“ 500 mg or 1000 mg ” as used herein , means the strength of tablet composition containing 500 mg clarithromycin , or the dose administered as 2 × 500 mg of clarithromycin , respectively . “ c max ” 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 . “ c min ” 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 . “ c avg ” as used herein , means the average concentration within the 24 - hour interval . “ t max ” 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 24 - hour interval for all the formulations . “ degree of fluctuation ( dfl )” as used herein , is expressed as : dfl =( c max − c min )/ c avg . “ 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 . “ 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 . “ 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 . the pharmaceutical composition of the invention comprise a pharmaceutically active compound and a pharmaceutically acceptable polymer . the pharmaceutically active compound is an erythromycin derivative . preferably , the erythromycin derivative is 6 - o - methoxy erythromycin a , known as clarithromycin . the amount of the erythromycin derivative varies from about 45 % to about 60 % by weight of the composition . preferably , the composition comprises about 50 % by weight 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 hydroxypropyl - methyl cellulose with viscosity ranging from about 50 cps to about 200 cps . the most preferred low viscosity polymer is a hydroxypropylmethyl cellulose with a viscosity of about 100 cps , commercially available under the tradename methocel ™ k 100 lv from the dow chemical company . the amount of the polymer in the composition generally varies from about 5 % to about 50 % by weight of the composition . preferably , the amount of polymers varies from about 10 % to about 35 % by weight of the composition . most preferably , the amount of polymer varies from about 10 % to about 30 % by weight 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 10 % by weight of the composition . preferably , the lubricants used are magnesium stearate and talc in the total amounts ranging from about 1 . 0 % to about 4 . 0 % by weight of the composition . the amount of fillers and extenders varies from about 10 % to about 40 % by weight of the composition . a particularly preferred composition for the extended release of the active compound therefrom comprises : about 500 mg of clarithromycin ; and from 100 to 300 mg of methocel k 100 lv . the formulations are generally prepared by dry blending the polymer , filler , erythromycin derivative , and other excipients followed by granulating the mixture using water until proper granulation is obtained . the granulation is done by methods known in the art . the wet granules are dried in a fluid bed dryer , 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 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 release - controlling coatings for the purpose of light protection , and swallowability . the coating may be colored 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 comprises film - forming polymers such as hydroxy - propyl 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 , flavoring 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 500 mg to 1000 mg once a day for five to fourteen days . 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 , ind .) 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 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 1000 mg 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 . methocel ™ ( 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 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 . 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 , randomized , four - period , balanced crossover study described below . twenty - four ( 24 ) 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 . 0 kg ( range : 51 . 5 to 85 kg ) and the mean height was 172 cm ( range : 157 to 192 cm ). clarithromycin 500 mg extended release tablets corresponding to the formulations a , b , and c of example 1 and the 500 mg ir clarithromycin tablet ( reference formulation ), currently sold by abbott laboratories under the tradename biaxin ™, were administered to the 23 healthy subjects . the study was conducted according to a single - dose , open - label , randomized four - period crossover design in which each subject received a single 500 mg dose of clarithromycin during each 30 minutes period after starting breakfast . wash - out periods of one week separated the doses . seven ( 7 ) ml blood samples were collected prior to dosing ( 0 hour ) and at 0 . 5 , 1 . 0 , 2 . 0 , 3 . 0 , 4 . 0 , 6 . 0 , 8 . 0 , 12 . 0 , 16 . 0 , 24 . 0 , 36 . 0 and 48 . 0 hour after each dose . plasma samples were assayed for clarithromycin at bas analytics ( west lafayette , ind .) using a validated high performance liquid chromatographic procedure . values for clarithromycin pharmacokinetic parameters , including observed c max , t max , and auc 0 - ∞, were calculated using standard noncompartmental methods . the mean plasma concentration - time profiles for the single - dose study are illustrated in fig1 . fig1 illustrates that all the three formulations of the invention are substantially equivalent in extended release of clarithromycin over a period of 24 hours . table ii summarizes the pharmacokinetic results obtained after single - dosing in the above study . table ii auc 0 -∞ formulation c max ( μg / ml ) t max ( h ) ( μg · 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 ± 7 . 5 * reference 2 . 57 ± 0 . 70 2 . 2 ± 0 . 5 17 . 7 ± 5 . 6 tablet * statistically significantly different from the ir reference tablet # statistically significantly different from formulations a and c in analysis of logarithms for c max , auc 0 - ∞, t max , and the logarithms of c max , and auc 0 - ∞, 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 auc 0 - ∞, bioequivalence of the er formulations to the ir reference formulation was assessed using the two one - sided tests procedure via 90 % 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 auc 0 - ∞ are set forth in table iii below . table iii relative bioavailability formulation 90 % confidence comparison point estimate 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 auc 0 - ∞ central values were lower for the three er formulations than for the reference ir tablet . the lower c max values and the later t max values suggest that all the er formulations with varying weight percent of polymer , provide extended - release of clarithromycin in vivo . the lower auc 0 - ∞ values for the er formulations may suggest that for a single 500 mg dose administered under nonfasting conditions , the extent of absorption of clarithromycin was reduced relative to that of the reference ir tablet . twenty - four ( 24 ) 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 was 72 kg ( range : 51 to 87 kg ) and the mean height was 176 cm ( range : 159 to 189 . 5 cm ). the clarithromycin dosage forms included 500 mg er tablets of example 1 containing 10 % or 20 % by weight of k 100 lv , respectively , and a reference 500 mg ir tablet ( biaxin ). the study was conducted according to a single - and multiple - dose , open - label , randomized three - period crossover design . a single 1000 mg dose of er formulation a tablets ( two 500 mg tablets ) was administered in the morning on day 1 . beginning on day 3 , a multiple dose regimen of 1000 mg clarithromycin ( two 500 mg tablets ) was administered each morning for three days ( days 3 - 5 ). a single 1000 mg dose of er formulation b tablets ( two 500 mg tablets ) was administered in the morning on day 1 . beginning on day 3 , a multiple dose regimen of 1000 mg clarithromycin ( two 500 mg tablets ) was administered each morning for three days ( days 3 - 5 ). a single 500 mg dose of ir tablet ( biaxin ) was administered in the morning on day 1 . beginning on day 3 , a multiple dose regimen of 500 mg reference tablet biaxin was administered every twelve hours for three days . 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 ( 7 ) ml blood samples were collected before dosing on day 1 ( 0 hr ) and at 0 . 5 , 1 . 0 , 2 . 0 , 3 . 0 , 4 . 0 , 6 . 0 , 8 . 0 , 12 . 0 , 16 . 0 , 24 . 0 , 36 . 0 , and 48 . 0 hour after dosing . for regimen c , the 12 hour 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 5 ml for bioassay and the remainder of the sample for high performance liquid chromatographic ( hplc ) assay . plasma samples were assayed for clarithromycin at bas analytics ( west lafayette , ind .) using a validated high performance liquid chromatographic procedure . pharmacokinetic parameter estimates were calculated using noncompartmental methods . for the day 1 data , the parameters estimated included c max , t max , auc 0 - ∞ or auc 0 - 48 , and t 1 / 2 . for the day 5 data , the parameters estimated included c max , t max , c min , auc 0 - 24 , and dfl . 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 c max and auc 0 -□ values for regimen c were normalized to a 1000 mg dose . for the day 1 and day 5 auc and c max 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 fig2 . table iv summarizes ( mean ± sd ) of the day 5 pharmacokinetic parameter estimates for the clarithromycin in the er and ir formulations . table iv formulation c max ( μg / ml ) c min ( μg / ml ) t max ( h ) auc 0 - 24 ( μg · h / ml0 fluctuation index a 2 . 45 ± 0 . 69 * 0 . 70 ± 0 . 37 8 . 6 ± 4 . 4 * 39 . 6 ± 12 . 8 1 . 11 ± 0 . 31 *† 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 ir formulation . † 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 auc 0 - 24 are set forth in table v below . the results presented are for logarithmic - transformed clarithromycin auc 0 - 24 values . table v relative bioavailability formulation 90 % confidence comparison point estimate interval a vs reference 0 . 964 0 . 893 - 1 . 039 b vs reference 0 . 970 0 . 899 - 1 . 046 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 auc 0 - 24 . the significantly lower c max central values and later t max 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 20 % polymer fluctuate less than those from the 10 % polymer tablet . the adverse effects , including taste perversion ( taste profile ), were studied for the multiple - dose regimes described above . the formulations a and b of example 1 ( 500 mg tablets ) and the ir biaxin ( reference ) 500 mg tablet were administered to healthy subjects in a multiple - dose regimen as described above . a single - dose ( 2 × 500 mg ) 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 2 × 500 mg regimen , once - a - day , followed the washout for the next three days . a single dose of 500 mg ir biaxin tablet was administered to the subjects , followed by a 48 hour wash - out period . multiple dosing with the 500 mg 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 . table vi dosing regimen a b reference body system ( n m 24 ) ( n m 23 ) ( n m 23 ) costart term percent of total subjects overall 9 ( 37 . 5 %) 10 ( 43 . 5 %) 11 ( 47 . 8 %) body as a whole 6 ( 25 . 0 %) 3 ( 13 . 0 %) 1 ( 4 . 3 %) asthenia 2 ( 8 . 3 %) 1 ( 4 . 3 %) 0 ( 0 . 0 %) chills 0 ( 0 . 0 %) 1 ( 4 . 3 %) 0 ( 0 . 0 %) headache 2 ( 8 . 3 %) 2 ( 8 . 7 %) 0 ( 0 . 0 %) neck rigidity 1 ( 4 . 2 %) 0 ( 0 . 0 %) 0 ( 0 . 0 %) pain 2 ( 8 . 3 %) 0 ( 0 . 0 %) 1 ( 4 . 3 %) cardiovascular system 1 ( 4 . 2 %) 0 ( 0 . 0 %) 0 ( 0 . 0 %) hypertension 1 ( 4 . 2 %) 0 ( 0 . 0 %) 0 ( 0 . 0 %) digestive system 4 ( 16 . 7 %) 4 ( 17 . 4 %) 4 ( 17 . 4 %) abdominal pain 1 ( 4 . 2 %) 0 ( 0 . 0 %) 0 ( 0 . 0 %) constipation 0 ( 0 . 0 %) 0 ( 0 . 0 %) 2 ( 8 . 7 %) diarrhea 2 ( 8 . 3 %) 3 ( 13 . 0 %) 1 ( 4 . 3 %) dyspepsia 2 ( 8 . 3 %) 2 ( 8 . 7 %) 1 ( 4 . 3 %) flatulence 0 ( 0 . 0 %) 1 ( 4 . 3 %) 0 ( 0 . 0 %) nausea 0 ( 0 . 0 %) 0 ( 0 . 0 %) 1 ( 4 . 3 %) nervous system 0 ( 0 . 0 %) 1 ( 4 . 3 %) 2 ( 8 . 7 %) depersonalization 0 ( 0 . 0 %) 1 ( 4 . 3 %) 0 ( 0 . 0 %) hypesthesia 0 ( 0 . 0 %) 1 ( 4 . 3 %) 1 ( 4 . 3 %) insomnia 0 ( 0 . 0 %) 1 ( 4 . 3 %) 0 ( 0 . 0 %) somnolence 0 ( 0 . 0 %) 0 ( 0 . 0 %) 1 ( 4 . 3 %) respiratory system 1 ( 4 . 2 %) 1 ( 4 . 3 %) 3 ( 13 . 0 %) cough increased 1 ( 4 . 2 %) 0 ( 0 . 0 %) 0 ( 0 . 0 %) hiccup 0 ( 0 . 0 %) 0 ( 0 . 0 %) 1 ( 4 . 3 %) pharyngitis 0 ( 0 . 0 %) 1 ( 4 . 3 %) 2 ( 8 . 7 %) rhinitis 1 ( 4 . 2 %) 1 ( 4 . 3 %) 0 ( 0 . 0 %) skin and appendages 0 ( 0 . 0 %) 2 ( 8 . 7 %) 2 ( 8 . 7 %) rash 0 ( 0 . 0 %) 1 ( 4 . 3 %) 1 ( 4 . 3 %) skin disorder 0 ( 0 . 0 %) 1 ( 4 . 3 %) 2 ( 8 . 7 %) special senses 3 ( 12 . 5 %) 3 ( 13 . 0 %) 6 ( 26 . 1 %) eye disorder 0 ( 0 . 0 %) 1 ( 4 . 3 %) 0 ( 0 . 0 %) taste perversion 3 ( 12 . 5 %) 2 ( 8 . 7 %) 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 . the results of a comparative pharmacokinetic study of the controlled release formulation a of the co - owned , pending u . s . patent application ser . no . 08 / 574 , 877 , filed dec . 19 , 1995 , as compared with the ir ( biaxin ) are set forth in table vii below . table vii clarithromycin 1000 mg clarithromycin once - daily 500 mg bid ( formulation reference 90 % pk - parameter a ) ( biaxin ) point confidence unit mean a s . d . b mean a s . d . b estimator c interval auc 0 - 24 ( μg * h / ml ) 27 . 298 10 . 086 28 . 256 10 . 770 97 . 4 86 . 9 - 109 . 2 c max ( μg / ml ) 2 . 432 0 . 905 2 . 701 0 . 785 89 . 0 78 . 2 - 101 . 3 t max ( h ) 5 . 217 1 . 858 2 . 043 0 . 706 c min ( μg / ml ) 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 for the composition of the invention is statistically lower than the ir in vivo profile . the lower dfl indicates that the er formulations of the invention provide less variable clarithromycin concentrations throughout the day than the ir and the sustained release compositions . the mean dfl values for the controlled release formulation and for the ir are substantially equal in value as can be seen in the above table . cf . 1 . 800 ± 0 . 572 ( for controlled release ) with 1 . 900 ± 0 . 616 ( ir ). two well - controlled , double - blind clinical trials were conducted to compare the safety and efficacy of extended - release clarithromycin ( er ) and immediate - release clarithromycin ( ir ) in patients with acute maxillary sinusitis ( ams ) and patients with acute bacterial exacerbation of chronic bronchitis ( aecb ). a total of 910 patients were enrolled for the studies . of the 910 patients , 459 patients were treated with er formulation of the invention and 444 patients were treated with the ir ( reference ) formulation . two hundred eighty three ( 283 ) patients , enrolled in the ams study , and 627 patients , enrolled in the aecb study , were randomly assigned in a 1 : 1 ratio to receive either the er formulation of the invention or the ir formulation . of the 283 patients enrolled in this study , 142 patients received a single dose of clarithromycin er tablets 500 mg × 2 qd ( 1000 mg daily ) for 14 days , and 141 patients received clarithromycin ir tablets , 500 mg bid ( 1000 mg daily ) for 14 days . of the 627 patients enrolled in this study , 317 patients received a single dose of clarithromycin er tablets 500 mg × 2 qd ( 1000 mg daily ) for 7 days , and 303 patients received clarithromycin ir tablets , 500 mg bid ( 1000 mg daily ) for 7 days . the results of the study are summarized below in table viii . table viii clarithromycin er reference 1000 mg . once - daily biaxin number of patients 0 . 6 % 3 . 0 %* discontinued due to drug - ( 3 / 459 ) ( 13 / 444 ) related gi adverse events number of patients with severe 0 . 2 % 2 . 0 %* drug - related gi adverse events 1 / 459 ( 8 / 444 ) * statistically significant p 0 . 05 level . from the above results , it can be seen that patients taking the extended - release formulation of clarithromycin were significantly less likely to stop taking clarithromycin due to gastrointestinal adverse events and these patients suffered significantly fewer severe gastrointestinal adverse effects .
disclosed is a pharmaceutical composition for extended release of an erythromycin derivative in the gastrointestinal environment . the composition comprises an erythromycin derivative and a pharmaceutically acceptable polymer so that , when ingested orally , the composition induces statistically significantly lower cmax in the plasma than an immediate release composition of the erythromycin derivative while maintaining bioavailability and minimum concentration substantially equivalent to that of the immediate release composition of the erythromycin derivative upon multiple dosing . the compositions of the invention have an improved taste profile and reduced gastrointestinal side effects as compared to those for the immediate release composition .