[go: up one dir, main page]

US20060039969A1 - Extended release formulations of erythromycin derivatives - Google Patents

Extended release formulations of erythromycin derivatives Download PDF

Info

Publication number
US20060039969A1
US20060039969A1 US11/091,637 US9163705A US2006039969A1 US 20060039969 A1 US20060039969 A1 US 20060039969A1 US 9163705 A US9163705 A US 9163705A US 2006039969 A1 US2006039969 A1 US 2006039969A1
Authority
US
United States
Prior art keywords
clarithromycin
composition
equal amount
lower mean
max
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/091,637
Inventor
Gerard Notario
Robert Palmer
Richard Hom
Jie Zhang
Karen Devcich
Susan Semla
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23651825&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20060039969(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US08/838,900 external-priority patent/US6010718A/en
Application filed by Individual filed Critical Individual
Priority to US11/091,637 priority Critical patent/US20060039969A1/en
Publication of US20060039969A1 publication Critical patent/US20060039969A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • 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.
  • 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.
  • the 6-O-methoxyerythromycin A clarithromycin
  • 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 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.
  • the C max values are not statistically significantly different from those for the IR formulation.
  • the C 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.
  • 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.
  • 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.
  • 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.
  • the present invention is an extended release pharmaceutical composition
  • an erythromycin derivative and a pharmaceutically acceptable polymer, wherein the composition has an improved taste profile relative to the immediate release formulation.
  • FIG. 1 illustrates the mean in vivo plasma concentration-time profiles following single dose of three 500 mg ER tablets containing clarithromycin and 10%, 20% or 30%, respectively, by weight of hydroxy-propylmethyl cellulose K 100 LV, as compared to that of the reference 500 mg IR clarithromycin tablet.
  • FIG. 2 illustrates the mean in vivo plasma concentration-time profiles following multiple doses of each of the two ER tablets containing 10% or 20%, respectively, of hydroxypropylmethyl cellulose K100 LV as compared to the reference IR tablet.
  • the dosage forms included two 500 mg ER tablets given once daily or one IR 500 mg clarithromycin every 12 hours, respectively, administered for three days with food.
  • FIG. 3 illustrates the mean in vivo plasma concentration-time profiles following multiple doses of clarithromycin once-daily 1000 mg (not an example of the invention) and IR 500 mg twice-a-day.
  • 500 mg or 1000 mg means the strength of tablet composition containing 500 mg clarithromycin, or the dose administered as 2 ⁇ 500 mg of clarithromycim, respectively.
  • C max means maximum plasma concentration of the erythromycin derivative, produced by the ingestion of the composition of the invention or the IR comparator.
  • C min 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 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.
  • DFL Degree of Fluctuation
  • 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.
  • 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.
  • 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.
  • the polymer is selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and methyl cellulose. More preferably, the polymer is hydroxypropylmethyl cellulose.
  • 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 MethocelTM 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • 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 claritdromycin 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.
  • MethocelTM (K 100 LV) available from The Dow Chemical Company was loaded into a mixer, and dry blended with clarithromycin. The mixture was granulated using water until proper granulation was obtained. The granulation was then dried, sifted and ground to appropriate size.
  • Talc and magnesium stearate were screened and blended with dry granulation. The granulation was then loaded into hopper and compressed into tablets. The tablets were then coated with an aqueous coating.
  • 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.
  • 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.
  • 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.
  • 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 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 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • C max C min T max AUC 0-24 Fluctuation Formulation ( ⁇ g/ml) ( ⁇ g/ml) (h) ( ⁇ g ⁇ h/mL0 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 3.21 ⁇ 0.78 0.78 ⁇ 0.29 1.9 ⁇ 0.6 40.8 ⁇ 11.8 1.47 ⁇ 0.26 Reference *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 Comparison Point Estimate 90% Confidence Interval A vs Reference 0.964 0.893-1.039 B vs Reference 0.970 0.899-1.046
  • 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.
  • 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.
  • Example 1 500 mg tablets
  • IR BIAXIN reference 500 mg tablet
  • 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 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).
  • ER extended-release clarithromycin
  • IR immediate-release clarithromycin
  • AMS acute maxillary sinusitis
  • AECB acute bacterial exacerbation of chronic bronchitis
  • clarithromycin ER tablets 500 mg ⁇ 2 QD (1000 mg daily) for 14 days
  • clarithromycin IR tablets 500 mg BID (1000 mg daily) for 14 days.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

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.

Description

  • The present application is a continuation-in-part of U.S. patent application Ser. No. 08/838,900, filed Apr. 11, 1997, now allowed.
    • 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 (Cmax) 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 Cmax values are not statistically significantly different from those for the IR formulation. And while the AUC0-24 is maintained, the Cmin 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.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 illustrates the mean in vivo plasma concentration-time profiles following single dose of three 500 mg ER tablets containing clarithromycin and 10%, 20% or 30%, respectively, by weight of hydroxy-propylmethyl cellulose K 100 LV, as compared to that of the reference 500 mg IR clarithromycin tablet.
  • FIG. 2 illustrates the mean in vivo plasma concentration-time profiles following multiple doses of each of the two ER tablets containing 10% or 20%, respectively, of hydroxypropylmethyl cellulose K100 LV as compared to the reference IR tablet. The dosage forms included two 500 mg ER tablets given once daily or one IR 500 mg clarithromycin every 12 hours, respectively, administered for three days with food.
  • FIG. 3 illustrates the mean in vivo plasma concentration-time profiles following multiple doses of clarithromycin once-daily 1000 mg (not an example of the invention) and IR 500 mg twice-a-day.
    • 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 2×500 mg of clarithromycim, respectively.
  • “Cmax” as used herein, means maximum plasma concentration of the erythromycin derivative, produced by the ingestion of the composition of the invention or the IR comparator.
  • “Cmin” as used herein, means minimum plasma concentration of the erythromycin derivative, produced by the ingestion of the composition of the invention or the IR comparator.
  • “Cavg” as used herein, means the average concentration within the 24-hour interval.
  • “Tmax” as used herein, means time to the maximum observed plasma concentration
  • “AUC” as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete 24 hour interval for all the formulations.
  • “Degree of Fluctuation (DFL)” as used herein, is expressed as: DFL=(Cmax−Cmin)/Cavg.
  • “Erythromycin derivative” as used herein, means erythromycin having no substituent groups, or having conventional substituent groups, in organic synthesis, in place of a hydrogen atom of the hydroxy groups and/or a methyl group of the 3′-dimethylamino group, which is prepared according to the conventional manner.
  • “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.
  • 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 claritdromycin 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™ (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 CR 200.00 100.00 300.00
    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 crossover 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™, 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 Cmax, Tmax, and AUC0-∞, 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
    AUC0-∞
    Formulation Cmax (μg/ml) Tmax (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 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 Cmax, AUC0-∞, Tmax, and the logarithms of Cmax, and AUC0-∞, 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 AUC0-∞, 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 AUC0-∞ 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 AUC0-∞ central values were lower for the three ER formulations than for the reference IR tablet. The lower Cmax values and the later Tmax values suggest that all the ER formulations with varying weight percent of polymer, provide extended-release of clarithromycin in vivo.
  • The lower AUC0-∞ 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 Cmax, Tmax, AUC0-∞ or AUC0-48, and t1/2. For the Day 5 data, the parameters estimated included Cmax, Tmax, Cmin, AUC0-24, and DFL.
  • Statistical Analyses
  • No statistical analyses were performed on the bioassay data. Analyses of variance (ANOVA) were performed for Day 1 and Day 5 pharmacokinetic variables with effects for regimen, period, sequence, and subject nested within sequence. The Cmax and AUC0- values for Regimen C were normalized to a 1000 mg dose. For the Day 1 and Day 5 AUC and Cmax 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
    Cmax Cmin Tmax AUC0-24 Fluctuation
    Formulation (μg/ml) (μg/ml) (h) (μg · h/mL0 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 3.21 ± 0.78 0.78 ± 0.29 1.9 ± 0.6 40.8 ± 11.8 1.47 ± 0.26
    Reference

    *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 AUC0-24 are set forth in Table V below. The results presented are for logarithmic-transformed clarithromycin AUC0-24 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 AUC0-24. The significantly lower Cmax central values and later Tmax values suggest that both the formulations provide extended release of clarithromycin in vivo. The significantly lower DFLs indicate that plasma concentrations fluctuate less for the ER tablet regimens than for the IR tablet regimen. Additionally, the significantly lower DFL for Regimen A compared to Regimen B indicates that plasma concentrations from the 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 (2×500 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.
  • 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
    A B Reference
    BODY SYSTEM (Nm 24) (Nm 23) (Nm 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.
    • 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
    1000 mg Clarithromycin
    Once-Daily 500 mg BID
    (Formulation Reference 90%
    PK-Parameter A) (BIAXIN) Point Confidence
    Unit Meana S.D.b Meana S.D.b Estimatorc Interval
    AUC0-24 (μg * h/ml) 27.298 10.086 28.256 10.770 97.4 86.9-109.2
    Cmax (μg/ml) 2.432 0.905 2.701 0.785 89.0 78.2-101.3
    Tmax (h) 5.217 1.858 2.043 0.706
    Cmin (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

    aarithmetic means

    bstandard deviation

    cdefined 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).
  • Study of Gastrointestinal Adverse Effects in Patients
  • 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.
  • Treatment
  • 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.
  • AMS Study
  • 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.
  • AECB Study
  • 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.

Claims (9)

1-20. (canceled)
21. A method of reducing gastrointestinal adverse events associated with clarithromycin therapy comprising: administering an extended release composition comprising clarithromycin wherein upon administration, the composition provides
a) a lower mean Cmax than the immediate release composition having an equal amount of clarithromycin, and
b) a lower mean Cmax than the controlled release formulation having an equal amount of clarithromycin, a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid.
22. A method of reducing gastrointestinal adverse events associated with clarithromycin therapy comprising: administering an extended release composition comprising clarithromycin wherein upon administration, the composition provides
a) a lower mean degree of flucuation than the immediate release composition having an equal amount of clarithromycin, and
b) a lower mean degree of fluctuation than the controlled release formulation having an equal amount of clarithromycin, a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid.
23. A method of reducing taste perversion associated with clarithromycin therapy comprising: administering an extended release composition comprising clarithromycin wherein upon administration, the composition provides
a) a lower mean Cmax than the immediate release composition having an equal amount of clarithromycin, and
b) a lower mean Cmax than the controlled release formulation having an equal amount of clarithromycin, a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid.
24. A method of reducing taste perversion associated with clarithromycin therapy comprising: administering an extended release composition comprising clarithromycin wherein upon administration, the composition provides
a) a lower mean degree of flucuation than the immediate release composition having an equal amount of clarithromycin, and
b) a lower mean degree of fluctuation than the controlled release formulation having an equal amount of clarithromycin, a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid.
25. A method of increasing compliance with clarithromycin therapy comprising: providing a pharmaceutical composition for extended release of clarithromycin having
a) a lower mean Cmax than the immediate release composition having an equal amount of clarithromycin, and
b) a lower mean Cmax than the controlled release formulation having an equal amount of clarithromycin, a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid.
26. A method of increasing compliance with clarithromycin therapy comprising: providing a pharmaceutical composition for extended release of clarithromycin having
a) a lower mean degree of flucuation than the immediate release composition having an equal amount of clarithromycin, and
b) a lower mean degree of fluctuation than the controlled release formulation having an equal amount of clarithromycin, a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid.
27. A method of increasing incidence of completion of a prescribed antibiotic therapy comprising providing a pharmaceutical compositon for extended release of clarithromycin having
a) a lower mean Cmax than the immediate release composition having an equal amount of clarithromycin, and
b) a lower mean Cmax than the controlled release formulation having an equal amount of clarithromycin, a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid.
28. A method of increasing incidence of completion of a prescribed antiobiotic therapy comprising providing a pharmaceutical compositon for extended release of clarithromycin having
a) a lower mean degree of flucuation than the immediate release composition having an equal amount of clarithromycin, and
b) a lower mean degree of fluctuation than the controlled release formulation having an equal amount of clarithromycin, a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid.
US11/091,637 1997-04-11 2005-03-28 Extended release formulations of erythromycin derivatives Abandoned US20060039969A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/091,637 US20060039969A1 (en) 1997-04-11 2005-03-28 Extended release formulations of erythromycin derivatives

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US4384897P 1997-04-11 1997-04-11
US08/838,900 US6010718A (en) 1997-04-11 1997-04-11 Extended release formulations of erythromycin derivatives
US09/416,916 US6551616B1 (en) 1997-04-11 1999-10-13 Extended release formulations of erythromycin derivatives
US10/302,166 US6872407B2 (en) 1997-04-11 2002-11-22 Extended release formulations of erythromycin derivatives
US11/091,637 US20060039969A1 (en) 1997-04-11 2005-03-28 Extended release formulations of erythromycin derivatives

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/302,166 Continuation US6872407B2 (en) 1997-04-11 2002-11-22 Extended release formulations of erythromycin derivatives

Publications (1)

Publication Number Publication Date
US20060039969A1 true US20060039969A1 (en) 2006-02-23

Family

ID=23651825

Family Applications (3)

Application Number Title Priority Date Filing Date
US09/416,916 Expired - Lifetime US6551616B1 (en) 1997-04-11 1999-10-13 Extended release formulations of erythromycin derivatives
US10/302,166 Expired - Lifetime US6872407B2 (en) 1997-04-11 2002-11-22 Extended release formulations of erythromycin derivatives
US11/091,637 Abandoned US20060039969A1 (en) 1997-04-11 2005-03-28 Extended release formulations of erythromycin derivatives

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US09/416,916 Expired - Lifetime US6551616B1 (en) 1997-04-11 1999-10-13 Extended release formulations of erythromycin derivatives
US10/302,166 Expired - Lifetime US6872407B2 (en) 1997-04-11 2002-11-22 Extended release formulations of erythromycin derivatives

Country Status (14)

Country Link
US (3) US6551616B1 (en)
EP (1) EP1223949A1 (en)
KR (1) KR20020068522A (en)
AR (1) AR026045A1 (en)
AU (1) AU1203601A (en)
BG (1) BG106683A (en)
BR (1) BR0010485A (en)
CA (1) CA2387621A1 (en)
HU (1) HUP0203540A3 (en)
IL (1) IL149033A0 (en)
NO (1) NO20021747D0 (en)
PL (1) PL354783A1 (en)
SK (1) SK4862002A3 (en)
WO (1) WO2001026663A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100239478A1 (en) * 2009-02-26 2010-09-23 Johnson Matthey Public Limited Company Filter

Families Citing this family (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6551616B1 (en) * 1997-04-11 2003-04-22 Abbott Laboratories Extended release formulations of erythromycin derivatives
US6565882B2 (en) 2000-02-24 2003-05-20 Advancis Pharmaceutical Corp Antibiotic composition with inhibitor
US6544555B2 (en) 2000-02-24 2003-04-08 Advancis Pharmaceutical Corp. Antibiotic product, use and formulation thereof
AU2578701A (en) * 2000-02-29 2001-09-12 Teva Pharma Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same
US6541014B2 (en) 2000-10-13 2003-04-01 Advancis Pharmaceutical Corp. Antiviral product, use and formulation thereof
US20020068078A1 (en) 2000-10-13 2002-06-06 Rudnic Edward M. Antifungal product, use and formulation thereof
US6878751B1 (en) * 2000-10-19 2005-04-12 Imperial College Of Science Technology And Medicine Administration of resveratrol to treat inflammatory respiratory disorders
US20020197314A1 (en) * 2001-02-23 2002-12-26 Rudnic Edward M. Anti-fungal composition
CA2405918A1 (en) * 2001-10-01 2003-04-01 Ind-Swift Limited Controlled release macrolide pharmaceutical formulations
US7815934B2 (en) * 2002-09-20 2010-10-19 Alpharma Pharmaceuticals, Llc Sequestering subunit and related compositions and methods
US20040131662A1 (en) 2003-11-12 2004-07-08 Davidson Robert S. Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films
US9561182B2 (en) * 2003-08-22 2017-02-07 Cure Pharmaceutical Corporation Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals
US8999372B2 (en) * 2002-11-14 2015-04-07 Cure Pharmaceutical Corporation Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use
US20040191302A1 (en) 2003-03-28 2004-09-30 Davidson Robert S. Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films
AU2004258949B2 (en) 2003-07-21 2011-02-10 Shionogi, Inc. Antibiotic product, use and formulation thereof
US8313775B2 (en) 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
AU2004258944B2 (en) 2003-07-21 2011-02-10 Shionogi, Inc. Antibiotic product, use and formulation thereof
US20050025825A1 (en) * 2003-07-31 2005-02-03 Xanodyne Pharmacal, Inc. Tranexamic acid formulations with reduced adverse effects
US20090214644A1 (en) * 2003-07-31 2009-08-27 Xanodyne Pharmaceuticals, Inc. Tranexamic acid formulations with reduced adverse effects
WO2005016311A1 (en) * 2003-08-11 2005-02-24 Advancis Pharmaceutical Corporation Robust pellet
JP2007502294A (en) 2003-08-12 2007-02-08 アドバンシス ファーマスーティカル コーポレイション Antibiotic preparations, their use and preparation
US8246996B2 (en) 2003-08-29 2012-08-21 Shionogi Inc. Antibiotic product, use and formulation thereof
US8460710B2 (en) 2003-09-15 2013-06-11 Shionogi, Inc. Antibiotic product, use and formulation thereof
BRPI0416535A (en) * 2003-12-04 2007-01-09 Pfizer Prod Inc spray freezing process employing an extruder to prepare multiparticulate azithromycin compositions preferably containing a poloxamer and a glyceride
WO2005053639A2 (en) * 2003-12-04 2005-06-16 Pfizer Products Inc. Controlled release multiparticulates formed with dissolution enhancers
CA2547597A1 (en) * 2003-12-04 2005-06-16 Pfizer Products Inc. Multiparticulate compositions with improved stability
US6984403B2 (en) * 2003-12-04 2006-01-10 Pfizer Inc. Azithromycin dosage forms with reduced side effects
WO2005053652A1 (en) 2003-12-04 2005-06-16 Pfizer Products Inc. Multiparticulate crystalline drug compositions containing a poloxamer and a glyceride
CN1889933A (en) * 2003-12-04 2007-01-03 辉瑞产品公司 Azithromycin multiparticulate dosage forms by liquid-based processes
RU2331410C2 (en) * 2003-12-04 2008-08-20 Пфайзер Продактс Инк. Method for pharmaceutical multiparticulates production
WO2005053656A1 (en) * 2003-12-04 2005-06-16 Pfizer Products Inc. Spray-congeal process using an extruder for preparing multiparticulate crystalline drug compositions containing preferably a poloxamer and a glyceride
AU2004308419B2 (en) * 2003-12-24 2011-06-02 Victory Pharma, Inc. Enhanced absorption of modified release dosage forms
US20050244495A1 (en) 2004-03-04 2005-11-03 Xanodyne Pharmaceuticals, Inc. Tranexamic acid formulations
US8022106B2 (en) * 2004-03-04 2011-09-20 Ferring B.V. Tranexamic acid formulations
US20050245614A1 (en) * 2004-03-04 2005-11-03 Xanodyne Pharmaceuticals, Inc. Tranexamic acid formulations
US7947739B2 (en) 2004-03-04 2011-05-24 Ferring B.V. Tranexamic acid formulations
US20090215898A1 (en) * 2004-03-04 2009-08-27 Xanodyne Pharmaceuticals, Inc. Tranexamic acid formulations
US20050260263A1 (en) * 2004-05-18 2005-11-24 Panion & Bf Biotech Inc. Sustained release formulation for sparingly soluble main drugs
JP2008505124A (en) 2004-07-02 2008-02-21 アドバンシス ファーマスーティカル コーポレイション Pulse delivery tablets
US8778924B2 (en) * 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
US8357394B2 (en) 2005-12-08 2013-01-22 Shionogi Inc. Compositions and methods for improved efficacy of penicillin-type antibiotics
US8299052B2 (en) 2006-05-05 2012-10-30 Shionogi Inc. Pharmaceutical compositions and methods for improved bacterial eradication
WO2007143507A2 (en) * 2006-06-05 2007-12-13 Auspex Pharmaceuticals, Inc. Preparation and utility of substituted erythromycin analogs
KR20140079441A (en) * 2006-06-19 2014-06-26 알파마 파머슈티컬스 엘엘씨 Pharmaceutical compositions
CA2665726C (en) * 2006-10-11 2016-04-19 Alpharma, Inc. Pharmaceutical compositions
AU2008346870A1 (en) * 2007-12-17 2009-07-16 Alpharma Pharmaceuticals, Llc Pharmaceutical composition
US20100151014A1 (en) * 2008-12-16 2010-06-17 Alpharma Pharmaceuticals, Llc Pharmaceutical composition
US8623418B2 (en) * 2007-12-17 2014-01-07 Alpharma Pharmaceuticals Llc Pharmaceutical composition
EP2224805A4 (en) * 2007-12-17 2013-10-16 Alpharma Pharmaceuticals Llc Pharmaceutical composition
US20100280117A1 (en) * 2009-04-30 2010-11-04 Xanodyne Pharmaceuticals, Inc. Menorrhagia Instrument and Method for the Treatment of Menstrual Bleeding Disorders
WO2011068721A1 (en) * 2009-12-03 2011-06-09 Opko Health, Inc. Hypersulfated disaccharide formulations
TW201815394A (en) 2016-08-16 2018-05-01 美商歐科製藥有限公司 Pure heptasulfated disaccharides having improved oral bioavailability
US10213394B1 (en) 2018-02-15 2019-02-26 Osmotica Kereskedelmi és Szolgáltató Korlátolt Felelõsségû Társaság Composition and method for treating neurological disease
US20190247331A1 (en) 2018-02-15 2019-08-15 Osmotica Kereskedelmi és Szolgáltató Korlátolt Felelõsségû Társaság Composition and method for treating neurological disease
US10213393B1 (en) 2018-02-15 2019-02-26 Osmotica Kereskedelmi és Szolgáltató Korlátolt Feleõsségû Társaság Composition and method for treating neurological disease

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3065143A (en) * 1960-04-19 1962-11-20 Richardson Merrell Inc Sustained release tablet
US3870790A (en) * 1970-01-22 1975-03-11 Forest Laboratories Solid pharmaceutical formulations containing hydroxypropyl methyl cellulose
US4226849A (en) * 1979-06-14 1980-10-07 Forest Laboratories Inc. Sustained release therapeutic compositions
US4369172A (en) * 1981-12-18 1983-01-18 Forest Laboratories Inc. Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose
US4808411A (en) * 1987-06-05 1989-02-28 Abbott Laboratories Antibiotic-polymer compositions
US4842865A (en) * 1986-04-24 1989-06-27 A. Nattermann & Cie Gmbh Use of glycofurol for the liquidization of pharmaceutical preparations to be filled into soft gelatine capsules
US4925675A (en) * 1988-08-19 1990-05-15 Himedics, Inc. Erythromycin microencapsulated granules
US5393765A (en) * 1993-12-13 1995-02-28 Hoffmann-La Roche Inc. Pharmaceutical compositions with constant erosion volume for zero order controlled release
US5633006A (en) * 1992-07-30 1997-05-27 Pfizer Inc. Taste-masking composition of bitter pharmaceutical agents
US5705190A (en) * 1995-12-19 1998-01-06 Abbott Laboratories Controlled release formulation for poorly soluble basic drugs
US5707646A (en) * 1992-03-12 1998-01-13 Taisho Pharmaceutical Co., Ltd. Taste masking pharmaceutical composition
US6010718A (en) * 1997-04-11 2000-01-04 Abbott Laboratories Extended release formulations of erythromycin derivatives
US6551616B1 (en) * 1997-04-11 2003-04-22 Abbott Laboratories Extended release formulations of erythromycin derivatives

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4389393A (en) 1982-03-26 1983-06-21 Forest Laboratories, Inc. Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose
FI69254C (en) 1984-02-01 1986-01-10 Lujari Instmsto Oy ANORDINATION OF THE AVIABILITY OF FASTA AEMNEN FRAON AVFALLSVATTEN
EP0188040B1 (en) 1985-01-11 1991-08-14 Abbott Laboratories Limited Slow release solid preparation
FR2585948B1 (en) 1985-08-06 1988-12-16 Pf Medicament PROCESS FOR THE MANUFACTURE OF INDOMETACIN TABLETS
JPH01308223A (en) 1988-02-22 1989-12-12 Taisho Pharmaceut Co Ltd Production of uniform fine film preparation
US4925765A (en) * 1988-12-23 1990-05-15 E. I. Du Pont De Nemours And Company Negative solid block toner
US5017383A (en) 1989-08-22 1991-05-21 Taisho Pharmaceutical Co., Ltd. Method of producing fine coated pharmaceutical preparation
RO114740B1 (en) 1994-05-06 1999-07-30 Pfizer COMPOSITION WITH CONTROLLED ELEMENT, PROCEDURE FOR OBTAINING THEM AND TREATMENT METHOD
US5919489A (en) 1995-11-01 1999-07-06 Abbott Laboratories Process for aqueous granulation of clarithromycin
US5972389A (en) 1996-09-19 1999-10-26 Depomed, Inc. Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter
DE19706979A1 (en) 1997-02-21 1998-08-27 Lindopharm Gmbh Combination preparation for oral erythromycins
DE19706978A1 (en) 1997-02-21 1998-08-27 Ulrich Dr Posanski Combination preparation for oral antibiotics
EP0943341A1 (en) 1998-02-18 1999-09-22 Oscar Gold Procedure to prepare granulated compositions that contain erythromycin macrolides and procedure to prepare pharmaceutical compositions that contain said macrolides

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3065143A (en) * 1960-04-19 1962-11-20 Richardson Merrell Inc Sustained release tablet
US3870790A (en) * 1970-01-22 1975-03-11 Forest Laboratories Solid pharmaceutical formulations containing hydroxypropyl methyl cellulose
US4226849A (en) * 1979-06-14 1980-10-07 Forest Laboratories Inc. Sustained release therapeutic compositions
US4369172A (en) * 1981-12-18 1983-01-18 Forest Laboratories Inc. Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose
US4842865A (en) * 1986-04-24 1989-06-27 A. Nattermann & Cie Gmbh Use of glycofurol for the liquidization of pharmaceutical preparations to be filled into soft gelatine capsules
US4808411A (en) * 1987-06-05 1989-02-28 Abbott Laboratories Antibiotic-polymer compositions
US4925675A (en) * 1988-08-19 1990-05-15 Himedics, Inc. Erythromycin microencapsulated granules
US5707646A (en) * 1992-03-12 1998-01-13 Taisho Pharmaceutical Co., Ltd. Taste masking pharmaceutical composition
US5633006A (en) * 1992-07-30 1997-05-27 Pfizer Inc. Taste-masking composition of bitter pharmaceutical agents
US5393765A (en) * 1993-12-13 1995-02-28 Hoffmann-La Roche Inc. Pharmaceutical compositions with constant erosion volume for zero order controlled release
US5705190A (en) * 1995-12-19 1998-01-06 Abbott Laboratories Controlled release formulation for poorly soluble basic drugs
US6010718A (en) * 1997-04-11 2000-01-04 Abbott Laboratories Extended release formulations of erythromycin derivatives
US6551616B1 (en) * 1997-04-11 2003-04-22 Abbott Laboratories Extended release formulations of erythromycin derivatives
US6872407B2 (en) * 1997-04-11 2005-03-29 Abbott Laboratories Extended release formulations of erythromycin derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100239478A1 (en) * 2009-02-26 2010-09-23 Johnson Matthey Public Limited Company Filter

Also Published As

Publication number Publication date
NO20021747D0 (en) 2002-04-12
AU1203601A (en) 2001-04-23
HUP0203540A3 (en) 2003-03-28
CA2387621A1 (en) 2001-04-19
KR20020068522A (en) 2002-08-27
US20030133981A1 (en) 2003-07-17
HUP0203540A2 (en) 2003-02-28
US6872407B2 (en) 2005-03-29
AR026045A1 (en) 2002-12-26
BR0010485A (en) 2002-08-20
US6551616B1 (en) 2003-04-22
SK4862002A3 (en) 2002-10-08
WO2001026663A1 (en) 2001-04-19
IL149033A0 (en) 2002-11-10
PL354783A1 (en) 2004-02-23
BG106683A (en) 2002-12-29
EP1223949A1 (en) 2002-07-24

Similar Documents

Publication Publication Date Title
US6551616B1 (en) Extended release formulations of erythromycin derivatives
US6010718A (en) Extended release formulations of erythromycin derivatives
US20050064033A1 (en) Extended release formulations of erythromycin derivatives
CA2358395C (en) Extended release formulations of erythromycin derivatives
CA2325541C (en) Extended release formulations of erythromycin derivatives
AU773863B2 (en) Extended release formulations of erythromycin derivatives
AU2007201031B2 (en) Extended release formulations of erythromycin derivatives
AU2003270948B2 (en) Extended Release Formulations of Erythromycin Derivatives
HK1027023B (en) Extended release formulations of clarithromycin
CA2465698A1 (en) Extended release formulations of erythromycin derivatives
AU2006201001A1 (en) Extended release formulations of erythromycin derivatives

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION