AU773863B2 - Extended release formulations of erythromycin derivatives - Google Patents

Description

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AUSTRALIA

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0000 S S S. S Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Abbott Laboratories CHAD 0377/AP6D-2 100 Abbott Park Road Abbott Park Illinois 60064-3500 United States of America Laman A. Al-Razzak, Sheri L. Crampton, Linda E.

Gustavson, Ho-Wah Hui, Nelly Milman, Susan J. Semla Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Extended Release Formulations of Erythromycin Derivatives The following statement is a full description of this invention, including the best method of performing it known to me/us:- 0505

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5845c 1 Extended Release Formulations of Erythromycin Derivatives Technical Field The present invention relates to pharmaceutical compositions of erythromycin derivatives with an extended release of an active compound in the gastrointestinal environment. More particularly, it relates to pharmaceutical compositions of clarithromycin which are ingested daily as a single oral administration.

Background of the Invention Erythromycin and its derivatives are known for their antibacterial activity against a number of organisms or activity in a number of indications and are typically administered as immediate release (IR) compositions, two or three times a day, for a regimen of 10 to 14 days. These compounds have a bitter taste. In particular, the 6-O-methoxyerythromycin A (clarithromycin) has a bitter metallic taste which can result in poor compliance of the regimen or selection of another, possibly less effective, therapeutic agent.

One approach to improve the possible non-compliance with the regimen has been to develop controlled release solid preparations containing these erythromycin derivatives in an alginate matrix comprising a water-soluble alginate and a complex salt of alginic acid, having one cation that yields a .o soluble alginate salt and another cation that alone yields an insoluble alginate salt. These formulations are described in US 4 842 866. However, in-vivo animal studies showed that reproducibly bioavailable 2 controlled release formulation were not possible using alginates or any other monolithic hydrogel tablets.

*00 *To overcome some of the problems associated with the formulations described in US. 4 842 866, improved controlled release formulations for poorly soluble basic drugs such as erythromycin derivatives including clarithromycin, have been developed and are described in, co-pending US Patent Application, 08/574,877. The formulations described in the patent application comprise a poorly soluble 25 basic drug and citric acid in an alginate matrix. The formulations are administered once a day and are directed towards increasing the bioavailability of the active ingredient so that it is bioequivalent with the current immediate release, twice-a-day compositions. However, these controlled release compositions do not purport to minimise the adverse effects related to gastrointestinal (GI) disorders including nausea and vomiting and a phenomenon described as taste perversion.

30 One approach to address taste perversion has been to develop acceptable palatable liquid oral dosage forms of these drugs as described in US 4 808 411. However, these formulations are administered twice-a-day for a period of 10 to 14 days and do not address the frequency and duration of the administration regimen, or the adverse effects related to GI disorders. Therefore, there still exists a need for developing a pharmaceutical composition which minimises the adverse effects described above and provides a degree of drug plasma concentration control which is equivalent to or better than the (IR) tablet or liquid formulations currently used.

Summary of the Invention It has been discovered that the extended release (ER) formulations of the present invention which comprise a pharmaceutically acceptable polymer, provide extended release clarithromycin in vivo when given once daily. Maximum concentrations (Cmax) of clarithromycin in plasma are statistically LibC/475168D1speci T 23. APR. 2004 14:24 SPRUSON AND FERGUSON 61292615486 NO. 0394 P. 9 2 significantly lower than the IR formulation given twice daily, and area under the plasma concentration-time curve (AUC) and the minimum plasma concentration are maintained over 24h. Incontrast, for the controlled release formulations described in co-pending US Application 08/574,877, the values are not statistically significantly different from those for the IR formulation. And while the AUC 0 -24 is maintained, the Cmi, is statistically significantly lower for the controlled-release formulations relative to the IM formulation.

The compositions of the invention have surprisingly a two-to three-fold reduction in inciderce rates for taste perversion compared to the I. formulation.

In one aspect the present invention provides a pharmaceutical composition for ,0 extended release of claithromycin in the gastrointestinal tract, to be administered orally, comprising clarithromycin and a pharmaceutically acceptable, hydrophilic, water-soluble polymer, which releases clarithromycin so that after a regimen of a single 1000 mg dose on :.day 1 and a multiple dose regimen of 1000 mg on days 3, 4 and 5, the maximum plasma Is concentration is reached after 6.9 3.3 hours, and the area under the plasma concentration time curve 0-24 hours is 40.2 13.8 ltg.h/mL, or S""which releases clarithromycin so that after a single 500 mg dose, the area under the plasma concentration time curve 0-co is 15.0 t 6.5 [g.h/mL.

In another, aspect the present invention provides use of clarithromycin and a pharmaceutically acceptable hydrophilic water-soluble polymer for manufacturing a pharmaceutical composition for extended release in the gastrointestinal environment for the treatment of bacterial infection in a mammal, wherein the composition is to be administered orally and wherein the composition releases clarithromycin so that after a regimen of a single 1000 mg dose on day I and a multiple dose regimen of 1000 mg on "gg- 25 days 3, 4 and 5, the maximum plasma concentration is reached after 6.9 3.3 hours, and the area under the plasma concentration-time curve 0-24 hours is 40.2 13.8 jtg.h/mL, or which releases clarithromycin so that after a single 500 mg dose, the area under the plasma concentration time curve 0-u is 15.0 6.5 1 g./mL.

In yet another aspect, the present invention relates to a pharmaceutical composition for extended release of an erythromycin derivative in the gastrointestinal environment, comprising an erythromycin derivative and from about 5 to about 50wt% of a pharmaceutically acceptable polymer, so that when ingested orally, the composition induces statistically significantly lower mean fluctuation index in the plasma than an immediate release composition of the erythromycin derivative while maintaining R LIBXX]04875.doc:npr COMS ID No: SMBI-00720061 Received by IP Australia: Time 14:26 Date 2004-04-23 r 23. APR. 2004 14:24 SPRUSON AND FERGUSON 61292615486 NO. 0394 P. 2a bioavailability substantially equivalent to that of the immediate release composition of the erythromycin derivative.

In still another aspect, the present invention relates to a pharmaceutical composition for extended release of an erythromycin derivative in the gastrointestinal environment, comprising an erythromycin derivative and from about 5 to about 50wt%/ of a pharmaceutically acceptable polymer, so that upon oral ingestion, maximum peak concentrations of the erythromycin derivative are lower than those produced by an immediate release pharmaceutical composition, and area under the concentration-time curve and the minimum plasma concentration are substantially equivalent to that of the immediate release pharmaceutical composition.

In yet still another aspect, the present invention relates to a method of using an extended release pharmaceutical composition comprising an erythromycin derivative and from about 5 to about 50wt% of a pharmaceutically acceptable polymer, comprising administering the composition in an effective amount for the treatment of bacterial is infection in a mammal, whereby an area under the concentration-time curve substantially equivalent to that for an immediate release pharmaceutical composition of the erythromycin derivative is maintained.

In yet another aspect, the present invention is an extended release pharmaceutical composition comprising an erythromycin derivative and a pharmaceutically acceptable 20 polymer, wherein the composition has an improved taste profile relative to the immediate release formulation.

Brief Description of the Drawings Figure 1 illustrates the mean in vivo plasma concentration-time profiles following single dose of three 500mg ER tablets containing clarithromycin and 10%, 20% or 30wt%, respectively, of hydroxypropylmethyl cellulose K100 LV, as compared to that of the reference 500mg IR clarithromycin tablet.

Figure 2 illustrates the mean in vive plasma concentration-time profiles following multiple doses of each of the two ER tablets containing 10% or 20%, respectively, of hydroxypropylmethyl cellulose K100 LV as compared to the reference IR tablet. The dosage forms included two 500mg ER tablets given once daily or one IR 500mg clarithromycin every 12 hours, respectively, administered for three days with food.

[R:,\IBXX]04875.doo:mpr COMS ID No: SMBI-00720061 Received by IP Australia: Time 14:26 Date 2004-04-23 Figure 3 illustrates the mean in vivo plasma concentration-time profiles following multiple doses of clarithromycin once-daily 1000mg (not an example of the invention) and IR 500mg twice-a-day.

Detailed Description of the Invention "500mg or 1000mg" as used herein, means the strength of tablet composition containing 500mg clarithromycin, or the dose administered as 2x500mg of clarithromycin, respectively.

"Cmax" as used herein, means maximum plasma concentration of the erythromycin derivative, produced by the ingestion of the composition of the invention or the IR comparator.

"Cmin" as used herein, means minimum plasma concentration of the erythromycin derivative, produced by the ingestion of the composition of the invention or the IR comparator.

"Cavg" as used herein, means the average concentration within the 24h interval.

"Tmax" as used herein, means time to the maximum observed plasma concentration.

"AUC" as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete 24h interval for all the formulations.

"Degree of Fluctuation (DFL)" as used herein, is expressed as: DFL=( Cmax-Cmin)/Cavg.

"Erythromycin derivative" as used herein, means erythromycin having no substituent groups, or having conventional substituent groups, in organic synthesis, in place of a hydrogen atom of the hydroxy groups and/or a methyl group of the 3'-dimethylamino group, which is prepared according to the conventional manner.

20 "Pharmaceutically acceptable" as used herein, means those compounds which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, in keeping with a reasonable benefit/risk ratio, and effective for their intended use in the chemotherapy and prophylaxis of antimicrobial infections.

25 "Adverse effects" as used herein, means those physiological effects to various systems in the body such as cardiovascular systems, nervous system, digestive system, and body as a whole, which cause pain and discomfort to the individual subject.

'Taste perversion" as used herein, means the perception of a bitter metallic taste normally associated with the erythromycin derivatives, particularly, with clarithromycin.

30 The pharmaceutical composition of the invention comprise a pharmaceutically active compound and a pharmaceutically acceptable polymer. The pharmaceutically active compound is an erythromycin S. derivative. Preferably, the erythromycin derivative is 6-0-methoxy erythromycin A, known as clarithromycin. The amount of the erythromycin derivative varies from about 45% to about 60wt% of the composition. Preferably, the composition comprises about 50wt% of the erythromycin derivative.

The pharmaceutically acceptable polymer is a water-soluble hydrophilic polymer selected from the group consisting of polyvinylpyrrolidine, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, vinyl acetate/crotonic acid copolymers, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof. Preferably, the polymer is selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and methyl cellulose. More preferably, the polymer is hydroxypropylmethyl cellulose. Most preferably, the polymer is a low viscosity LibC/475168Dispeci hydroxypropylmethyl cellulose with viscosity ranging from about 50cps to about 200cps. The most preferred low viscosity polymer is a hydroxypropylmethyl cellulose with a viscosity of about 100cps, commercially available under the Tradename MethocelTM K 100 LV from The Dow Chemical Company.

The amount of the polymer in the composition generally varies from about 5% to about 50wt% of the composition. Preferably, the amount of polymers varies from about 10% to about 35wt% of the composition. Most preferably, the amount of polymer varies from about 10% to about 30wt% of the polymer.

The composition of the invention further comprise pharmaceutically acceptable excipients and/or fillers and extenders, such as lactose, starches, glucose, sucrose, mannitol, and silicic acid, lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.

The amount of the lubricants generally varies from about 0.5% to about 10wt% of the composition. Preferably, the lubricants used are magnesium stearate and talc in the total amounts ranging from about 1.0% to about 4.0wt% of the composition. The amount of fillers and extenders varies from about 10% to about 40wt% of the composition.

A particularly preferred composition for the extended release of the active compound therefrom comprises: about 500mg of clarithromycin; and from 100 to 300mg of Methocel K 100 LV.

The formulations are generally prepared by dry blending the polymer, filler, erythromycin S* derivative, and other excipients followed by granulating the mixture using water until proper granulation 20 is obtained. The granulation is done by methods known in the art. The wet granules are dried in a fluid bed drier, sifted and ground to appropriate size. Lubricating agents are mixed with the dried granulation to obtain the final formulation.

The compositions of the invention can be administered orally in the form of tablets, pills, or suspensions. The tablets can be prepared by techniques known in the art and contain a therapeutically 25 useful amount of erythromycin derivative and such excipients as are necessary to form the tablet by such techniques. Tablets and pills can additionally be prepared with enteric coatings and other releasecontrolling coatings for the purpose of light protection, and swallowability. The coating may be coloured with a pharmaceutically accepted dye. The amount of dye and other excipients in the coating liquid may vary and will not impact the performance of the extended release tablets. The coating liquid generally 30 comprises film forming polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose ester or ether, an acrylic polymer or a mixture of polymers. The coating solution is generally an aqueous solution further comprising propylene glycol, sorbitan monoleate, sorbic acid, fillers such as titanium dioxide, a pharmaceutically acceptable dye.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water. Such compositions may also comprise adjuvants, such as wetting agents; emulsifying and suspending agents; and sweetening, flavouring and perfuming agents.

The daily dose of the composition of this invention administered to a host in single dose can be in the amounts from 500mg to 1000mg once-a-day for five to fourteen days.

LibC/475168Dlspeci Pharmacokinetic Study The bioavailability study for the formulations of the invention can be done by administering the ER formulation in a tablet form to healthy subjects and measuring the levels of erythromycin derivative in the plasma at different time intervals over a period of twenty four hours.

Plasma samples are assayed for erythromycin derivative at BAS Analytics (West Lafayette, Indiana) using a validated high-performance liquid chromatographic procedure similar to that described in the literature. See for example, Chu S-Y, et al., "Simultaneous determination of clarithromycin and 14(R)-hydroxyclarithromycin in plasma and urine using high-performance liquid chromatography with electrochemical detection", J. Chromatog., 571, pp 199-208 (1991).

Adverse Effects and Taste Profile Adverse effects including those related to the digestive system, nervous system, respiratory system and special senses, including taste perversion, are measured by dosing subjects with multiple doses of 1000mg of ER and IR tablets per day, respectively. The adverse effects are monitored, reported spontaneously by subjects and recorded on case report forms for the study database.

The invention will be understood more clearly from the following Examples, which are given solely by way of illustration and serve to provide a clear understanding of the invention and to illustrate its different embodiments as well as its various advantages.

Example 1 Preparation of Formulation MethocelTM (K 100 LV) available from The Dow Chemical Company was loaded into a mixer, and dry blended with clarithromycin. The mixture was granulated using water until proper granulation was obtained. The granulation was then dried, sifted and ground to appropriate size.

Talc and magnesium stearate were screened and blended with dry granulation. The granulation was then loaded into hopper and compressed into tablets. The tablets were then coated with an 25 aqueous coating.

Three different formulations A, B, and C were prepared according to the general method described above. The compositions of three different tablet formulations are given below in Table 1.

Table 1 Ingredient A mg/tablet B mg/tablet C mg/tablet Water (USP, purified) Q.S. Q.S. Q.S.

Clarithromycin 500.00 500.00 500.00 Methocel K 100 LV Premium CR Grade* 200.00 100.00 300.00 Lactose, monohydrate 260.00 360.00 160.00 Talc, USP 30.00 30.00 30.00 Magnesium Stearate 10.00 10.00 10.00 *Available from The Dow Chemical Company Example 2 Pharmacokinetic Study of the Extended Release Formulation The bioavailability study to determine the concentration-time plasma profile was done on healthy subjects. The study was conducted as a Phase I, single-dose, open, randomised, four-period, balanced cross-over study described below.

LibC/475168D1speci Single-Dose Study Twenty-four healthy adult subjects were enrolled and 23 completed all phases of the study. For the 23 subjects who completed all phases of the study (12 males, 11 females), the mean age was 29 years (range: 19 to 49 years), the mean weight was 69.0kg (range: 51.5 to 85kg) and the mean height was 172cm (range: 157 to 192cm).

Clarithromycin 500mg extended release tablets corresponding to the formulations A, B, and C of Example 1 and the 500mg IR clarithromycin tablet (Reference Formulation), currently sold by Abbott Laboratories under the Tradename BIAXINTM, were administered to the 23 healthy subjects.

The study was conducted according to a single-dose, open-label, randomised four-period crossover design in which each subject received a single 500mg dose of clarithromycin during each minutes period after starting breakfast. Wash-out periods of one week separated the doses.

Seven mL blood samples were collected prior to dosing (Oh) and at 0.5, 1.0, 2.0, 3.0, 4.0, 12.0, 16.0, 24.0, 36.0 and 48.0h after each dose. Plasma samples were assayed for clarithromycin at BAS Analytics (West Lafayette, Indiana) using a validated high performance liquid chromatographic procedure.

Pharmacokinetic Analyses Values for clarithromycin pharmacokinetic parameters, including observed Cmax, Tmax, and AUCowere calculated using standard noncompartmental methods.

20 The mean plasma concentration-time profiles for the single-dose study are illustrated in Fig. 1.

Fig. 1 illustrates that all the three formulations of the invention are substantially equivalent in extended release of clarithromycin over a period of 24h.

Table II summarises the pharmacokinetic results obtained after single-dosing in the above study.

Table II

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555 *500 25 00 Formulation Cmax (I/mL) Tmax AUCo-oo(.h/mL) A 1.19±0.60* 5.0±1.7* 15.0±6.5* B 1.33±0.70*# 5.5±2.4* 15.1±6.5* C 1.01±0.48* 5.5±2.2* 14.8±75* Reference Tablet 2.57±0.70 2.2±0.5 17.7±5.6 Statistically significantly different from the IR reference tablet Statistically significantly different from Formulations A and C in analysis of logarithms.

Statistical Analyses For Cma, AUCoo, Tmax, and the logarithms of Cmax, and AUCo-o, an analysis of variance (ANOVA) was performed with sequence, subject nested within sequence, period and formulation as the sources of variation. Effects for subjects were random and all other effects were fixed. Within the framework of ANOVA, the formulations were compared pairwise, with each test at a significance level of 0.05. Also within the framework of the ANOVA for the logarithm of AUCo,, bioequivalence of the ER formulations to the IR reference formulation was assessed using the two one-sided tests procedure via confidence intervals. The confidence intervals were obtained by exponetiating the endpoints of the confidence intervals for the difference of logarithm means.

Point estimates of relative bioavailability and 90% confidence intervals for the two one-sided tests procedure from analysis of log-transformed AUCo, are set forth in Table III below.

Table III LibC/475168D1speci Formulation Comparison Relative Bioavailability Point Estimate 90% Confidence Interval A vs Reference 0.815 0.737 0.902 B vs Reference 0.835 0.755 0.925 C vs Reference 0.787 0.711 0.871 The AUCo-o central values were lower for the three ER formulations than for the reference IR tablet. The lower Cmax values and the later Tmax values suggest that all the ER formulations with varying weight percent of polymer, provide extended-release of clarithromycin in vivo.

The lower AUCo, values for the ER formulations may suggest that for a single 500mg dose administered under nonfasting conditions, the extent of absorption of clarithromycin was reduced relative to that of the reference IR tablet.

Multiple-Dose Study Twenty-four healthy adult subjects were enrolled and 23 completed all phases of the study. Of the 23 who completed the study (19 males, 4 females), the mean age was 30 years (range: 20 to 47 years), the mean weight 5 was 72kg (range: 51 to 87kg) and the mean height was 176cm (range: 159 to 189.5cm).

The clarithromycin dosage forms included 500mg ER tablets of Example 1 containing 10% or S. 20% by weight of K 100 LV, respectively, and a reference 500mg IR tablet (BIAXIN).

The study was conducted according to a single- and multiple-dose, open-label, randomised 1i three-period crossover design.

Ce Regimen A A single 1000mg dose of ER formulation A tablets (two 500mg tablets) was administered in the morning on Day 1. Beginning on Day 3, a multiple dose regimen of 1000mg clarithromycin (two 500mg tablets) was administered each morning for three days (Days Regimen B A single 1000mg dose of ER formulation B tablets (two 500mg tablets) was administered in the morning on Day 1. Beginning on Day 3, a multiple dose regimen of 1000mg clarithromycin (two 500mg tablets) was administered each morning for three days (Days "Regimen C A single 500mg dose of IR tablet (BIAXIN) was administered in the morning on Day 1. Beginning on Day 3, a multiple dose regimen of 500mg reference tablet BIAXIN was administered every twelve hours for three days.

S. Each morning dose was administered thirty minutes after breakfast. Every evening dose was administered thirty minutes after starting the evening snack.

Wash-out periods of at least one week separated the last dose in a period and the first dose in the following period.

Seven mL blood samples were collected before dosing on Day 1 (Oh) and at 0.5, 1.0, 2.0, 6.0, 8.0, 12.0, 16.0, 24.0, 36.0, and 48.0h after dosing. For Regimen C, the 12h sample was collected within 5 minutes before the evening dose on Day 5. Plasma harvested from each blood sample was divided into two parts: approximately 5mL for bioassay and the remainder of the sample for high performance liquid chromatographic (HPLC) assay. Plasma samples were assayed for LibC/475168D1speci clarithromycin at BAS Analytics (West Lafayette, Indiana) using a validated high performance liquid chromatographic procedure.

Pharmacokinetic Analyses Pharmacokinetic parameter estimates were calculated using noncom partmental methods. For the Day 1 data, the parameters estimated included Crax, Tmax, AUCo, or AUC0-48, and t1/2. For the Day data, the parameters estimated included Cm.a, Tr., Cmin, AUCo-24, and DFL.

Statistical Analyses No statistical analyses were performed on the bioassay data. Analyses of variance (ANOVA) were performed for Day 1 and Day 5 pharmacokinetic variables with effects for regimen, period, sequence, and subject nested within sequence. The Cmax, and AUCo-, values for Regimen C were normalised to a 1000mg dose. For the Day 1 and Day 5 AUC and Cma. values and for the Day 5 DFL values for both analytes, logarithmic transformation was employed. Each of the Regimens A and B were compared to the reference Regimen C at a significance level of 0.05. Within the framework of the ANOVAs for the Day 5 AUC values, equivalence of the ER formulations of the invention to the IR reference tablet was assessed using the two one-sided tests procedure via 90% confidence intervals.

The mean plasma concentration-time profiles for the multiple-dose study are illustrated in Fig. 2.

Table IV summarises (mean+SD) of the Day 5 pharmacokinetic parameter estimates for the clarithromycin in the ER and IR formulations.

0 :o0 Table IV Formulation C.a Groin (IJg/mL) Tma, AUCo.24 (l.h/mL) Fluctuation Index A 2.45+0.69* 0.70± 0.37 8.6± 4.4* 3.96± 12.8 1.1 1± 0.31" 1 B 2.66+0.87* 0.67±0.39 6.9+3.3* 40.2±13.8 1.24±0.37" IR Reference 3.21±0.78 0.78±0.29 1.9± 0.6 40.8±11.8 1.47±0.26 Statistically significantly different from the reference I R formulation.

f Statistically significantly different from Regimen B.

Point estimates of the relative bioavailability and 90% confidence intervals for the two one-sided tests procedures of Day 5 AUCO24 are set forth in Table V below. The results presented are for logarithmic-transformed clarithromycin AUC0-24 values.

Table V Formulation Comparison -Relative Bioavailability Point Estimate 90% Confidence Interval A vs Reference 0.964 0.893 1.039 B vs Reference 0.970 0.899 1.046 0:7o 0.

For this multiple dose study under nonfasting conditions, both the 10% and 20% polymer ER formulations were bioequivalent to the reference IR tablet with respect to the AUCo-24. The significantly lower Crnax central values and later Tmax values suggest that both the formulations provide extended release of clarithromycin in vivo. The significantly lower DFLs indicate that plasma concentrations fluctuate less for the ER tablet regimens than for the IR tablet regimen. Additionally, the significantly lower DFL for Regimen A compared to Regimen B indicates that plasma concentrations from the polymer fluctuate less than those from the 10% polymer tablet.

LObC/475168DMspeci Adverse Effects The adverse effects, including taste perversion (taste profile), were studied for the multiple-dose regimes described above.

Multiple-Dose Study The formulations A and B of Example 1 (500mg tablets) and the IR BIAXIN (reference) 500mg tablet were administered to healthy subjects in a multiple-dose regimen as described above.

Formulation of the Invention A single dose (2X500mg) of the formulations A and B of Example 1, was administered to the subjects, followed by a 48 hour wash-out period. Multiple dosing in the morning with the 2X500mg regimen, once-a-day, followed the washout for the next three days.

Reference A single dose of 500mg IR BIAXIN tablet was administered to the subjects, followed by a 48 hour wash-out period. Multiple dosing with the 500mg tablet, twice-a-day followed the washout for three days.

The adverse effects to the body as a whole, cardiovascular system, digestive system, nervous system, respiratory system, skin and appendages, and special senses were measured by monitoring the subjects at regular time intervals. Subjects who reported the same COSTART term more than once were counted only once for that COSTART term.

The results of the adverse effects are set forth in Table VI below.

20 Table VI 0 GS e

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00 0 6 A *5 Dosing Regimen Body System Costart A (Nm24) B (Nm 23) Reference (Nm 23) Term Percent of Total Subjects Overall 9 10(43.5%) 11(47.8%) Body As A Whole 6 3(13.0%) 1 Asthenia 2 1 0 Chills 0 1 0 Headache 2 0 Neck Rigidity 1 0 0 Pain 1(4.3%) Cardiovascular System 1 0 0 Hypertension 1 0 0 Digestive System 4(16.7%) 4(17.4%) 4 (17.4%) Abdominal Pain 0 Constipation 0 2 Diarrhoea 2 3(13.0%) 1(4.3%) Dyspepsia 2 1(4.3%) Flatulence 0 0 Nausea 0 1 Nervous System 0 2 Depersonalisation 0 0 Hypaesthesia 0 1(4.3%) Insomnia 0 0 Somnolence 0 0 1 Respiratory System 3 (13.0%) Cough Increased 1 0 Hiccup 0 1(4.3%) Pharyngitis 0 2 LibC/475168D1speci Dosing Regimen Body System Costart A (Nm24) B (Nm 23) Reference (Nm 23) Term Percent of Total Subjects Rhinitis 1 0 Skin and Appendages 0 2 2 Rash 0 1(4.3%) Skin Disorder 0 1 2 Special Senses 3 3(13.0%) 6(26.1%) Eye Disorder 0 1 0 Taste Perversion 3 2 6 (26.1%) It is evident from the above Table VI that the adverse effects to the digestive, nervous and respiratory systems normally associated with BIAXIN are reduced with the ER tablets. The taste perversion with the formulations of the invention is significantly reduced. It is reasonably believed that the reduced adverse effects, particularly taste perversion, would lead to better compliance and a higher incidence of completion of the prescribed treatment regimen.

Comparative Example 3 The results of a comparative pharmacokinetic study of the controlled release formulation A of the co-owned, pending US Patent Application 08/574,877, as compared with the IR (BIAXIN) are set forth in Table VII below.

Table VII 00S0 0 0 0 0 0St 0 a S 0 PIK-Parameter Clarithromycin 1000mg Clarithromycin 500mg Point Estimatorc 90% Confidence Once-Daily (Formulation A) BID Reference (BIAXIN) Interval Unit Meana S.D.b Meana S.D.b AUCo- 2 4 *h/mL) 27.298 10.086 28.256 10.770 97.4 86.9-109.2 Cmax (g/mL) 2.432 0.905 2.701 0.785 89.0 78.2- 101.3 Tmax 5.217 1.858 2.043 0.706 Cmin 0.469 0.292 0.597 0.241 71.7 60.0- 85.7 DFL 1.800 0.572 1.900 0.616 a arithmetic means b standard deviation c defined as the ratio of the geometric means of test vs. reference formulation The mean DFL values for the controlled release formulation and for the IR are substantially equal S 15 in value as can be seen in the above Table. c.f. 1.800±0.572 (for controlled release) with 1.900±0.616

(IR).

The mean DFL for the composition of the invention is statistically lower than the IR in vivo profile.

S The lower DFL indicates that the ER formulations of the invention provide less variable clarithromycin S° concentrations throughout the day than the IR and the sustained release compositions.

LibC/475168D1speci

Claims (9)

1. 2. The pharmaceutical composition for extended release according to claim 1, which releases clarithromycin so that after single 500 mg dose, the maximum plasma concentration is reached 5.5 2.4 hours after dosing and the maximum plasma concentration is 1.33 0.70 pg/mL. 15 3. The pharmaceutical composition for extended release according to claim 1, which releases clarithromycin so that after a regimen of a single 1000 mg dose *on day 1 and a multiple dose regimen of 100 mg on days 3, 4 and 5, thie maximum plasma concentration is 2.66 0.87 lg/mL and the fluctuation index is 1.24 0.37.
2. 4. The pharmaceutical composition for extended release according to claim 1, 20 wherein the polymer is selected from the group consisting of polyvinylpyrrolidine, hydroxypropyl cellulose, hydroxypropylmethyl cellulose methyl cellulose, vinyl acetate/crotonic acid copolymers, methacrylic acid copolymers, maleic anhydride/methyl *vinyl either copolymers and derivatives mixtures thereof
3. 5. The pharmaceutical composition for extended release according to claim 1, 25 wherein the polymer is present in an amount from 5 to 50% by weight.
4. 6. The pharmaceutical composition for extended release according to claim 1, wherein the clarithromycin is present in an amount from 45% to 60% by weight.
5. 7. The pharmaceutical composition for extended release according to claim 4, wherein the polymer is hydroxypropylmethyl cellulose.
6. 8. The pharmaceutical composition for extended release according to claim wherein the composition comprises from 5 to 45% by weight of the polymer.
7. 9. The pharmaceutical composition for extended release according to claim 8, wherein the composition comprises 50% by weight of the clarithromycin. The pharmaceutical composition for extended release according to claim 9 wherein the composition comprises from 10 to 30% by weight of the polymer. [I\LBXX]04875doc:mpr COMS ID No: SMBI-00720061 Received by IP Australia: Time 14:26 Date 2004-04-23 F 21 APR. 2004 14:25 SPRUSON AND FERGUSON 61292615486 NO. 0394 P. 12
8. 11. Use of clarithromycin and a phannaceutically acceptable hydrophilic water- soluble polymer for manufacturing a pharmaceutical composition for extended release in the gastrointestinal environment for the treatment of bacterial infection in a mammal, wherein the composition is to be administered orally and wherein the composition s releases clarithromycin so that after a regimen of a single 1000 mg dose on day I and a multiple dose regimen of 1000 mg on days 3, 4 and 5, the maximum plasma concentration is reached after 6.9 3-3 hours, and the area under the plasma concentration-time curve 0-24 hours is 40.2 13.8 gtg.h/mL, or which releases clarithromycin so that after a single 500 mg dose, the area under the plasma concentration time curve 0-co is 15-0 to pg.h/mL. Dated 23 April 2004 ABBOTT LABORATORIES Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON B @00* *090 S. 9 6 9 9 9900 9 9 9 b@ 9S*9 9
9. 99.. 9 @999 9 905@ 9 09@@ 99 9* 9 9 0 9. 9 0@ 9 @9 [R;\LIBXX]04875.doc:mpr COMS ID No: SMBI-00720061 Received by IP Australia: Time 14:26 Date 2004-04-23