Extended release formulations of erythromycin derivatives

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 C.sub.max 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.

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 soluble alginate salt and another cation that alone yields an insoluble 
alginate salt. These formulations are described in U.S. Pat. No. 
4,842,866, issued Jun. 27, 1989. However, in-vivo animal studies showed 
that reproducibly bioavailable controlled release formulation were not 
possible using alginates or any other monolithic hydrogel tablets. 
To overcome some of the problems associated with the formulations described 
in U.S. Pat. No. 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 commonly owned, 
co-pending U.S. patent application Ser. No. 08/574,877, filed Dec. 19, 
1995. The formulations described in the patent application comprise a 
poorly soluble 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 minimize the adverse effects related to gastrointestinal (GI) 
disorders including nausea and vomiting and a phenomenon described as 
taste perversion. 
One approach to address taste perversion has been to develop acceptable 
palatable liquid oral dosage forms of these drugs as described in U.S. 
Pat. No. 4,808,411, issued Feb. 28, 1989. 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 minimizes 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 (C.sub.max) of clarithromycin in plasma are 
statistically 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 24 hours. In contrast, 
for the controlled release formulations described in the co-pending U.S. 
application Ser. No. 08/574,877, filed Dec. 19, 1995, the C.sub.max values 
are not statistically significantly different from those for the IR 
formulation. And while the AUC.sub.0-24 is maintained, the C.sub.min is 
statistically significantly lower for the controlled-release formulations 
relative to the IR formulation. The compositions of the invention have 
surprisingly a two-to three-fold reduction in incidence rates for taste 
perversion compared to the IR formulation. 
In one 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 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 bioavailability substantially 
equivalent to that of the immediate release composition of the 
erythromycin derivative. 
In 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 a 
pharmaceutically acceptable polymer, so that upon oral ingestion, maximum 
peak concentrations of the erythromycin derivative are statistically 
significantly lower than those produced by an immediate release 
pharmaceutical composition, and an 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 a pharmaceutically acceptable polymer, 
comprising administering the composition in an effective amount for the 
treatment of bacterial infection in a mammal, whereby an area under the 
concentration-time curve 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 polymer, wherein the composition has an 
improved taste profile relative to the immediate release formulation.

DETAILED DESCRIPTION OF THE INVENTION 
"500 mg or 1000 mg" as used herein, means the strength of tablet 
composition containing 500 mg clarithromycin, or the dose administered as 
2.times.500 mg of clarithromycin, respectively. 
"C.sub.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.sub.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.sub.avg " as used herein, means the average concentration within the 
24-hour interval. 
"T.sub.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: 
EQU DFL=(C.sub.max -C.sub.min)/C.sub.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.TM. 
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. 
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, 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 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 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. 
EXAMPLES 
Example 1 
Preparation of Formulation 
Methocel.TM. (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. 
TABLE 1 
______________________________________ 
A B C 
Ingredient mg/tablet 
mg/tablet mg/tablet 
______________________________________ 
Water (USP, purified) 
Q.S. Q.S. Q.S. 
Clarithromycin 500.00 500.00 500.00 
Methocel K 100 LV Premium 
200.00 100.00 300.00 
CR Grade* 
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, randomized, four-period, balanced cross-over study 
described below. 
Single-Dose Study 
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.TM., 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. 
Pharmacokinetic Analyses 
Values for clarithromycin pharmacokinetic parameters, including observed 
C.sub.max, T.sub.max, and AUC.sub.0-.infin., were calculated using 
standard noncompartmental methods. 
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 24 hours. 
Table II summarizes the pharmacokinetic results obtained after 
single-dosing in the above study. 
TABLE II 
______________________________________ 
AUC.sub.0-.infin. 
Formulation C.sub.max (.mu.g/ml) 
T.sub.max (h) 
(.mu.g.multidot.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 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 C.sub.max, AUC.sub.0-.infin., T.sub.max, and the logarithms of 
C.sub.max, and AUC.sub.0-.infin., 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.sub.0-.infin., 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.sub.0-.infin. are set forth in Table III below. 
TABLE III 
______________________________________ 
Relative Bioavailability 
Formulation Comparison 
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 AUC.sub.0-.infin. central values were lower for the three ER 
formulations than for the reference IR tablet. The lower C.sub.max values 
and the later T.sub.max values suggest that all the ER formulations with 
varying weight percent of polymer, provide extended-release of 
clarithromycin in vivo. 
The lower AUC.sub.0-.infin. 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. 
Multiple-Dose Study 
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. 
Regimen A 
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). 
Regimen B 
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). 
Regimen C 
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 Analyses 
Pharmacokinetic parameter estimates were calculated using noncompartmental 
methods. For the Day 1 data, the parameters estimated included C.sub.max, 
T.sub.max, AUC.sub.0-.infin. or AUC.sub.0-48, and t.sub.1/2. For the Day 5 
data, the parameters estimated included C.sub.max, T.sub.max, C.sub.min, 
AUC.sub.0-24, 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 C.sub.max and AUC.sub.0-.infin. values for Regimen C 
were normalized to a 1000 mg dose. For the Day 1 and Day 5 AUC and 
C.sub.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 FIG. 2. 
Table IV summarizes (mean.+-.SD) of the Day 5 pharmacokinetic parameter 
estimates for the clarithromycin in the ER and IR formulations. 
TABLE IV 
______________________________________ 
For- 
mu- 
la- C.sub.max C.sub.max 
T.sub.max 
AUC.sub.0-24 
Fluctuation 
tion (.mu.g/ml) 
(.mu.g/ml) 
(h) (.mu.g.multidot.h/mLO 
Index 
______________________________________ 
A 2.45 .+-. 0.69* 
0.70 .+-. 
8.6 .+-. 4.4* 
39.6 .+-. 12.8 
1.11 .+-. 
0.37 0.31*.dagger. 
B 2.66 .+-. 0.87* 
0.67 .+-. 
6.9 .+-. 3.3* 
40.2 .+-. 13.8 
1.24 .+-. 0.37* 
0.39 
IR 3.21 .+-. 0.78 
0.78 .+-. 
1.9 .+-. 0.6 
40.8 .+-. 11.8 
1.47 .+-. 0.26 
Ref- 0.29 
er- 
ence 
______________________________________ 
*Statistically significantly different from the reference IR formulation. 
.dagger.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.sub.0-24 are 
set forth in Table V below. The results presented are for 
logarithmic-transformed clarithromycin AUC.sub.0-24 values. 
TABLE V 
______________________________________ 
Relative Bioavailability 
Formulation Comparison 
Point Estimate 
90% Confidence 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.sub.0-24. The significantly lower C.sub.max 
central values and later T.sub.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. 
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 (500 mg tablets) and the IR BIAXIN 
(reference) 500 mg tablet were administered to healthy subjects in a 
multiple-dose regimen as described above. 
Formulations of the Invention 
A single dose (2.times.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.times.500 mg regimen, 
once-a-day, followed the washout for the next three days. 
REFERENCE 
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 
Percent of Total Subjects 
BODY SYSTEM A B Reference 
COSTART TERM 
(N.sub.m 24) 
(N.sub.m 23) 
(N.sub.m 23) 
______________________________________ 
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. 
Comparative Example 3 
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 
Clarithromycin 
1000 mg 500 mg BID 
Once-Daily 
Reference 
PK-Parameter 
(Formulation A) 
(BIAXIN) 
Point 
90% Confidence 
Unit Mean.sup.a 
S.D..sup.b 
Mean.sup.a 
S.D..sup.b 
Estimator.sup.c 
Interval 
__________________________________________________________________________ 
AUC.sub.0-24 
(.mu.g*h/ml) 
27.298 
10.086 
28.256 
10.770 
97.4 86.9-109.2 
C.sub.max 
(.mu.g/ml) 
2.432 
0.905 
2.701 
0.785 
89.0 78.2-101.3 
T.sub.max 
(h) 5.217 
1.858 
2.043 
0.706 
C.sub.min 
(.mu.g/ml) 
0.469 
0.292 
0.597 
0.241 
71.7 60.0-85.7 
DFL 1.800 
0.572 
1.900 
0.616 
__________________________________________________________________________ 
.sup.a arithmetic means 
.sup.b standard deviation 
.sup.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 in value as can be seen in the above Table. cf. 
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. 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.