WO1995009601A1 - Utilisation de l'azithromycine pour le traitement de la parodontite de l'adulte - Google Patents

Utilisation de l'azithromycine pour le traitement de la parodontite de l'adulte Download PDF

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Publication number
WO1995009601A1
WO1995009601A1 PCT/US1994/010804 US9410804W WO9509601A1 WO 1995009601 A1 WO1995009601 A1 WO 1995009601A1 US 9410804 W US9410804 W US 9410804W WO 9509601 A1 WO9509601 A1 WO 9509601A1
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WO
WIPO (PCT)
Prior art keywords
azithromycin
carrier
composition
oral
treatment
Prior art date
Application number
PCT/US1994/010804
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English (en)
Inventor
Kenneth Shyer Kornman
Original Assignee
The Procter & Gamble Company
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
Application filed by The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to JP7510845A priority Critical patent/JPH09503504A/ja
Priority to EP94930468A priority patent/EP0721324A1/fr
Priority to AU79579/94A priority patent/AU7957994A/en
Publication of WO1995009601A1 publication Critical patent/WO1995009601A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/602—Glycosides, e.g. rutin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0063—Periodont
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

  • This invention involves a novel use of azithromycin for treating adult periodontitis.
  • Periodontal disease comprises a group of inflammatory conditions of periodontal tissues with a common etiologic agent: bacteria in the form of dental plaque.
  • Periodontal disease is the most frequent cause of tooth loss in adults. After 40 years of age, the majority of the population exhibits some sign of periodontitis. Periodontitis develops following plaque accumulation and will not develop in the absence of plaque. If plaque is present, the bacteria metabolize and produce acids and toxins which can irritate the gums and cause gingival inflammation, gingivitis. Although not all gingivitis sites in the presence of plaque develop loss of connective tissue attachment and/or alveolar bone resorption (a disease called periodontitis) all periodontitis is preceded by gingivitis. Although it is unknown what triggers the conversion from gingivitis to periodontitis, it could be bacterial accumulation due to poor oral hygiene, or systemic factors, or a combination of these.
  • Tissue destruction may occur as a slow continuous process, or as the result of repeated episodes of active disease alternating with intervals of disease remission and repair.
  • An individual may have sites within his or her mouth which are healthy and others which have varying stages of disease coexisting.
  • Periodontitis There are several different forms of periodontitis in humans. The distinct diseases may have different etiologies and are likely to progress and respond differently to a given therapy. Common adult periodontitis is the most common form of periodontitis and typically does not appear until a subject is 35 years of age or older. It is preceded by gingivitis and the establishment of a pathogenic subgigival microflora. The presence of microbial deposits and calculus is usually commensurate with the amount of periodontal destruction. When host defenses are insufficient, specific pathogens in the subgingival microflora will increase and cause tissue breakdown.
  • the subgingival microflora in periodontitis is very complex microbiota with elevated proportions of motile, gram-negative, capnophilic and anaerobic species. There are specific microorganisms that appear to be more strongly associated with these lesions.
  • the main microorganisms associated with adult periodontitis are: Porphyromonas gingivalis, Prevotella intermedia; Eikenella corrodens, Fusobacterium nucleatum; Wolinella recta; Selenomonas sproda; Eubacterium timidum, Eubacterium brachyii, Peptosteptococcus micros; and spirochetes, including Treponema denticola.
  • Rapidly progressive periodontitis is a clinical condition which affects yound adults (20-35 years of age) with generalized sever and rapid bone loss. Overt clinical inflammation is not always seen. Small amounts of plaque and calculus may b present. The lesions are associated with elevated proportions of Porphyromonas gingivalis, Bacteroides capillosus, Prevotella intermedia, Bacteroides forsythus, Actinobacillus species, Eikenella corrodens, and Wolinella recta either individually or in different patterns.
  • Refractory adult periodontitis refers to periodontal lesions or clinical conditions which are refractory (unresponsive) to periodontal treatment.
  • the microflora of these lesions are Actinobacillus actinomycetemcomitans (A.a.), Porphyomonas gingivalis and Pr- -tella intermedia. It has been theorized that this group of pathogens is reponi .se for this clinical condition.
  • Juvenile periodontitis typically has an onset age around the age of puberty of a subject.
  • the disease manifests itself as inflammation and rapid destruction of the peridontal tissues around more than one tooth in the permanent dentition. These lesions progress rapidly after onset but tend to slow with time. There is often (not always) a small amount of supragingival plaque and calculus which is not commensurate with the amount of destruction present.
  • A.a. is the most frequently isolated species from subgingival microflora of sites experiencing disease. However, some subgingival pathogens isolated have also been found in elevated proportion in these lesions, including Eikenella corrodens, Fusobacterium nucleatum, Bacteroides capillosus and Eubacterium brachyii.
  • Prepubertal periodontits has its onset during or immediately following eruption of primary teeth (4-8 years of age). This disease typically manifests itself as a very severe and rapid peridontal destruction around the primary teeth.
  • A.a. is the most prominent pathogen frequently associated with other microorganisms such as Selenomonas sproda, Prevotella intermedia, and Eikenella corrodens.
  • some antibiotics are known to be useful in the treatment of adult periodontitis, not all are useful for such therapy. Some, such as tetracycline, tend to encourage the production of resistant strains of bacteria. Some antibiotics, those not having a long half-life, require multiple dosages per day to achieve efficacy. This is not very conducive to consistant compliance by the patient. Some antibiotics can cause systemic complications, such as stomach upset and nausea.
  • compositions and methods of this invention using azithromycin are safe and effective for the treatment of adult periodontitis.
  • Methods of this invention afford efficacy greater than methods among those described in the art.
  • Azithromycin can be delivered perorally, systemically, or topically in the oral cavity.
  • This invention relates to methods for treatment of adult periodontitis in a human or other animal subject, comprising administering to the subject having such disease a safe and effective amount of azithromycin.
  • This invention also relates to compositions for use in such treatment.
  • Periodontitis means an abnormally deep gingival sulcus, which is due to the apical migration of the gingival attachment, associated with periodontitis.
  • Periodontal disease means, those diseases which attack the gingiva and the underlying alveolar bone supporting the teeth. Periodontal disease includes gingivitis (inflammation of the gums), and all forms of periodontitis, as well as series of oral diseases exhibiting various syndromes which vary from each other according to the stage or situation of the disease or the age of the patient, and have not been definitely subclassified.
  • Adult periodontitis refers to the forms of periodontitis typically associated with Porphyromonas gingivalis bacterium, and whose age of onset is about 20 years of age or older; such diseases can include common adult periodontitis, refractory adult periodontitis, and rapidly progressive periodontitis.
  • Adult periodontitis is a condition whose predominant putative ediologic agent is not Actinobacillus actinomycetemcomitans ("A.a ").
  • A.a.- associated periodontitis refers to the clinical conditions of periodontitis whose predominant putative ediologic agent is the bacterium, A.a.; such clinical conditions can include juvenile periodontitis and prepubertal periodontitis.
  • This invention involves methods for treatment of adult periodontitis in a human or other animal subject, comprising administering to the subject having such disease a safe and effective amount of azithromycin.
  • safe and effective amount means an amount of compound or composition sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • the safe and effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending health care provider.
  • 4,517,359 the disclosure of which is incorporated herein by reference.
  • pharmaceutically-acceptable salts of azithromycin including but not limited to the hydrochloride, tartrate, malate, malic, acetate, and sulfate salts.
  • Treatments of adult periodontit'- utilizing azithromycin therapy may be achieved by delivering azithromycin sysiemicaliy, e.g. through peroral dosage, or achieved through sustained release drug delivery, or achieved topically.
  • Dose forms suitable for use in this invention include those which provide systemic delivery of azithromycin.
  • Systemic dosage forms may be any form suitable and safe for human systemic administration, such as tablets, capsules, suspensions, injectable solutions, and other typical systemic dose forms well known in the field.
  • Peroral dosage compositions useful in the methods of this invention are preferably provided in unit dosage form.
  • a "unit dosage form” is a composition of this invention containing an amount of drug, i.e. azithromycin or a pharmaceutically-acceptable salt thereof, that is suitable for administration to a human or other animal subject, in a single dose, according to good medical practice.
  • These compositions preferably contain from about 10 mg (milligrams) to about 1,000 mg, more preferably from about 100 mg to about 750 mg, more preferably from about 250 mg to about 500 mg, also more preferably, from about 300 to about 400 mg of azithromycin or a pharmaceutically-acceptable salt thereof.
  • a variety of pharmaceutically-acceptable gastric delivery carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. The amount of carrier employed in conjunction with the azithromycin is sufficient to provide a practical quantity of material for administration per unit dose. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, each incorporated by reference herein: 7 Modern Pharmaceutics. Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981 ); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).
  • oral dosage forms can be used, including such solid forms as tablets, capsules, granules, and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of azithromycin -or a pharmaceutically-acceptable salt thereof. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • Capsules are presently available under the trade name ZithromaxTM and provided by Pfizer Inc.
  • compositions of this invention for use in treatment of adult periodontitis in a human or other animal subject comprise comprise: a) a safe and effective amount of azithromycin or a pharmaceutically-acceptable salt thereof; and b) a sustained release oral drug delivery system.
  • sustained release oral drug delivery systems may utilize non-bioerodible, biocompatible polymers capable of being formed into a solid, such as those described in U.S. Pat. No. 5,114,718, issued May 19, 1992 to Damani, incorporated herein by reference.
  • Such polymers may include polyurethanes, collagen, polyacrylates, elastomeric copolymers (including polyisobutylene and ethylene vinyl acetate copolymers), cellulosic polymers (including hydroxymethyl cellulose, hyroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose and esters such as cellulose acetate and cellulose acetate phthalate), ethylene vinyl alcohol copolymers, polystyrene, polyvinyl chloride, polycarbonate, and polyethylene among many others.
  • Preferred polymers are ethylene vinyl acetate, polyisobutylene and polyurethane with ethylene vinyl acetate being the preferred material.
  • Sustained release oral drug delivery systems may also utilize bioerodible polymers such as those described in U.S. Pat. 5,198,220, issued Mar. 20, 1993 to Damani, and in U.S. Pat. No. 5,173, 299, issued Dec. 22, 1992 to Damani, both incorporated herein by reference.
  • Other bioerodible polymers useful in this invention include those polymer materials which are safe for use in the oral cavity of a human or other animal, which are solubilized or plasticized by inclusion of leachable solvents and thereby hardened upon placement of compositions containing the polymer into the periodontal tissue, and which slowly degrade in the periodontal tissue.
  • Such polymers are known, including for example polymers and copolymers such as glycerides, polyacrylates, polylactic acid (“PLA”), polyglycolic acid (“PLG”), polylactyl-co- glycolic acid (“PLGA”), polyaminoacids such as polyaspartate, chitosan, collagen, polyalbumin, gelatin, hydrolyzed animal protein, alginic acid and its derivatives, xanthan and other water soluble gums, polyanhydride, and poly orthoesters.
  • Preferred are polymers and copolymers of polylactic acid (“PLA”), polyglycolic acid (“PLG”), and polylactyl-co-glycolic acid (“PLGA”).
  • Preferred bioerodible polymers useful for this invention are the copolymers containing mixtures of lactide and glycolide monomers.
  • Lactide monomeric species preferably comprise from about 15% to about 85%, most preferably from about 35% to about 65% of the polymers, while glycolide monomeric species comprise from about 15% to about 85% of the polymer, preferably from about 35% to about 65% on a molar basis.
  • the molecular weight of the copolymer typically lies in the range of from about 1000 to about 120,000 (number average).
  • fluid gel or paste-like compositions containing such copolymers is their transformation into near solid phase in the presence of aqueous fluid such as water, aqueous buffers, serum, crevicular fluid, or other body fluid.
  • aqueous fluid such as water, aqueous buffers, serum, crevicular fluid, or other body fluid.
  • a sample of such a gel is placed into a tube containing water or human serum, the composition becomes nearly solid in the receptor phase.
  • aqueous fluid such as water, aqueous buffers, serum, crevicular fluid, or other body fluid.
  • compositions of this invention Conventional methods and apparatuses may be used to formulate compositions of this invention. Combinations of polymers may be used.
  • the polymers generally comprise from about 1 % to about 90%, preferably from about 10% to about 70%, of the compositions/devices useful for the methods of this inventions. Generally, for the most preferred copolymers containing lactide and glycolide, less polymer is necessary as the amount of lactide is increased.
  • the amount of azithromycin used in sustained release oral drug delivery compositions of this invention may be from about 0.5% to about 95% preferably from about 5% to about 50%, more preferably from about 10% to about 35% by weight of the composition.
  • the compositions/devices may be designed to release azithromycin to provide a minimum concentration of active drug of from about 1 ⁇ g per milliliter crevicular fluid up to about 5000 ⁇ g per milliliter, more preferably from about 5 ⁇ g per milliliter to about 100 ⁇ g per milliliter crevicular fluid.
  • One ⁇ g per milliliter crevicular fluid is substantially equivalent to 1 ⁇ g per gram gingiva.
  • compositions comprising a "pharmaceutically-acceptable topical oral carrier", as used herein, denotes a carrier for the active compound of this invention comprising solid or liquid filler diluents suitable for use in contact with the oral tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
  • topical oral carrier when combined with an active of this invention, results in a composition which is administered topically to the oral cavity.
  • Such compositions are held in the oral cavity for a period of time, and then largely expectorated rather than being swallowed.
  • Such compositions include dentifrice, toothpaste, mouthwash, mouth rinse, and dental rinse, chewing gum, and lozenge carriers.
  • a safe and effective amount of azithromycin or a pharmaceutically-acceptable salt thereof comprise: a) a safe and effective amount of azithromycin or a pharmaceutically-acceptable salt thereof; and b) a pharmaceutically-acceptable topical oral carrier.
  • Components of such compositions and topical oral carriers are described in U.S. Patent No. 4,994,262 issued Feb. 19, 1991 , to Charbonneau et al., and in U.S. Pat. No. 4,990,329, issued Feb. 5, 1991 , to Sampathkumar; both incorporated herein by reference.
  • the azithromycin would be present at from about 0.01 % to about 2% more preferably from about 0.1% to about 1%, more preferably still from about 0.1% to about 0.5% of a liquid carrier, such as a mouthwash, or a dental rinse. If incorporated into a dentifrice topical oral carrier, the azithromycin would be present at from about 0.1 % to about 20%, more preferably from about 1% to about 10%, more preferably still from about 15% to about 5%.
  • This invention also relates to methods for treatment of adult periodontitis in a human or other animal si : ct, comprising administering to the subject having such disease a safe and elective amount of azithromycin.
  • Systemic dosage forms may be any form suitable and safe for human systemic administration, such as tablets, capsules, suspensions, injectable solutions, and other typical systemic dose forms well known in the field. Capsules are presently available under the trade name ZithromaxTM and provided by Pfizer Inc.
  • the peroral dosage amounts of azithromycin may be from about 10 mg to about 1000 mg per dose, preferably from about 100 mg to about 750 mg, also more preferably still from about 250 mg to about 500 mg, also more preferably from about 300 mg to about 400 mg azithromycin.
  • a dose is taken preferably from once every other day to about four times per day, more preferably from about once per day to about twice per day, more preferably once per day. More preferred still is a 500 mg dose once on a first day and a 250 mg dose once per day thereafter for from about 5 days to about 30 days, more preferably from about 5 days to about 10 days.
  • compositions are administered by gently placing the product in subgingival cavities of infected teeth. If the composition is one which hardens when inserted into the gingival pocket, the composition may be administered with a syringe or like apparatus fitted with a needle or catheter. The composition is injected into or near the base of the pocket; the syringe tip is slowly withdrawn as the pocket is filled. If the composition is one which is solid when inserted, the composition may be inserted into the pocket using dental instruments, including but not limited to, cotton pliers, forceps, a refraction cord, and plastic instruments.
  • dental instruments including but not limited to, cotton pliers, forceps, a refraction cord, and plastic instruments.
  • a solid composition may be trimmed with a scalpel or other sharp instrument to fit a subgingival cavity before insertion.
  • a scalpel or other sharp instrument to fit a subgingival cavity before insertion.
  • from about 0.05 mL to about 2 mL, preferably from about 0.1 mL to about 1 mL of composition is used. If the composition is non-bioerodible, it should be removed from about seven to about fourteen days after insertion. If the composition is bioerodible there should be no need to remove the composition after insertion.
  • compositions may be utilized in conventional fashion, preferably from about once weekly to about three times daily, more preferably from about twice weekly to about twice daily, more preferably still from about once daily to about twice daily.
  • compositions of this invention can be made using methods which are commonly used to produce oral care products.
  • Example I The compositions of this invention can be made using methods which are commonly used to produce oral care products.
  • composition The following is a representative example of a a syringeable gel composition.
  • Component % wt of composition Component % wt of composition
  • Glycerol monooleate is heated to about 60°C. Hydroxypropyl methylcellulose is dispersed with agitation to uniformity. Azythromycin is mixed at about 40°C to uniformity and the mixture is cooled to room temperature. 0.1 mL of the gel is applied by injecting the gel into the base of a gingival pocket with a syringe fitted with a needle. The syringe tip is withdrawn as the pocket is filled. Once inserted, the composition undergoes a phase transition to cubic crystalline phase with increased viscosity. The sustained release drug delivery system is removed after ten days. The result is reduced gingival inflammation and a decrease in pocket depth.
  • Example II The following is a representative example of a sustained release composition for insertion into a peridontal pocket.
  • the polylactic acid polymer having an average molecular weight of about 4000 is blended with azythromycin.
  • the mixture is blended to uniformity at about 60°C.
  • the blend is extruded to form desired shapes for their insertion into subgingival cavities.
  • a dentist inserts 0.05 mL of the extruded composition into a subgingival cavity of a subject having adult periodontitis using cotton pliers.
  • the composition undergoes gradual degredation and does not need to be removed. The result is a reduction in gingival inflammation and pocketing.
  • a human subject ar'icted with adult periodontitis ingests a dose of 500 mg of azithromycin in the form of two ZithromaxTM capsules (250 mg of azithromycin each) on a first day. For each of five days immediately succeeding the first day, the subject ingests a dose of 250 mg azithromycin in the form of one ZithromaxTM capsule per day. The result is a reduction in gingival inflammation and pocketing.
  • a person introduces fifteen mL of the mouth rinse comprising azithromycin to the oral cavity.
  • the liquid is then agitated for 90 seconds within the oral cavity to obtain a good distribution of the mouth rinse over the tissues of the oral cavity.
  • the mouth rinse is expectorated from the oral cavity. This proceedure is done twice per day for total of ten days. The result is reduced gingival inflammation and pocket depth.

Abstract

L'invention concerne des procédés de traitement de la parodontite de l'adulte chez l'humain ou tout autre animal qui consiste à administrer au sujet atteint de cette maladie une dose inoffensive et efficace d'azithromycine. L'invention porte également sur les compositions utilisées dans ce type de traitement.
PCT/US1994/010804 1993-10-01 1994-09-23 Utilisation de l'azithromycine pour le traitement de la parodontite de l'adulte WO1995009601A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP7510845A JPH09503504A (ja) 1993-10-01 1994-09-23 成人歯周炎の治療のためのアジトロマイシンの用途とこの用途のための局所組成物
EP94930468A EP0721324A1 (fr) 1993-10-01 1994-09-23 Utilisation de l'azithromycine pour le traitement de la parodontite de l'adulte
AU79579/94A AU7957994A (en) 1993-10-01 1994-09-23 Use of azithromycin for the treatment of adult periodontitis and topical compositions for this use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13125293A 1993-10-01 1993-10-01
US08/131,252 1993-10-01

Publications (1)

Publication Number Publication Date
WO1995009601A1 true WO1995009601A1 (fr) 1995-04-13

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PCT/US1994/010804 WO1995009601A1 (fr) 1993-10-01 1994-09-23 Utilisation de l'azithromycine pour le traitement de la parodontite de l'adulte

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EP (1) EP0721324A1 (fr)
JP (1) JPH09503504A (fr)
AU (1) AU7957994A (fr)
CA (1) CA2173109A1 (fr)
PE (1) PE2096A1 (fr)
WO (1) WO1995009601A1 (fr)

Cited By (14)

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WO1995030422A1 (fr) * 1994-05-06 1995-11-16 Pfizer Inc. Formes galeniques a liberation controlee de l'azithromycine
EP0925789A1 (fr) * 1997-12-02 1999-06-30 Pfizer Products Inc. Composition topique contenant de l'azithromycine pour le traitement d'infections oculaires
EP0711506A3 (fr) * 1994-10-14 1999-10-27 Rijksuniversiteit te Groningen Gomme à mâcher
WO2000057866A2 (fr) * 1999-03-31 2000-10-05 Insite Vision Incorporated Traitement ou prevention topique d'infections oculaires
WO2001052662A2 (fr) * 2000-01-24 2001-07-26 Roberto Cappellari Chewing gum degradable
CN1081037C (zh) * 1997-12-29 2002-03-20 锦州九天药业有限公司 阿奇霉素栓及软膏
EP1206930A2 (fr) * 2000-10-20 2002-05-22 KI Dental Incorporated Agent pour le soin ou le traitement buccal
WO2002087596A2 (fr) * 2001-04-27 2002-11-07 Pliva D.D. Nouvelle indication therapeutique d'azithromycine pour le traitement des maladies inflammatoires non infectieuses
WO2004034804A1 (fr) * 2002-07-24 2004-04-29 Nagaoka Co., Ltd. Composition de base de chewing-gum
EP1500389A1 (fr) * 2003-07-24 2005-01-26 Matsumoto Dental University Agent d'elimination de film biologique
US6861411B1 (en) 1997-12-02 2005-03-01 Pfizer, Inc. Method of treating eye infections with azithromycin
US6914051B1 (en) * 2000-06-28 2005-07-05 David M Allen Penetrating antibiotic gel for soft tissue diseases
US7056893B2 (en) 1999-03-31 2006-06-06 Insite Vision, Inc. Topical treatment for prevention of ocular infections
USRE39149E1 (en) 1994-04-29 2006-06-27 Pfizer Inc. Method of administering azithromycin

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US6239112B1 (en) * 1998-07-09 2001-05-29 Merial, Inc. Water miscible macrolide solutions

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EP0711506A3 (fr) * 1994-10-14 1999-10-27 Rijksuniversiteit te Groningen Gomme à mâcher
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US6861411B1 (en) 1997-12-02 2005-03-01 Pfizer, Inc. Method of treating eye infections with azithromycin
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WO2000057866A3 (fr) * 1999-03-31 2001-08-16 Insite Vision Inc Traitement ou prevention topique d'infections oculaires
US7749970B2 (en) 1999-03-31 2010-07-06 Insite Vision Incorporated Topical treatment of prevention of ocular infections
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WO2001052662A3 (fr) * 2000-01-24 2002-03-14 Roberto Cappellari Chewing gum degradable
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EP1206930A2 (fr) * 2000-10-20 2002-05-22 KI Dental Incorporated Agent pour le soin ou le traitement buccal
WO2002087596A3 (fr) * 2001-04-27 2003-01-03 Pliva D D Nouvelle indication therapeutique d'azithromycine pour le traitement des maladies inflammatoires non infectieuses
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WO2004034804A1 (fr) * 2002-07-24 2004-04-29 Nagaoka Co., Ltd. Composition de base de chewing-gum
US7820213B2 (en) 2002-07-24 2010-10-26 Nagaoka & Co., Ltd. Chewing gum base composition
EP1500389A1 (fr) * 2003-07-24 2005-01-26 Matsumoto Dental University Agent d'elimination de film biologique

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EP0721324A1 (fr) 1996-07-17
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CA2173109A1 (fr) 1995-04-13
JPH09503504A (ja) 1997-04-08

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