CA2433962C - Antibacterial clarithromycin compositions and processes for making the same - Google Patents
Antibacterial clarithromycin compositions and processes for making the same Download PDFInfo
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- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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Abstract
Abridged clarithromycin antibacterial compositions and methods for making the same are disclosed
Description
ANTIBACTERIAL C'.LARiTI-IROMYCIN COMPOSITIONS AND
PROCESSES FUR MAKING THE SAME
FIELD OF THE WVENTION
This invention is directed to abridged clarithromycin antibacterial compositions and methods for making the same.
Clarithromycin is employed in the manufacture; of commercially-available antibiotic compositions for human administration. For example, an orally-administered antibacterial composition of clarithromycin in tablet form consists essentially of clarithromycin and a number of excipients which, in toto, control the bioavailability of the 10 antibiotic.
The removal of one or more of these excipients from the composition to provide an abridged antibacterial composition of clarithromycin with substantially similar antibiotic activity of the clarithromycin would provide a more streamlined, less costly avenue toward commercial-availability of the drug. in addition, an abridged antibacterial composition of 15 clarithromycin, if smaller in size or offering other advantages, would be better tolerated by patients. Therefore, there is an existing need in the formulations art for an abridged antibacterial composition of clarithromycin.
SUMMARY OF THE INVENTION
The first embodiment of this invention, therefore, is directed to an abridged 20 antibacterial clarithromycin composition consisting essentially of clarithromyein, water, an infra-granular excipient, and an extra-granular excipient, in which the granular excipient consists essentially of povidone, sodium croscannellose, and microcrystailine celluose, and the extra-granular excipient consists essentially of sodium croscarmellose, microcrystalline celluose, colloidal silicon dioxide, and impalpable magnesium stearate
PROCESSES FUR MAKING THE SAME
FIELD OF THE WVENTION
This invention is directed to abridged clarithromycin antibacterial compositions and methods for making the same.
Clarithromycin is employed in the manufacture; of commercially-available antibiotic compositions for human administration. For example, an orally-administered antibacterial composition of clarithromycin in tablet form consists essentially of clarithromycin and a number of excipients which, in toto, control the bioavailability of the 10 antibiotic.
The removal of one or more of these excipients from the composition to provide an abridged antibacterial composition of clarithromycin with substantially similar antibiotic activity of the clarithromycin would provide a more streamlined, less costly avenue toward commercial-availability of the drug. in addition, an abridged antibacterial composition of 15 clarithromycin, if smaller in size or offering other advantages, would be better tolerated by patients. Therefore, there is an existing need in the formulations art for an abridged antibacterial composition of clarithromycin.
SUMMARY OF THE INVENTION
The first embodiment of this invention, therefore, is directed to an abridged 20 antibacterial clarithromycin composition consisting essentially of clarithromyein, water, an infra-granular excipient, and an extra-granular excipient, in which the granular excipient consists essentially of povidone, sodium croscannellose, and microcrystailine celluose, and the extra-granular excipient consists essentially of sodium croscarmellose, microcrystalline celluose, colloidal silicon dioxide, and impalpable magnesium stearate
2 5 powder.
A second embodiment of this invention is directed to a process for making an abridged antibacterial clarithromycin composition, the process comprising the steps of:
(a) granulating a mixture consisting essentially of povidone, clarithromycin, sodium croscarmellose, microcrystalline eelluose, and water to provide a wet infra-granular excipient;
5 (b) drying the wet intro-granular excipient to provide a dry infra-granular excipient;
and (c) mixing the dry infra-granular excipient and an extra-granular excipient, the extra-granular excipient consisting essentially of sodium croscanneliose, microcrystalline celluose, colloidal silicon dioxide, and impalpable magnesium stearate powder.
10 A third embodiment of this invention is directed to a medicament consisting essentially of an abridged antibacterial clarithromycin composition.
A fourth embodiment of this invention is directed to use of an abridged antibacterial clarithromycin composition in the preparation of a medicament, the medicament being useful for prophylaxis or 15 treatment of bacterial infections in a mammal.
DETAILED DESCRIPTIC)N OF THE 1T1VENTION
The currently commercially-available, non-abridged clarithromycin composition consists essentially of the following components: ciarithromycin, colloidal silicon dioxide, D&C yellow dye No. 10, extra-g~ranufar sodium croscannellose, extra-granular 20 microcrystalline celluose (Avicel~ PH-l02), infra-granular sodium croscarmellose, intra-granular microcrystalline celluose (Avicel~ PH-101 ), magnesium stearute powder, povidone, pre-gelatinized starch, 200 proof alcohol, stearic acid, talc, and water.
This invention is directed to abridged antibacterial clarithromycin compositions, hereinafter referred to as "abridged compositions," which contain any amount of 25 clarithromycin and from which at least one of the aforementioned components have been omitted.
In a preferred first embodiment, the abridged compositions contain the same amount of clarithromycin which is cuirendy available in non-abridged adult and pediatric formulations, such as, for example, 250 mg of clarithromycin or 500 mg of clarithromycin
A second embodiment of this invention is directed to a process for making an abridged antibacterial clarithromycin composition, the process comprising the steps of:
(a) granulating a mixture consisting essentially of povidone, clarithromycin, sodium croscarmellose, microcrystalline eelluose, and water to provide a wet infra-granular excipient;
5 (b) drying the wet intro-granular excipient to provide a dry infra-granular excipient;
and (c) mixing the dry infra-granular excipient and an extra-granular excipient, the extra-granular excipient consisting essentially of sodium croscanneliose, microcrystalline celluose, colloidal silicon dioxide, and impalpable magnesium stearate powder.
10 A third embodiment of this invention is directed to a medicament consisting essentially of an abridged antibacterial clarithromycin composition.
A fourth embodiment of this invention is directed to use of an abridged antibacterial clarithromycin composition in the preparation of a medicament, the medicament being useful for prophylaxis or 15 treatment of bacterial infections in a mammal.
DETAILED DESCRIPTIC)N OF THE 1T1VENTION
The currently commercially-available, non-abridged clarithromycin composition consists essentially of the following components: ciarithromycin, colloidal silicon dioxide, D&C yellow dye No. 10, extra-g~ranufar sodium croscannellose, extra-granular 20 microcrystalline celluose (Avicel~ PH-l02), infra-granular sodium croscarmellose, intra-granular microcrystalline celluose (Avicel~ PH-101 ), magnesium stearute powder, povidone, pre-gelatinized starch, 200 proof alcohol, stearic acid, talc, and water.
This invention is directed to abridged antibacterial clarithromycin compositions, hereinafter referred to as "abridged compositions," which contain any amount of 25 clarithromycin and from which at least one of the aforementioned components have been omitted.
In a preferred first embodiment, the abridged compositions contain the same amount of clarithromycin which is cuirendy available in non-abridged adult and pediatric formulations, such as, for example, 250 mg of clarithromycin or 500 mg of clarithromycin
3 o for the adult formulations and aqueous solutions comprising 125 mg per 5 mL or 250 mg per 5 mL of clarithromycin for the pediatric formulations.
In still another preferred first embodiment, the 200 proof alcohol, stearic acid, and talc have been omitted from the abridged compositions.
In still yet another preferred first embodiment, the 200 proof alcohol, stearic acid, talc pre-gelatinized starch and D&C yellow dye No. 10 have been omitted from the abridged compositions.
In still even yet another preferred first embodiment, the microcrystalline celluose of the infra-granular excipient comprises Avicel~ PH-101.
In still even yet another preferred first embodiment, the microcrystalline celluose of the extra-granular excipient comprises Avicel~ PH-102.
In still even yet another preferred first embodiment, the colloidal silicon dioxide of the extra-granular excipient comprises Cab-O-SiITM M-5.
In still even yet another preferred first embodiment, the abridged compositions contain 4.0% to 5.9% by weight povidone, 3.0% to 6.8% by weight infra-granular sodium croscarmellose, 2.2% to 7.5% by weight infra-granular microcrystalline celluose, 3.0% to 6.8% by weight extra-granular sodium croscarmellose, 6.9% to 15.9% by weight extra-granular microcrystalline celluose, 0.5% to 0.8% by weight, colloidal silicon dioxide, and 1.5% to 2.5% by weight magnesium stearate powder.
In a more preferred first embodiment, the abridged compositions contain 4.9%
by weight povidone, 4.9% by weight infra-granular sodium croscarmellose, 4.9% by weight 2 0 extra-granular sodium croscarmellose, 11.6% by weight extra-granular sodium croscarmellose, 0.5% by weight colloidal silicon dioxide (Cab-O-SiITM M-5), and 1.5% by weight magnesium stearate powder.
In another preferred first embodiment, the abridged compositions are substantially bioequivalent to the non-abridged formulations.
2 5 In still another preferred first embodiment, the abridged compositions are for oral administration in tablet form, such as, for example, tablets which weigh 750 mg.
These preferred embodiments may combine to provide an abridged antibacterial composition for the oral administration of clarithromycin in tablet form, the tablet weighing 750 mg and consisting essentially of 250 mg of clarithromycin, water, an 3 0 infra-granular excipient, and an extra-granular excipient, in which the granular excipient consists essentially of
In still another preferred first embodiment, the 200 proof alcohol, stearic acid, and talc have been omitted from the abridged compositions.
In still yet another preferred first embodiment, the 200 proof alcohol, stearic acid, talc pre-gelatinized starch and D&C yellow dye No. 10 have been omitted from the abridged compositions.
In still even yet another preferred first embodiment, the microcrystalline celluose of the infra-granular excipient comprises Avicel~ PH-101.
In still even yet another preferred first embodiment, the microcrystalline celluose of the extra-granular excipient comprises Avicel~ PH-102.
In still even yet another preferred first embodiment, the colloidal silicon dioxide of the extra-granular excipient comprises Cab-O-SiITM M-5.
In still even yet another preferred first embodiment, the abridged compositions contain 4.0% to 5.9% by weight povidone, 3.0% to 6.8% by weight infra-granular sodium croscarmellose, 2.2% to 7.5% by weight infra-granular microcrystalline celluose, 3.0% to 6.8% by weight extra-granular sodium croscarmellose, 6.9% to 15.9% by weight extra-granular microcrystalline celluose, 0.5% to 0.8% by weight, colloidal silicon dioxide, and 1.5% to 2.5% by weight magnesium stearate powder.
In a more preferred first embodiment, the abridged compositions contain 4.9%
by weight povidone, 4.9% by weight infra-granular sodium croscarmellose, 4.9% by weight 2 0 extra-granular sodium croscarmellose, 11.6% by weight extra-granular sodium croscarmellose, 0.5% by weight colloidal silicon dioxide (Cab-O-SiITM M-5), and 1.5% by weight magnesium stearate powder.
In another preferred first embodiment, the abridged compositions are substantially bioequivalent to the non-abridged formulations.
2 5 In still another preferred first embodiment, the abridged compositions are for oral administration in tablet form, such as, for example, tablets which weigh 750 mg.
These preferred embodiments may combine to provide an abridged antibacterial composition for the oral administration of clarithromycin in tablet form, the tablet weighing 750 mg and consisting essentially of 250 mg of clarithromycin, water, an 3 0 infra-granular excipient, and an extra-granular excipient, in which the granular excipient consists essentially of
4.9% by weight povidone, 4,9% by weight sodium croscarmetlose, and microcrystalline celluose (Avicel~ PH-101 ), and the extra-granular excipient consists essentially of 4.9°lo by weight sodium croscarmellose> 11.6% by weight microcrystalline celluose (Avicel~ PH-l02), U.5% by
5 weight colloidal silicon dioxide (Cab-O-Sil M-5), and 1.5°!n by weight impalpable magnesium stearate powder; and an abridged antibacterial composition for oral administration of clarithromycin in tablet form, the tablet weighing 750 mg and consisting essentially of 500 mg of clarithromycin, water, an infra-granular excipient, and an extra-granular excipient, in which the granular 10 excipient consists essentially of 4.9% by weight povidone, 4.9°k by weight sodium croscarmellose, and microcrystalline eelluose (Avicel~ PH-101 )> and the extra-granular excipient consists essentially of 4.996 by weight sodium croscarmellose, 11.6% by weight microcrystailine celluose (Avicel~ PH-102), 0.5% by 15 weight colloidal silicon dioxide. ((:ab-O-Sil M-5). and 1.5% by weight impalpable magnesium stearate powder.
In a preferred second embodiment, the microcrystalline celluose of the intra-granular excipient comprises AvicelU PH-101, the microcrystalline celluose of the extra-granular excipient comprises Avicel~ PH-102, and the colloidal silicon dioxide of the 20 extra-granular excipient comprises Cab-O-Sil M-5.
In another preferred second embodiment, the process further comprises adding a solution of povidone in water to the material to be granulated in step (a), in which the amount of water is present in 390!o by weight to 44~k~ by weight of the material to be granulated.
In a preferred third or fourth embodiment, the medicament is a 750 mg tablet containing 250 mg clarithromycin, an infra-granular excipient, and an extra-granular excipient.
In another preferred third or fourth embodiment, the medicament is a 750 mg tablet 2 5 containing 500 mg clarithromycin, an infra-granular excipient, and an extra-granular excipient.
The following bioequivalenee study was conducted at Sea View Research, Ine.
(Miami, FL).
5 Fifty-six (56) healthy adult male and female subjects were enrolled in the study.
Fifty-four (54) subjects completed all four periods of the study, Subject 6 received only one dose of study drug and was terminated froth the study due to a positive drug screen.
Subject 45 received three doses of the study drug and was terminated from the study due to adverse events. Neither of the terminated subjects had complete data for the reference 10 formulation under nonfasting or fasting conditions. For the 54 subjects (36 males and 18 females) who completed the study, nine were Caucasian, three were Black, and 42 were Hispanic. The mean age was 34.4 years (range: l9 to 49 years), the mean weight was 71.4 kg (range: 52 to 89.5 kg) and the mean height was 167.2 cm (range: !49 to 196 cm).
Formulation A: test clarithromycin SOU mg tablet formulation manufactured by Abbott Laboratories (Abbott Park, 1L).
Formulation B: reference (BIAXIN~) clarithromycin 500 mg tablet formulation manufactured by Abbott Health Products Inc. (Barceloneta, Puerto Rico).
This was a Phase I, single-dose, open-label, randomized, four-period, complete-crossover study. Regimen A was defined as one tablet of Formulation A (test) administered approximately 3U minutes after the start of breakfast. Regimen B
was 2 5 defined as one tablet of Formulation A (test) administered after an eight-hour fast.
Regimen C was defined as one tablet of Formulation B (reference) administered approximately 30 minutes after the start of breakfast. Regimen D was defined as one tablet of Formulation B (reference) administered after an eight-hour fast.
3 0 SAMPLE COLLEC.'TION
Blood samples (7 mL) were collected into heparinized evacuated collection tubes prior to dosing (0 hour) and at 0.5. 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 1S, 18 and 24 hours after dosing in each study period.
ANALYTICAL METHODOLOGY
Plasma samples were analyzed for clarithromycin at BAS Analytics (West Lafayette, Indiana) using a validated HPLC procedure. 'fhe lower limit of quantification was 0.0156 pg/mL. The assays were conducted from December 19, 1997 through January 28, 1998.
PHARMAGOKINETIC ANALYSES
Pharmacokinetic parameter values were estimated for clarithromycin using noncompartmental methods. The pharmacokinetic parameters included maximum observed plasma concentration (C",~,), the time of C",;,x {'I'",ax), the area under the plasma concentration-time curve from time (1 to the time of the lust measurable plasma concentration (AUCo_i~,), the AIJC extrapolated to infinite time (AUCo-~,), the terminal elimination rate constant (p) and the half-life (ti~~).
STATISTICAL ANALYSES
Analyses of variance (ANOVAs) were also performed for T",ax (hours) and the natural logarithms of Cmax (pg/mL), AUCo_,;", {~g~h/mL), and AUCo_~ (pg~h/mL).
The model included effects for sequence, subject nested within sequence, and period and regimen. Within the ANOVA modeling framework, the test formulation under fasting 2 0 conditions (Regimen B) was compared to the reference formulation under fasting conditions (Regimen D), the test formulation under nonfasting conditions (Regimen A) was compared to the reference formulation under nonfasting conditions (Regimen C), and the test formulation under nonfasting conditions (Regimen A) was compared to the test formulation under fasting conditions (Regimen B), each with an alpha level of 0.05.
2 5 Within the framework of the ANOVA's for the logarithms of CmaX and AUC, the bioavailability of the test formulation under fasting conditions (Regimen B) relative to the reference formulation under fasting conditions (Regimen U) was assessed by the two one-sided tests procedure viu 90°/~ confidence intervals. The confidence interval for relative bioavailability was obtained by exponentiuting the endpoints of a confidence interval for 3 0 the difference of logarithm means. Similarly, the bioavailability of the test formulation
In a preferred second embodiment, the microcrystalline celluose of the intra-granular excipient comprises AvicelU PH-101, the microcrystalline celluose of the extra-granular excipient comprises Avicel~ PH-102, and the colloidal silicon dioxide of the 20 extra-granular excipient comprises Cab-O-Sil M-5.
In another preferred second embodiment, the process further comprises adding a solution of povidone in water to the material to be granulated in step (a), in which the amount of water is present in 390!o by weight to 44~k~ by weight of the material to be granulated.
In a preferred third or fourth embodiment, the medicament is a 750 mg tablet containing 250 mg clarithromycin, an infra-granular excipient, and an extra-granular excipient.
In another preferred third or fourth embodiment, the medicament is a 750 mg tablet 2 5 containing 500 mg clarithromycin, an infra-granular excipient, and an extra-granular excipient.
The following bioequivalenee study was conducted at Sea View Research, Ine.
(Miami, FL).
5 Fifty-six (56) healthy adult male and female subjects were enrolled in the study.
Fifty-four (54) subjects completed all four periods of the study, Subject 6 received only one dose of study drug and was terminated froth the study due to a positive drug screen.
Subject 45 received three doses of the study drug and was terminated from the study due to adverse events. Neither of the terminated subjects had complete data for the reference 10 formulation under nonfasting or fasting conditions. For the 54 subjects (36 males and 18 females) who completed the study, nine were Caucasian, three were Black, and 42 were Hispanic. The mean age was 34.4 years (range: l9 to 49 years), the mean weight was 71.4 kg (range: 52 to 89.5 kg) and the mean height was 167.2 cm (range: !49 to 196 cm).
Formulation A: test clarithromycin SOU mg tablet formulation manufactured by Abbott Laboratories (Abbott Park, 1L).
Formulation B: reference (BIAXIN~) clarithromycin 500 mg tablet formulation manufactured by Abbott Health Products Inc. (Barceloneta, Puerto Rico).
This was a Phase I, single-dose, open-label, randomized, four-period, complete-crossover study. Regimen A was defined as one tablet of Formulation A (test) administered approximately 3U minutes after the start of breakfast. Regimen B
was 2 5 defined as one tablet of Formulation A (test) administered after an eight-hour fast.
Regimen C was defined as one tablet of Formulation B (reference) administered approximately 30 minutes after the start of breakfast. Regimen D was defined as one tablet of Formulation B (reference) administered after an eight-hour fast.
3 0 SAMPLE COLLEC.'TION
Blood samples (7 mL) were collected into heparinized evacuated collection tubes prior to dosing (0 hour) and at 0.5. 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 1S, 18 and 24 hours after dosing in each study period.
ANALYTICAL METHODOLOGY
Plasma samples were analyzed for clarithromycin at BAS Analytics (West Lafayette, Indiana) using a validated HPLC procedure. 'fhe lower limit of quantification was 0.0156 pg/mL. The assays were conducted from December 19, 1997 through January 28, 1998.
PHARMAGOKINETIC ANALYSES
Pharmacokinetic parameter values were estimated for clarithromycin using noncompartmental methods. The pharmacokinetic parameters included maximum observed plasma concentration (C",~,), the time of C",;,x {'I'",ax), the area under the plasma concentration-time curve from time (1 to the time of the lust measurable plasma concentration (AUCo_i~,), the AIJC extrapolated to infinite time (AUCo-~,), the terminal elimination rate constant (p) and the half-life (ti~~).
STATISTICAL ANALYSES
Analyses of variance (ANOVAs) were also performed for T",ax (hours) and the natural logarithms of Cmax (pg/mL), AUCo_,;", {~g~h/mL), and AUCo_~ (pg~h/mL).
The model included effects for sequence, subject nested within sequence, and period and regimen. Within the ANOVA modeling framework, the test formulation under fasting 2 0 conditions (Regimen B) was compared to the reference formulation under fasting conditions (Regimen D), the test formulation under nonfasting conditions (Regimen A) was compared to the reference formulation under nonfasting conditions (Regimen C), and the test formulation under nonfasting conditions (Regimen A) was compared to the test formulation under fasting conditions (Regimen B), each with an alpha level of 0.05.
2 5 Within the framework of the ANOVA's for the logarithms of CmaX and AUC, the bioavailability of the test formulation under fasting conditions (Regimen B) relative to the reference formulation under fasting conditions (Regimen U) was assessed by the two one-sided tests procedure viu 90°/~ confidence intervals. The confidence interval for relative bioavailability was obtained by exponentiuting the endpoints of a confidence interval for 3 0 the difference of logarithm means. Similarly, the bioavailability of the test formulation
-6~-under nonfasting conditions (Regimen A) relative to that of the test formulation under fasting conditions (Regimen B) was assessed vin 95% confidence intervals.
RESALTS
5 Summaries (mean ~ standard deviation) of the phannacokinetic parameter estimates for clarithromycin are presented hereinbelow.
Regimen Cmax ~rmax AUCo_i;", AUC.'o_" 1n2 A 2.9811.12h'' 2.511.0' 16.816.(1 17.316.2 4.3 10 B 2.3810.86 1.910.8' 16.315.0 17.816.8 4.3 C 2.6511.17 2.4~0.6 2.416.5 16.116.6 4.3 D 2.3910.98 2.412,1 16.916.0 !7.616.1 4.7 3Significantly different (p<U.OS) From reference formulation under fasting conditions 15 (Regimen D).
bSignificantly different (p<0.05) from reference formulation under nonfasting conditions (Regimen C).
'Significantly different (p<0.05) from test formulation under fasting conditions (Regimen B).
20 Half-life is presented as the harmonic mean: this parameter was not subjected to statistical analysis.
These data illustrate the bioequivalence of the abridged and non-abridged 500 mg clarithromycin formulations.
25 The following will provide a better understanding of the compositions and processes of this invention.
Both microcrystalline celluloses were purchased from FMC BioPolymer (Cork, Ireland); Magnesium Stearate was purchased from Mallinckrodt-Baker, Inc (ST
Louis, 3 0 Mo); Collodial silicon dioxide was purchased from Cabot Corp. (Tuscola.
IL); povidone was purchased from ISP Technologies (Texas City. TX); sodium croscarmellose was purchased from Noviant (Nijmegan, Netherlands); or from FMC BioPolymer (Newark, DE).
_7_ GRANULATION
Povidone (K-value Range 29-32, 125.8() kg) was dissolved in purified water (1384.89 kg) to prepare an approximately 8.33% w/w solution.
5 Clarithromycin bulk drug (1360.(X) kg), sodium croscarmellose (100.64 kg), and microcrystalline cellulose, (1'H-101, I(X>.64 kg) were charged into a high intensity 1200L
Gral masser bowl, mixed for 5 minutes on low speed (chopper off), treated with the 8.33%
w/w povidone in water (U.774 kg of solution per kg of material to be granulated) at the rate of 30 kg per minute at low speed (chupper and mixer), and granulated on high speed (chopper and mixer) for 4 minutes (9 minutes total granulation time).
A power increase from the baseline was determined, and if the significant power increase was observed, the next step was conducted immediately. If a significant power increase was not observed, further granulation was conducted using additional purified water. When significant power increase was attained, the mixture was granulated for one additional minute (chopper and mixer on high).
The contents of the high intensity masser were discharged into a fluid bed dryer bowl and dried to provide a loss on drying of not more than 0.8~7o using a gravimetric moisture tester. The bowl of wet granulation was positioned in an Aeromatic Dryer, and the filter bag was shaken manually, as needed, to keep most of the granulation in the dryer 2 0 bowl. A shock cycle and/or agitator was used as needed to fluidize any stationary material.
The bowl was removed from the fluid bed dryer, and its contents were discharged, with an inverter cone-attached, into an impact mill, granulation mill dried through a 2AA
band (or 14 mesh screen) at medium speed with knives Forward, and discharged into appropriate containers.
LUBRICATION
Approximately one-half of the granulation was charged into a V-blender followed by sodium croscarmellase (100.64 kg), microcrystallinc cellulose (PH-102, 236.64 kg), magnesium stearate (29.92 kg), and colloidal silicon dioxide (1(1.88 kg) through a 30 mesh 3 0 screen using a speed sifter, followed by transfer of the remainder of the granulation, and blended for at least 30 minutes using a 15U cubic foot V-blender or for at least 20 minutes using a 75 cubic foot V-blender, and discharged into appropriate containers.
Room RH
control must not be more than 2~% Ior low setting) during this step.
5 The tablets were compressed using a rotary tablet compressing machine installed with ovaloid lower punch with Abbo Code KL and ovaloid upper punch with Abbott Corporate Logo. A de-duster was employed, as necessary. The theoretical weight of 10 tablets was 7.50g.
COLOR COAT>TIG LIQUID MANUFACTURE
A color coating liquid was prepared by adding a portion of purified water (792.82L) into the mix tank, mixing at high speed while reducing speed, as necessary to minimize foaming, treating the mixture with Opadry Yellow~ (YS-5-12749, 85.65 kg) and propylene glycol (21.63 kg), mixing until all solid dissolved, and mixing the coating liquid at least one hour prior to sampling.
The tablets were coated with 400 mL of color coating liquid per kg weight of uncoated tablets using an Accela-Cota or equivalent size vented perforated pan coater.
The target run size for 60" pan water is approximately 245 kg. Mixers were used to maintain motion in the liquids to keep the solids suspended. A distance between the nozzles and tablet bed was maintained while running. These parameters are summarized in TABLE 1 below.
Parameter Set PointRange Unit () of Measure Air Supply Upper Limit 95 NIA C
Temperature for Color Exhaust Air Temperature 48 5 C
for Color Application Supply Air Rate ~ 4000 NIA SCFM
Liquid Flow Rate, Volume,0.65 0.2 Kg/min Color ' Atomization Pressure for 80 ~ 5 ~ PSIG
C."olor _g_ Pan Speed ~ 6 2 RPM
Distance Between Nozzles 9 1 Inches and Tablet Bed, Coior The foregoing is merely illustrative of the invention and is not intended to limit the same to the disclosed compounds and processes. Variations and changes which arc obvious to one skilled in the art, as defined in the claims, are intended to be within the scope and nature of the invention.
RESALTS
5 Summaries (mean ~ standard deviation) of the phannacokinetic parameter estimates for clarithromycin are presented hereinbelow.
Regimen Cmax ~rmax AUCo_i;", AUC.'o_" 1n2 A 2.9811.12h'' 2.511.0' 16.816.(1 17.316.2 4.3 10 B 2.3810.86 1.910.8' 16.315.0 17.816.8 4.3 C 2.6511.17 2.4~0.6 2.416.5 16.116.6 4.3 D 2.3910.98 2.412,1 16.916.0 !7.616.1 4.7 3Significantly different (p<U.OS) From reference formulation under fasting conditions 15 (Regimen D).
bSignificantly different (p<0.05) from reference formulation under nonfasting conditions (Regimen C).
'Significantly different (p<0.05) from test formulation under fasting conditions (Regimen B).
20 Half-life is presented as the harmonic mean: this parameter was not subjected to statistical analysis.
These data illustrate the bioequivalence of the abridged and non-abridged 500 mg clarithromycin formulations.
25 The following will provide a better understanding of the compositions and processes of this invention.
Both microcrystalline celluloses were purchased from FMC BioPolymer (Cork, Ireland); Magnesium Stearate was purchased from Mallinckrodt-Baker, Inc (ST
Louis, 3 0 Mo); Collodial silicon dioxide was purchased from Cabot Corp. (Tuscola.
IL); povidone was purchased from ISP Technologies (Texas City. TX); sodium croscarmellose was purchased from Noviant (Nijmegan, Netherlands); or from FMC BioPolymer (Newark, DE).
_7_ GRANULATION
Povidone (K-value Range 29-32, 125.8() kg) was dissolved in purified water (1384.89 kg) to prepare an approximately 8.33% w/w solution.
5 Clarithromycin bulk drug (1360.(X) kg), sodium croscarmellose (100.64 kg), and microcrystalline cellulose, (1'H-101, I(X>.64 kg) were charged into a high intensity 1200L
Gral masser bowl, mixed for 5 minutes on low speed (chopper off), treated with the 8.33%
w/w povidone in water (U.774 kg of solution per kg of material to be granulated) at the rate of 30 kg per minute at low speed (chupper and mixer), and granulated on high speed (chopper and mixer) for 4 minutes (9 minutes total granulation time).
A power increase from the baseline was determined, and if the significant power increase was observed, the next step was conducted immediately. If a significant power increase was not observed, further granulation was conducted using additional purified water. When significant power increase was attained, the mixture was granulated for one additional minute (chopper and mixer on high).
The contents of the high intensity masser were discharged into a fluid bed dryer bowl and dried to provide a loss on drying of not more than 0.8~7o using a gravimetric moisture tester. The bowl of wet granulation was positioned in an Aeromatic Dryer, and the filter bag was shaken manually, as needed, to keep most of the granulation in the dryer 2 0 bowl. A shock cycle and/or agitator was used as needed to fluidize any stationary material.
The bowl was removed from the fluid bed dryer, and its contents were discharged, with an inverter cone-attached, into an impact mill, granulation mill dried through a 2AA
band (or 14 mesh screen) at medium speed with knives Forward, and discharged into appropriate containers.
LUBRICATION
Approximately one-half of the granulation was charged into a V-blender followed by sodium croscarmellase (100.64 kg), microcrystallinc cellulose (PH-102, 236.64 kg), magnesium stearate (29.92 kg), and colloidal silicon dioxide (1(1.88 kg) through a 30 mesh 3 0 screen using a speed sifter, followed by transfer of the remainder of the granulation, and blended for at least 30 minutes using a 15U cubic foot V-blender or for at least 20 minutes using a 75 cubic foot V-blender, and discharged into appropriate containers.
Room RH
control must not be more than 2~% Ior low setting) during this step.
5 The tablets were compressed using a rotary tablet compressing machine installed with ovaloid lower punch with Abbo Code KL and ovaloid upper punch with Abbott Corporate Logo. A de-duster was employed, as necessary. The theoretical weight of 10 tablets was 7.50g.
COLOR COAT>TIG LIQUID MANUFACTURE
A color coating liquid was prepared by adding a portion of purified water (792.82L) into the mix tank, mixing at high speed while reducing speed, as necessary to minimize foaming, treating the mixture with Opadry Yellow~ (YS-5-12749, 85.65 kg) and propylene glycol (21.63 kg), mixing until all solid dissolved, and mixing the coating liquid at least one hour prior to sampling.
The tablets were coated with 400 mL of color coating liquid per kg weight of uncoated tablets using an Accela-Cota or equivalent size vented perforated pan coater.
The target run size for 60" pan water is approximately 245 kg. Mixers were used to maintain motion in the liquids to keep the solids suspended. A distance between the nozzles and tablet bed was maintained while running. These parameters are summarized in TABLE 1 below.
Parameter Set PointRange Unit () of Measure Air Supply Upper Limit 95 NIA C
Temperature for Color Exhaust Air Temperature 48 5 C
for Color Application Supply Air Rate ~ 4000 NIA SCFM
Liquid Flow Rate, Volume,0.65 0.2 Kg/min Color ' Atomization Pressure for 80 ~ 5 ~ PSIG
C."olor _g_ Pan Speed ~ 6 2 RPM
Distance Between Nozzles 9 1 Inches and Tablet Bed, Coior The foregoing is merely illustrative of the invention and is not intended to limit the same to the disclosed compounds and processes. Variations and changes which arc obvious to one skilled in the art, as defined in the claims, are intended to be within the scope and nature of the invention.
Claims
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An aqueous abridged antibacterial composition for pediatric use consisting essentially of 125 or 250 mg of clarithromycin per 5 mL, an intra-granular excipient, and an extra-granular excipient, in which the intra-granular excipient consists essentially of povidone, sodium croscarmellose, and microcrystalline cellulose (Avicel®
PH-101), and the extra-granular excipient consists essentially of sodium croscarmellose, microcrystalline (Avicel® PH-102), colloidal silicon dioxide (Cab-O-Sil .TM. M-5), and impalpable magnesium stearate powder, wherein the abridged composition omits proof alcohol, stearic acid, talc, pre-gelatinized starch, and D&C yellow dye No. 10.
PH-101), and the extra-granular excipient consists essentially of sodium croscarmellose, microcrystalline (Avicel® PH-102), colloidal silicon dioxide (Cab-O-Sil .TM. M-5), and impalpable magnesium stearate powder, wherein the abridged composition omits proof alcohol, stearic acid, talc, pre-gelatinized starch, and D&C yellow dye No. 10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2433962A CA2433962C (en) | 2002-07-19 | 2002-07-19 | Antibacterial clarithromycin compositions and processes for making the same |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2433962A CA2433962C (en) | 2002-07-19 | 2002-07-19 | Antibacterial clarithromycin compositions and processes for making the same |
| CA002393614A CA2393614C (en) | 2002-07-19 | 2002-07-19 | Antibacterial clarithromycin compositions and processes for making the same |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002393614A Division CA2393614C (en) | 2002-07-19 | 2002-07-19 | Antibacterial clarithromycin compositions and processes for making the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2433962A1 CA2433962A1 (en) | 2002-10-28 |
| CA2433962C true CA2433962C (en) | 2012-10-30 |
Family
ID=4171189
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2433962A Expired - Lifetime CA2433962C (en) | 2002-07-19 | 2002-07-19 | Antibacterial clarithromycin compositions and processes for making the same |
| CA002393614A Expired - Lifetime CA2393614C (en) | 2002-07-19 | 2002-07-19 | Antibacterial clarithromycin compositions and processes for making the same |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002393614A Expired - Lifetime CA2393614C (en) | 2002-07-19 | 2002-07-19 | Antibacterial clarithromycin compositions and processes for making the same |
Country Status (1)
| Country | Link |
|---|---|
| CA (2) | CA2433962C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20050062514A (en) * | 2002-07-16 | 2005-06-23 | 랜박시 래보러터리스 리미티드 | Dispersible tablets for oral administration |
| TR201010860A2 (en) * | 2010-11-05 | 2012-05-21 | Bi̇lgi̇ç Mahmut | Production method for cefdinir formulations. |
| TR201009167A2 (en) * | 2010-11-05 | 2012-05-21 | Bi̇lgi̇ç Mahmut | Pharmaceutical granules containing cephalosporin. |
-
2002
- 2002-07-19 CA CA2433962A patent/CA2433962C/en not_active Expired - Lifetime
- 2002-07-19 CA CA002393614A patent/CA2393614C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2393614C (en) | 2003-09-30 |
| CA2433962A1 (en) | 2002-10-28 |
| CA2393614A1 (en) | 2002-10-28 |
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