total 450.00

The tablets were prepared by conventional steps of mixing, roîl conipac-tion, sieving, blending with the lubricants and compression into bi-layered 10 tablets. 70 mg of barium sulphate was incorporated into the bioadhesive layerto function as x-ray contrast medium. Gastric rétention studies of the bio-adhesive bi-layered tablets were done on healthy male volunteers who were -25- 01238 1 given two tablets following a standard breakfast. X-ray images were recordedperiodically. The bioadhesive tablets were retained in the stomach for 2.5 to 3.5 hrs.

Hydrophilic matrix tablets with the composition given in Table 9 were also5 prepared. TABLE 9

Ingrédient Weight (mg/tablet) Ciprofloxacin hydrochloride monohydrate 599.99 Hydroxypropyl methylcellulose (Methocel K4M) 20.00 Hydroxypropylcellulose-L 40.00 Citric Acid 25.00 Disodium hydrogen phosphate 25.00 Talc 10.00 Magnésium Stéarate 10.00 Total 729.99 70mg of barium sulfate was also incorporated into the above composition.10 The tablets were prepared by conventional steps of mixing, roll compaction, sieving, blending with the lubricants and compression into tablets.

Floating capsules with the composition given in Table 10 were alsoprepared. -26- 012381 TABLE 10

Ingrédient Weight (mg/capsule) Ciprofloxacin hydrochloride monohydrate 599.99 Hydroxypropyl methylcellulose(Methocel K4M) 30.00 Hydroxypropylcellulose-L 30.00 Citric Acid 5.00 Disodium hydrogen phosphate 5.00 Talc 4.00 Magnésium Stéarate 6.00 Total 679.99 50 mg of barium suiphate was incorporated into the above composition. 5 Gastric rétention studies were done on healthy male volunteers who were giventwo tablets/capsules after a standard breakfast. X-ray images were recordedperiodically. The hydrophilic matrix tablets were retained for 2 to 2.5 hrs, and the floating capsules for 3.5 to 4.5 hrs.

Gastric rétention studies were also done on the ciprofloxacin base10 formulation of a similar composition as given in Example 2. The volunteers weregiven two tablets after a standard breakfast. Magnetic résonance imagingconfirmed that the tablets according to the présent invention were retained in the stomach for a period of 5 to 7 hrs.

In another experiment, a randomized, three-treatment, three period,15 cross-over pilot bioavailability study was conducted for formulation A (twociprofloxacin hydrochloride 500 mg tablets, for once-daily administration,prepared according to Example 1), formulation B (ciprofloxacin free base 1000 -27 - 01238 1 r/c mg tablets, foronce-daily administration, prepared according to Example 2), andreference formulation R (Cipro™ (Bayer Corp.) 500 mg immédiate release tabletsgiven twice daily). The tablets were administered 30 minutes after a standardbreakfast. The mean sérum concentration-time profile is given in Figure 1. 5 Figure 1 is based on the following data listed in Table 11, below. TABLE 11

Time (Hr) Mean Concentrations (mcg/mL) A B R 0 0.0000 0.0000 0.0000 0.5 * * 0.30000 1 0.0489 0.3720 1.8379 1.5 * ★ 2.0779 2 0.1557 0.9940 1.8546 2.5 ★ ★ 1.6348 3 1.1806- 1.5004 1.3731 4 2.7070 2.1164 1.0868 5 2.8478 1.8898 0.7638 6 1.7944 1.3594 0.5404 8 1.2467 0.9494 0.3579 10 0.9367 0.7855 0.2323 12 0.6503 0.8714 0.1687 12.5 * « 0.1594 13 * ♦ 0.3916 13.5 * h 0.8982 14 0.4171 0.6831 1.0993 14.5 * ♦ 1.1432 15 ★ * 1.3889 16 0.2753 0.4826 1.1187 17 ★ * 0.9377 18 0.1901 0.3812 0.7633 20 * « 0.4864 22 ★ ★ 0.3766 24 0.1039 0.1778 0.2825 A: 500 mg X 2 OD Fed (FDA Meal)B: 1000 mg OD, Fed (FDA Meal) R: 500 mg b.l.d. Fed (FDA Meal) 10 *For OD formulation these sampling points were not included

Both the once-daily formulations (A and B) gave an extent of absorptioncomparable to the immédiate release tablets (R). Thus, it can be inferred that -28- 012381 the time period of release of drug into gastric fluid was adjusted such that it was about the same as or less than the rétention time of the tablets at the site of absorption. Furthermore, formulation B gave a sérum concentration time profilethat would be désirable for a once-daily formulation in that the peak sérum 5 concentration was comparable to that for the immédiate release drug, and theeffective sérum concentrations of the drug were maintained for longer periods. EXAMPLE 5

In some respects, formulation B of the prior Exampie did not give as goodresults as the twice-daily Cipro™ 500 mg tablets. For example, the Area Under 10 the Curve above the Minimum Inhibitory Concentration (AUC above MIC) forformulation B was less than that of conventional Cipro™ tablets.

An improved once-daily 1,000 mg ciprofloxacin free base formulation (the“OD" formulation) was deveioped, the composition of which is given in Table 12.In the OD formulation, the amount of gelling agent (sodium alginate) is about 15 one-half that of formulation B (0.49% vs. 1.0%). TABLE 12

Ingrédients Weight (mg/tablet) % w/w of thedrug Ciprofloxacin base 1000.0 69.9 Sodium alginate 5.0 0.34 Xanthan gum 15.0 1.03 Sodium bicarbonate 200.0 13.74 Cross-Linked polyvinyl pyrrolidone(Kollidon CL-M) 176.8 12.15 Magnésium stéarate 33.0 2.26 Talc 10.0 0.68 Total 1440 100 -29- 012381

PC

Tablets were prepared from the components in Table 12 and tested fordissolution as described earlier. Remarkably, it was observed that the in vitrodissolution profile of the OD formulation (Table 13) was much faster releasingthan formulation B. Thus, more than 80% of the drug in the OD tablets wasreleased within 4 hours as compared to 8 hours for formulation B. Compare

Table 12 with Table 13. TABLE 13

Time (hrs.) Cumulative percent Release 1 35.49 2 53.61 4 82.33 6 98.72

The mean stomach rétention of the OD tablets was studied by magneticrésonance imaging and was found to be 5.33 hours which correlated well withthe 6 hour dissolution profile of these tablets.

In order to compare the pharmacokinetic and pharmacodynamie para-meters of this once daily formulation, a randomized, three period, balancedcrossover bioavailability study was conducted in 12 healthy, adult male humansubjects, between 18-45 years of âge where one dose of ciprofloxacin 1000 mgOD tablets was administered 30 minutes after a standard high fat breakfast. Theimmédiate release Cipro™ tablets were tested under both fed and fastedconditions. -30-

I ?< 0J238 1

Under fed conditions, two oral doses of 500 mg immédiate releaseCipro™ tablets were given. The first oral dose was given within 30 minutes ofa high fat breakfast and the second dose was given 12 hours later after a highfat meal (dinner). 5 Under fasted conditions, two oral doses of 500 mg tablets of the Cipro™ immédiate release tablets were administered. The first oral dose was given afteran overnight fast, and the second oral dose was given 12 hours later but fourhours after a light meal.

The results of the study are shown in Figs. 2 and 3, where Fig. 2 shows 10 the plasma concentration over time of the OD tablets (fed) vs. Cipro™ (fed), andFig. 3 shows the plasma concentration of the OD tablets (fed) vs. Cipro™(fasted). Figures 2 and 3 are based on the following data iisted in Table 14 andTable 15, respectively, below. -31 - 012381

PC TABLE 14

Mean Concentrations (mcg/mL) Time (Hr) A C 0 0.0000 0.0000 0.5 0.2190 4 1 1.0964 0.3430 1.5 1.9702 « 2 2.0397 0.9751 2.5 1.8232 « 3 1.5617 1.6335 4 1.2265 2.6216 5 1.0123 2.9162 6 0.7777 2.0336 8 0.5291 1.4256 10 0.3527 1.3841 12 0.2608 0.9790 12.5 0.3159 * 13 0.4176 « 13.5 0.8401 ♦ 14 1.9238 0.5942 14.5 1.8384 4 15 1.6543 4 15 1.2336 0.4393 17 0.9689 4 18 0.8258 0.3357 20 0.5962 4 22 0.4366 * 24 | 0.3653 0.1843 A: 500 mg b.l.d. Fed (FDA Meal) C: 1000 mgOD Fed (FDA Meal) *For OD formulation these sampling points were not included -32- 012381 TABLE 15

Time (Hr) Mean Concentrations (mcg/mL) B C 0 0.0000 0.0000 0.5 1.3580 * 1 2.4747 0.3430 1.5 2.7413 2 2.3684 0.9751 2.5 2.0204 * 3 1.5997 1.6335 4 1.1985 2.6216 5 0.9429 2.9162 6 0.7298 2.0336 8 0.5172 1.4256 10 0.3575 1.3841 12 0.2709 0.9790 12.5 0.9855 ★ 13 2.5113 ★ 13.5 2.7718 * 14 2.4376 0.5942 14.5 1.9856 ★ 15 1.7173 * 16 1.1702 0.4393 17 0.8631 * 18 0.7360 0.3357 20 0.5095 * 22 0.4207 * 24 0.3431 0.1843 B: 500 mg b.l.d. Fasting C: 1000 mg OD Fed (FDA Meal) *For OD formulation these sampling points were not included

The OD formulation gave a plasma concentration time profile désirablefor once daily dosage form in that the peak plasma concentration (Cmax) wascomparable to that for the immédiate release drug indicating a similar rate ofabsorption of the drug. The total bioavailability of the drug AUC(!M (Area Under 10 the Curve) was also comparable to that of immédiate release tablets indicatingthat ail of the drug is released from the formulation during its résidence time in the stomach. See Table 16. -33- 012381 TABLE 16

Study Cmax (pg/ml) AUC M(pg.h/ml) Ciprofloxacin 1000 mg. OD (Fed) 3.04 24.81 Cipro™ 500 mg Bid (Fasted) 3.17 26.28 Cipro™ 500 Mg Bid (Fed) 2.66 22.39

Table 17 gives the AUC above MIC at the three levels of 0.1 pg/ml, 0.25

5 pg/ml and 0.5 pg/ml for ciprofloxacin OD 1000 mg vs. Cipro™ 500 mg bid.These values for ciprofloxacin OD were betterthan those for Cipro™ immédiaterelease tablets administered twice daily underfed conditions, indicating bettertherapeutic efficacy of the OD formulation when both immédiate and controlleddosage forms were administered after food. The therapeutic efficacy of the OD 10 tablets under fed condition was comparable to the therapeutic efficacy of theCipro™ immédiate release tablets administered under fasting conditions.

Based on the above results seen in Figures 1,2, and 3, it is anticipatedthat a sustained release solid dosage form of ciprofloxacin would hâve to providepharmacokinetic performance as measured by mean sérum concentration, area 15 under the serum/plasma concentration-time curve above minimum inhibitoryconcentrations and durations above minimum inhibitory serum/plasmaconcentrations of at ieast 70% as compared to immédiate release divided dosetreatment. While the above results hâve been specifically identified for 1,000 mgtablets, it is anticipated that 100-1,000 mg tablets of ciprofloxacin, orally 20 administered to humans under fed conditions, would provide a médicament -34- 012381 serum/plasma concentration - time curve with an area under the curve (time zéro to infinity), ranging from 3.5 to about 30 pg-hours/ml. Similarly, it is anticipated that the 100 mg-1,000 mg tablets would provide a mean peak serum/plasma concentration ranging from about 0.5 to about 4 pg/ml. Further, it is anticipated that the 100 mg-1,000 mg tablets would provide a médicament serum/plasma concentration - time curve with an area under the curve (above« a minimum inhibitory concentration of 0.1 pg/ml), ranging from about 3 to about26 pg-hours/ml. It is also anticipated that the 100 mg-1,000 mg tablets wouldprovide a médicament serum/plasma concentration - time curve with an areaunder the curve (above a minimum inhibitory concentration of 0.25 pg/ml),ranging from about 2 to about 22 pg-hours/ml. Finally, it is anticipated that they100 mg-1,000 mg tablets would provide a médicament serum/plasma concentra-tion - time curve with an area under the curve (above a minimum inhibitoryconcentration of 0.5 pm/ml), ranging from about 1 to about 18 pg-hours/ml.

TABLE 17AUC above MIC

Treatment 0.1 pg/mi.h 0.25 pg/mi.h 0.5 pg/mi.h Ciprofloxacin base 1000 mg, OD (Fed) 20.7 ± 4.4 17.4 ±4.3 13.2 ±4.1 Cipro™ 2 x 500 mg bid (Fasted) 21.5 ±3.7 18.0 + 3.8 13.4 ± 4.0 Cipro™ 2 x 500 mg bid (Fed) 17.68 + 3.9 14.2 ±3.9 9.7 ± 3.4

Thus, a minor change in the percentage of hydrophilic poiymer (sodiumalginate) from 0.71% w/w of the composition to 0.34% w/w of the compositionresulted in a dramatic and unexpected improvement in the pharmacodynamie -35- 012381 and pharmacokinetic parameters, which are important measures of therapeuticefficacy. EXAMPLE 6

This example illustrâtes tbe présent invention when the active ingrédient5 is ciprofloxacin base: TABLE 18

Ingrédient Weight (mg/tablet) % w/w Ciprofloxacin 1012.10 68.53 Xanthan Gum 45.0 3.05 Sodium Bicarbonate 200 13.54 Crospovidone 176.82 11.97 Magnésium Stéarate 33 2.23 Talc 10 0.68 Total 1476.92 100

The tablets were prepared as described in Example 2. The tabiets were tested for dissolution as described in Example 1. The dissolution results are10 given in Table 19. TABLE 19

Time (hrs) Cumulative Percent Release 1 34 2 51.4 4 69.0 6 94.8 8 100.5 EXAMPLE 7

This example illustrâtes the présent invention when the active ingrédient15 is ciprofloxacin base: -36- 01238 1 TABLE 20

Ingrédient Weight (mg/tablet) % w/w Ciprofloxacin 1012.10 69.47 Sodium Alginate 25 1.72 Sodium Bicarbonate 200 13.73 Crospovidone 176.82 12.14 Magnésium Stéarate 33 2.27 Talc 10 0.69 Total 1456.92 100.02

The tablets were prepared as described in Exampîe 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are5 given in Table 21. TABLE 21

Time (hrs.) Cumulative Percent Release 1 34.6 2 52 3 68.4 4 79.5 6 92.4 8 95.7 -37- Ü 1 238 1 EXAMPLE 8

This example illustrâtes the présent invention when the active ingrédientis ciprofloxacin base: TABLE 22

Ingrédient Weight (mg/tablet) % w/w Ciprofloxacin 1012.10 69 Sodium Alginate 5.0 0.34 Sodium Bicarbonate 200 13.63 Crospovidone 176.82 • 12.05 Magnésium Stéarate 33 2.25 Talc 10 0.68 Methocel K15M 30 2.04 Total 1466.92 99.99

The tablets were prepared as described in Example 2. The tablets weretested for dissolution as described in Example 1. The dissolution results are given in Table 23. 10 TABLE 23

Time (hrs.) Cumulative Percent Release 1 43.6 2 57.6 3 74.4 4 87.0 6 97.5 8 100.2 -38- 012381 EXAMPLE 9

This example illustrâtes the présent invention when the active ingrédientis ciprofloxacin base: TABLE 24 ingrédient Weight (mg/tabiet) % w/w Ciprofloxacin 1015.18 75.15 Sodium Alginate 5.0 0.37 Xanthan Gum 15 1.11 Sodium Bicarbonate 200 14.8 Crospovidone 72.75 5.39 Magnésium Stéarate 33 2.44 Talc 10 0.74 Total 1350.93 100

The tablets were prepared as described in Example 2. The tablets weretested for dissolution as described in Example 1. The dissolution results aregiven in Table 25. 10 TABLE 25

Time (hrs.) Cumulative Percent Release 1 39.2 2 54.2 3 72.39 4 84.9 6 100.29 EXAMPLE 10

This example illustrâtes the présent invention when the active ingrédientis ciprofloxacin base: -39- 012381

PC TABLE 26

Ingrédient Weight (mg/tablet) % w/w Ciprofloxacin 1015.18 67.35 Sodium Alginate 5.0 0.33 Xanthan Gum 15 1.0 Crospovidone 176.82 11.73 Magnésium Stéarate 33 2.19 Talc 10 0.66 Sodium Carbonate 252.32 16.74 Total 1507.32 100

The tablets were préparée! as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are5 given in Table 27. TABLE 27

Time (hrs.) Cumulative Percent Release 1 31.34 2 59.86 3 75.3 4 81.69 6 90.39 8 91.5 EXAMPLE 11

This example illustrâtes the présent invention when the active ingrédient10 is ciprofloxacin base: -40- 012381 0' TABLE 28

Ingrédient Weight (mg/tablet) % w/w Ciprofloxacin 1015.18 69.66 Sodium Alginate 7.28 0.5 Xanthan Gum 15 1.03 Sodium Bicarbonate 200 13.72 Crospovidone 176.82 12.13 Magnésium Stéarate 33 2.26 Talc 10 0.69 Total 1457.28 99.99

The tablets were prepared as described in Example 2. The tablets weretested for dissolution as described in Example 1. The dissolution results are 5 given in Table 29. TABLE 29

Time (hrs.) Cumulative Percent Release 1 40.06 2 59.26 3 86.19 4 96.39 6 100.2 EXAMPLE 12

This example illustrâtes the présent invention when the active ingrédient10 is ciprofloxacin base: -41 - 012381 TABLE 30

Ingrédient Weight (mg/tablet) % w/w Ciprofloxacin 1015.18 70.43 Sodium Alginate 5.0 0.35 Xanthan Gum 1.46 0.1 Sodium Bicarbonate 200 13.87 Crospovidone 176.82 12.27 Magnésium Stéarate 33 2.29 Talc 10 0.69 Total 1441.46 100

The tablets were prepared as described in Exampie 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are5 given in Table 31. TABLE 31

Time (hrs.) Cumulative Percent Release 1 33.34 2 58.94 3 76.11 4 83.91 6 95.7 EXAMPLE 13 . 10 This example illustrâtes the présent invention when the active ingrédient is ciprofloxacin base: -42- 012381 TABLE 32

Ingrédient Weight (mg/tablet) % w/w Ciprofloxacin 1015.18 69.44 Sodium Alginate 5.0 0.34 Xanthan Gum 21.83 1.5 Sodium Bicarbonate 200 13.68 Crospovidone 176.82 12.1 Magnésium Stéarate 33 2.26 Talc 10 0.68 Total 1461.83 100

The tablets were prepared as described in Example 2. The tablets were5 tested for dissolution as described in Example 1. The dissolution results are given in Table 33. TABLE 33

Time (hrs.) Cumulative Percent Reiease 1 44.2 2 61.86 3 87.9 4 98.7 6 106.95 EXAMPLE 14 10 This example illustrâtes the présent invention when the active ingrédient is ciprofloxacin base: -43- 0 1238 1 * * TABLE 34

Ingrédient Weight (mg/tablet) % w/w Ciprofloxacin 1016.19 72.51 Sodium Alginate 5.0 0.36 Xanthan Gum 15 1.07 Sodium Bicarbonate 145.5 10.38 Crospovidone 176.82 12.61 Magnésium Stéarate 33 2.35 Talc 10 0.71 Total 1401.51 99.99

The tablets were prepared as described in Example 2. The tablets weretested for dissolution as described in Example 1. The dissolution results are 5 given in Table 35. TABLE 35

Time (hrs.) Cumulative Percent Release 1 44.46 2 56.8 3 65.91 4 74.19 6 89.31 8 98.49

Table 36 below summarizes Examples 5-14 above with respect to theiringrédients and includes the dissolution profile of each formulation. 10 -44- 012381 TABLE 36 | % w/w in Example j 14 72.15 r>- q T— | 0.36 I 12.61 ! 10.38 J 2.97:1 tive Release | 44.46 I 56.8 I V O) d CD 74.19 | 89.31 I 98.49 | CO | 69.44 in | 0.34 | 12.1 | 13.68 | 4.41:1 44.2 | 61.86 | q CO I Z'96 106.95 I CM l 70.43 d I 0.351 12.27 | 13.87 I 0.29:1 33.34 | 58.94 I co r- 83.91 I 95.7 | 99 69 I | 1.03 | 0.5 12.13 | 13.72 j 2.06:1 CO O d M- 59.26 | σ> cd CO 96.39 I 100.2 I O | 67.35 q | 0.33 11.73 | None Tt N* <0 V 3.03:1 31.4 | 59.86 I q LO r- 81.69 | 90.39 | 91.5 | O) | 75.15 V~ | 0.37 i 5.39 | 14.8 | 3:1 Percent Cumula 39.2 I 54.2 ) Tf CM r- 84.9 | 100.29 I CO ’69 | I None | 0.34 12.05 | 13.63 ! ! 2.04 | NA 43.6 | 57.6 | xr Tt r- q l< CO 97.5 I 100.2 I N- | 69.47 I None I 1.72 12.14 I 13.73 | VN 34.6 I 52.I St «5 CD 79.5 | . 92.4 I 95.7 I CD | 68.53 | 3.05 | None 11.97 | 13.54 | NA ”4· CO 51.4 | | ‘69 94.8 | 100.5 Γ 69.9 q CO d 12.15 | 13.74 3.03:1 ! 35.49I | 53.611 82.33) 98.72| Ingrédient I Ciprofloxacin base I Xanthan gum 0.5-2.0 I Sodium alginate 0.2-0.9 XL polyvinylpyrrolidone 5-20 I Sodium bicarbonate 10-25 Φ *-» ro c O XJ k. ra o ε O ω I Methocel K 15 M [Ratio Xanthan: Alginate].10:1-1:1 Time (hours) CM CO CD 00 45 0123β 1 »{ EXAMPLE 15

This example illustrâtes the présent invention when the active ingrédientis ciprofloxacin base: TABLE 37

Ingrédient Weight (mg/tablet) % w/w Ciprofloxacin 1015.18 67.98 Sodium Alginate 5.0 0.003 Xanthan Gum 15.0 0.01 Crospovidone 176.82 11.84 Mag. Stéarate 33.0 2.21 Talc 10.0 0.67 Calcium Carbonate 238.27 15.96 Total 1493.27 98.673

The tablets were prepared as described in Example 2. The tablets weretested for dissolution as described in Example 1. The dissolution results aregiven in Table 38. 10 TABLE 38

Time (hrs.) Cumulative Percent Release 1 44.4 2 62.4 3 73.11 4 78.0 6 84.09 8 87.0 -46- 012381 EXAMPLE 16

This example illustrâtes the présent invention when the active ingrédientis ciprofloxacin base: TABLE 39

Ingrédient Weight (mg/tabiet) % w/w Ciprofloxacin 1015.18 69.32 Sodium Alginate 14.55 0.009 Xanthan Gum 15.0 0.01 Sod. Bicarbonate 200.0 13.66 Crospovidone 176.82 12.07 Magnésium Stéarate 33.0 2.25 Talc 10.0 0.68 TOTAL 1464.55 97.32

The tablets were prepared as described in Example 2. The tablets weretested for dissolution as described in Example 1. The dissolution results aregiven in Table 40. 10 TABLE 40

Time (hrs.) Cumulative Percent Release 1 37.9 2 45.06 3 65.91 4 71.1 6 78.81 -47- 012381 EXAMPLE 17

This example illustrâtes the présent invention when the active ingrédientis ciprofloxacin base: TABLE 41

Ingrédient Weight (mg/tablet) % w/w Ciprofloxacin 1015.18 67.11 Sodium Alginate 5.0 0.003 Xanthan Gum 72.75 4.81 Sodium Bicarbonate 200.0 13.22 Crospovidone 176.82 11.69 Magnésium Stéarate 33.0 2.18 Talc 10.0 0.006 TOTAL 1512.75 99.019

The tablets were prepared as described in Example 2. The tablets weretested for dissolution as described in Example 1. The dissolution résulte aregiven in Table 42. 10 TABLE 42

Time (hrs.) Cumulative Percent Release 1 32.26 2 47.2 3 63.3 4 74.01 6 94.2

Other than the above experiments, the following formulations were madeinto tablets as described above. Dissolution and floating characteristics testing -48- 012381 was also done for the following formulations. One or the other, i.e., thedissolution profile orfloating characteristics, were found to be unsatisfactory incomparison to the above examples, for tablets according to the following formulations: 5 TABLE 43

Ingrédient Example 18 Example 19 Ciprofloxacin 1015.18 1015.18 Sodium Alginate 0 5.0 Xanthan Gum 15.0 0 Sodium Bicarbonate 200.0 200.0 Crospovidone 176.82 176.82 Magnésium Stéarate 33.0 33.0 Talc 10.0 10.0 TOTAL 1450.00 1440.0 DISSOLUTION Time (hrs.) Cumulative Percent Release 1 68.8 52.5 2 93.2 68.94 3 104.1 90.39 4 - 100.8 6 - 104.79 8 - - -49- 012381

PC TABLE 44

Ingrédients Example 20 Example 21 Example 22 Example 23 Exampie 24 Ciprofloxacin 1016.19 1016.19 1012.1 1016.19 1012.1 Sodium Alginate 5.0 5.0 5.0 5.0 5.0 Sodium Bicarbonate 200.0 200.0 200.0 200.0 200.0 Crospovidone 176.82 176.82 176.82 176.82 176.82 Magnésium Stéarate 33.0 33.0 33.0 33.0 33.0 Talc 10.0 10.0 10.0 10.0 10.0 Methocel K15M 15.0 - - - - Gellan Gum(Gelrite) - 15.0 30.0 - - Carrageenan - - - 15.0 45.0 TOTAL 1456.01 1456.01 1466.92 1456.01 1481.92 DISSOLUTION Time (hrs.) Cumulative Percent Release 1 48.66 50.74 49.6 72.46 88.8 2 63.54 62.86 58.2 81.54 93.2 3 80.31 74.19 67.2 87.09 97.8 4 89.49 80.79 74.4 92.1 99.0 6 100.11 91.71 88.2 96.45 100.2 8 101.7 99.99 95.1 97.11 101.1 -50- 012381 TABLE 45

Ingrédients Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Ciprofloxacin 1015.18 1012.1 1015.18 1012.1 1015.18 1012.1 Xanthan Gum 15.0 15.0 15.0 15.0 15.0 15.0 Sodium Bicarbonate 200.0 200.0 200.0 200.0 200.0 200.0 Crospovidone 176.82 176.82 176.82 176.82 176.82 176.82 Magnésium Stéarate 33.0 33.0 33.0 33.0 33.0 33.0 Talc 10.0 10.0 10.0 10.0 10.0 10.0 Carbopol 971 P 5.0 10.0 - - - - Methyl Cellulose - - 5.0 20.0 - - Eudragit EPO - - - - 5.0 30.0 TOTAL 1455.0 1446.92 1455.0 1456.92 1455.0 1466.92 DISSOLUTION Time (hrs.) Cumulative Percent Release 1 45.2 56.8 74.26 68.2 94.26 101.4 2 59.34 67.0 87.06 83.0 94.94 - 3 71.79 76.8 95.61 92.4 97.89 - 4 80.91 84.9 97.71 95.4 98.79 - 6 92.01 95.1 99.21 99.0 - - 8 93.0 97.5 100.59 100.8 - - -51 - U12381 Ρί TABLE 46

Ingrédient Example 31 Example 32 Example 33 Example 34 Example 35 Example 36 Ciprofloxacin 1015.18 1012.1 1015.18 1012.1 1015.18 1012.1 Sodium Alginate 5.0 5.0 5.0 5.0 5.0 5.0 Xanthan Gum 15.0 15.0 15.0 15.0 15.0 15.0 Sodium Bicarbonate 200.0 200.0 200.0 200.0 200.0 200.0 Magnésium Stéarate 33.0 33.0 33.0 33.0 33.0 33.0 Talc 10.0 10.0 10.0 10.0 10.0 10.0 Ac-di-sol 176.82 100.0 - - - - Sodium Starchglycolate - - 176.82 125.0 - - MCC (Avicel pH101) - - - - 176.82 125.0 TOTAL 1455.0 1375.1 1455.0 1400.1 1455.0 1400.1 DISSOLUTION Time (hrs.) Cumulative Percent Reiease 1 42.86 47.6 57.46 53.8 67.4 62.6 2 51.4 55.8 65.6 62.4 79.26 74.4 3 60.21 62.4 72.81 70.8 86.7 84.9 4 66.81 67.5 77.19 75.6 91.5 88.2 6 81.09 76.2 84.69 82.4 95.49 94.8 8 87.6 83.1 92.31 88.2 98.79 97.2 -52- 012381 TABLE 47

Ingrédient Example 37 Example 38 Example 39 Ciprofloxacin 1015.18 1015.18 1015.18 Sodium Alginate 5.0 5.0 5.0 Xanthan Gum 15.0 15.0 15.0 Sodium Bicarbonate 200.0 200.0 200.0 Crospovidone 0 261.9 363.75 Magnésium Stéarate 33.0 33.0 33.0 Talc 10.0 10,0 10.0 TOTAL 1278.18 1540.08 1641.93 DISSOLUTION Time (hrs.) Cumulative Percent Release 1 66.66 49.2 57.26 2 79.8 75.66 77.74 3 91.2 96.99 106.2 4 94.71 100.71 - 6 97.59 - - -53- 012381 TABLE 48 ingrédients Example 40 Example 41 Example 42 Ciprofloxacin 1016.19 1016.19 1016.19 Sodium Alginate 5.0 5.0 5.0 Sodium Bicarbonate 200.0 200.0 200.0 Crospovidone 176.82 176.82 176.82 Magnésium Stéarate 33.0 33.0 33.0 Talc 10.0 10.0 10.0 Methocel K15M 15.0 - - Gellan gum (Gelrite) - 15.0 - Carrageenan - - 15.0 TOTAL 1456.01 1456.01 1456.01 DISSOLUTION Time (hrs.) Cumulative Percent Release 1 48.66 50.74 72.46 2 63.54 62.86 81.54 3 80.31 74.19 87.09 4 89.49 80.79 92.1 6 100.11 91.71 96.45 8 101.7 99.99 97.11 -54- 012381 TABLE 49

Ingrédients Example 43 Ex ample 44 Example 45 Ciprofloxacin 1015.18 1015.18 1015.18 Xanthan Gum 15.0 15.0 15.0 Sodium Bicarbonate ’ 200.0 200.0 200.0 Crospovidone 176.82 176.82 176.82 Magnésium Stéarate 33.0 33.0 33.0 Talc 10.0 10.0 10.0 Carbopoi 971 P 5.0 - - Methyl Cellulose - 5.0 - Eudragit EPO - - 5.0 TOTAL 1455.01 1455.01 1455.01 DISSOLUTION Time (hrs.) Cumulative Percent Release 1 45.2 74.26 94.26 2 59.34 87.06 94.94 3 71.79 95.61 97.89 4 80.91 97.71 98.79 6 92.01 99.21 - 8 93.0 100.59 - -55- 012381 TABLE 50

Ingrédients Exemple 46 Example 47 Example 48 Ciprofloxacin 1015.18 1015.18 1015.18 Sodium Alginate 5.0 5.0 5.0 Xanthan Gum 15.0 15.0 15.0 Sodium Bicarbonate 200.0 200.0 200.0 Magnésium Stéarate 33.0 33.0 33.0 Talc 10.0 10.0 10.0 Ac-di-sol 176.82 - - Sodium Starch glycolate - 176.82 - MCC (Avicel pH 101) - 176.82 - TOTAL 1455.0 1455.0 1455.0 DISSOLUTION Time (hrs.) Cumulative Percent Release 1 42.86 57.46 67.4 2 51.4 65.6 79.26 3 60.21 72.81 86.7 4 66.81 77.19 91.5 6 81.09 84.69 95.49 8 87.6 92.31 98.79 -56- 012381 TABLE 51

Ingrédients Example 49 Ciprofloxacin 1015.18 Sodium Alginate 5.0 Xanthan Gum 15.0 Crospovidone 176.82 Magnésium Stéarate 33.0 Talc 10.0 Potassium Bicarbonate 238.34 TOTAL 1493.34 DISSOLUTION Time (hrs.) Cumulative Percent Reiease 1 69.06 2 77.74 3 85.2 4 87.0 6 87.0 8 98.1 -57- Û'1238 1 TABLE 52

Ingrédient Example 50 Example 51 Ciprofloxacin 1015.18 1015.18 Sod. Alginate 0 1.46 Xanthan Gum 15.0 15.0 Sodium Bicarbonate 200.0 200.0 Crospovidone 176.82 176.82 Magnésium Stéarate 33.0 33.0 Talc 10.0 10.0 TOTAL 1450.00 1451.46 DISSOLUTION Time (hrs.) Cumulative Percent Release 1 68.8 51.46 2 93.2 65.34 3 104.1 84.39 4 - 92.79 6 - 97.41 -58- 012381 A'O' TABLE 53

Ingrédient Example 52 Ciprofloxacin 1015.18 Sodium Alginate 5.0 Sodium Bicarbonate 200.0 Crospovidone 176.82 Magnésium Stéarate 33.0 Talc 10.0 TOTAL 1440.0 DISSOLUTION Time (hrs.) Cumulative Percent Release 1 52.5 2 68.94 3 90.39 4 100.8 6 104.79 -59- 012381

PC TABLE 54

Ingrédient Example 53 Example 54 Example 55 Example 56 Ciprofloxacin 1015.18 1016.19 1015.18 1015.18 Sodium Alginate 5.0 5.0 5.0 5.0 Xanthan Gum 15.0 15.0 15.0 15.0 Sodium Bicarbonate 0 72.75 291.0 436.5 Crospovidone 176.82 176.82 176.82 176.82 Magnésium Stéarate 33.0 33.0 33.0 33.0 Taie 10.0 10.0 10.0 10.0 TOTAL 1255.0 1328.76 1546.0 1691.5 DISSOLUTION Time (hrs) % released 1 73.06 50.86 49.0 42.46 2 73.7 63.6 72.14 74.66 3 - 73.89 96.3 96.6 4 94.8 83.7 103.8 104.1 6 87.9 93.51 - - 8 - 98.19 - -

While the invention has been described by référencé to spécifieexamples, this was for purposes of illustration only. Numerous alternative 5 embodiments wifl be apparent to those skilled in the art and are considered tobe within the scope of the invention. -60-

Claims (43)

012381 CLAIMS

1. A once daily tablet formulation for oral administration in humans for thecontrolled release of ciprofloxacin comprising a pharmaceuticallyeffective amount of ciprofloxacin, from about 0.1% to about 8.0% of aviscolyzing agent and/or a gelling agent, about 5.0% to about 15% of a 5 gas generating agent, and about 3.0% to about 15% of a swellingagent, said percentages being w/w of the composition.

2. A once daily tablet formulation for oral administration in humans for thecontrolled release of ciprofloxacin comprising a pharmaceuticallyeffective amount of ciprofloxacin, from about 0.2% to about 5.0% of a 10 viscolyzing agent and/or a gelling agent, about 5.0% to about 15% of agas generating agent, and about 5.0% to about 15% of a swellingagent, said percentages being w/w of the composition.

3. The formulation of claim 1 or 2, wherein the viscolyzing agent is eithera carbohydrate gum or cellulose ethers.

4. The formulation of claim 3, wherein the carbohydrate gum is xanthangum and the cellulose ether is hydroxypropyl methylcellulose.(methocel).

5. The formulation of claim 1 or 2, wherein the gelling agent is sodiumalginate. -61 - 012381

6. The formulation of claim 1 or 2, wherein either or both the viscolyzingagent and gelling agent are used.

7. The formulation of claim 6, wherein the viscolyzing agent is xanthan gum.

8. The formulation of claim 3, wherein the gas generating agent is selected from the group consisting of sodium bicarbonate, calciumcarbonate, sodium carbonate, and mixtures thereof.

9. The formulation of claim 3, wherein the swelling agent is crosslinkedpolyvinylpyrrolidone. 10 15

10. A once daily formulation for oral administration in humans for thecontrolled release of ciprofloxacin comprising a pharmaceuticallyeffective amount of ciprofloxacin, about 0.2% to about 0.5% sodiumalginate, about 0.5 to about 2.0% xanthan gum, about 10.0% to about25% sodium bicarbonate, and about 5.0% to about 20% cross-linkedpolyvinylpyrrolidone, said percentages being w/w of the composition,wherein the weight ratio of sodium alginate to xanthan gum is betweenabout 1:1 to about 1:10.

11. The formulation of claim 10 comprising 69.9% ciprofloxacin base,0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium -62- 01238] bicarbonate, 12.1% cross-linked polyvinylpyrrolidone, and optionallyother pharmaceutical excipients.

12. The formulation of claim 10 in the form of a tablet.

13. A once daily homogenous, single layer tablet formulation for oral 5 administration in humans for the controlled release of ciprofloxacin in the stomach or upper part of the small intestine comprising a pharma-ceutically 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% 10 cross-linked polyvinylpyrrolidone, said percentages being w/w of the composition, wherein the weight ratio of sodium alginate to xanthangum is between about 1:1 to about 1:10.

14. The formulation of claim 13 comprising 69.9% ciprofloxacin base,0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium 15 bicarbonate, 12.1% cross-linked polyvinylpyrrolidone, and optionally other pharmaceutical excipients.

15. A once daily tablet formulation for oral administration in humans for thecontrolled release of ciprofloxacin in the stomach or upper part of thesmall intestine comprising a pharmaceutically effective amount of 20 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 -63- U1238 1 >( bicarbonate, and about 5.0% to about 20% cross-linked polyvinyl-pyrrolidone, said percentages being w/w of the composition, whereinthe weight ratio of sodium alginate to xanthan gum is between about1:1 to about 1:10, said ingrédients présent in said relative proportions 5 in a single layer.

16. The formulation of claim 15 comprising 69.9% ciprofloxacin base,0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodiumbicarbonate, 12.1% cross-linked polyvinylpyrrolidone, and optionallyother pharmaceutical excipients. *0

17. The formulation of claim 15 in the form of a tablet.

18. A once daily tablet formulation for oral administration in humans for thecontrolled release of ciprofloxacin in the stomach or upper part of thesmall intestine comprising a pharmaceutically effective amount ofciprofloxacin, about 0.2% to about 0.5% sodium alginate, about 0.5 to 15 about 2.0% xanthan gum, about 10.0% to about 25% sodium bicarbonate, and about 5.0% to about 20% cross-linked polyvinyl-pyrrolidone, said percentages being w/w of the composition, whereinthe weight ratio of sodium alginate to xanthan gum is between about1:1 to about 1:10.

19. The formulation of claim 18 comprising 69.9% ciprofloxacin base,0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium -64- 012381 bicarbonate, 12.1% cross-linked polyvinylpyrrolidone, and optionallyother pharmaceutical excipients.

20. The formulation of claim 18 in the form of a tablet.

21. A sustained release formulation comprising ciprofloxacin which 5 releases more than 50% of the drug in less than 4 hours and reieases more than 60% of the drug in less than 8 hours.

22. A sustained release formulation which releases more than 50% of thedrug within about 2-4 hours and releases more than 60% of the drug within about 4-8 hours.

23. The formulation of claim 22, suitable for once-a-day profile.

24. The formulation of claim 23 in the form of a tablet or a capsule.

25. The formulation of claim 24 in the form of a tablet which is coated witha pharmaceutically acceptable excipient.

26. A sustained release formulation comprising 100-1000 mg of 15 ciprofloxacin and pharmaceutically acceptable excipients, wherein the total weight of the dosage unit is less than 2000 mg.

27. The formulation of claim 26 wherein the pharmaceutically acceptableexcipients comprises a viscolyzing agent and/or a gelling agent, a gasgenerating component, and a swelling agent. -65- U I 238t

28. The formulation of daim 27, which comprises 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.

29. The formulation ofclaim 28, which comprises from about 0.2% to about 5.0% of a viscolyzing 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, said percentages being w/w of the composition.

30. ' The formulation of daim 29, wherein the viscolyzing agent is either *0 xanthan gum or hydroxypropyl methylcellulose (methocel) and the gelling agent is sodium alginate.

31. The formulation of claim 30, wherein both the viscolyzing agent andsodium alginate are used.

32. The formulation of claim 31, wherein the viscolyzing agent is xanthan 15 gum.

33. The formulation of claim 28, wherein the gas generating agent isselected from the group consisting of sodium bicarbonate, calciumcarbonate, sodium carbonate and mixtures thereof.

34. The formulation of claim 28, wherein the swelling agent is crosslinked 20 polyvinylpyrrolidone. -66- 012381

35. The formulation of claim 26 which is suitable for once-a-day profile.

36. The formulation of claim 26 in the form of tablet or capsule.

37. The formulation of claim 26 in the form of a tablet which is coated witha pharmaceutically acceptable excipient. 5

38. A sustained release solid dosage form of ciprofloxacin which, when orally administered in humans underfed conditions, provides meanpeak serum/plasma concentration, area underthe serum/plasmaconcentration-tîme curve above minimum inhibitory concentrations anddurations above minimum inhibitory serum/plasma concentrations, of tû not less than 70% when compared with respect to divided doses of équivalent amountof conventional immédiate release ciprofloxacinsolid dosage form.

39. The sustained release solid dosage form of claim 38 which, whenorally administered in humans underfed conditions, provides a 15 médicament serum/plasma concentration - time curve with an area under the curve, time zéro to infinity, ranging from about 3.5 to about30 pg-hours/ml.

40. The sustained release solid dosage form of claim 38 which, whenorally administered in humans underfed conditions, provides a mean -67- 012381 peak serum/plasma concentration ranging from about 0.5 to about 4pg/ml.

41. The sustained release solid dosage form of claim 38 which, whenorally administered in humans under fed conditions, provides a 5 médicament serum/plasma concentration - time curve with an area under the curve above a minimum inhibitory concentration of 0.1 pg/ml,ranging from about 3 to about 26 pg-hours/ml.

42. The sustained release solid dosage form of claim 38 which, whenorally administered in humans under fed conditions, provides a *0 médicament serum/plasma concentration - time curve with an area under the curve above a minimum inhibitory concentration of 0.25pg/ml, ranging from about 2 to about 22 pg-hours/ml.

43. The sustained release solid dosage form of claim 38 which, whenorally administered in humans under fed conditions, provides a 15 médicament serum/plasma concentration - time curve with an area under the curve above a minimum inhibitory concentration of 0.5 pg/ml,ranging from about 1 to about 18 pg-hours/ml. -68-