WO1990014094A1 - Composition de clarithromycine injectable - Google Patents

Composition de clarithromycine injectable Download PDF

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Publication number
WO1990014094A1
WO1990014094A1 PCT/US1990/003063 US9003063W WO9014094A1 WO 1990014094 A1 WO1990014094 A1 WO 1990014094A1 US 9003063 W US9003063 W US 9003063W WO 9014094 A1 WO9014094 A1 WO 9014094A1
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WO
WIPO (PCT)
Prior art keywords
composition
clarithromycin
acid
oil
stabilizing agent
Prior art date
Application number
PCT/US1990/003063
Other languages
English (en)
Inventor
Ho-Wah Hui
Chung-Chiang Hsu
John B. Cannon
Michael W. Lovell
Original Assignee
Abbott Laboratories
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 Abbott Laboratories filed Critical Abbott Laboratories
Priority to CA002056445A priority Critical patent/CA2056445A1/fr
Priority to KR1019910701690A priority patent/KR920700655A/ko
Publication of WO1990014094A1 publication Critical patent/WO1990014094A1/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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10C—WORKING-UP PITCH, ASPHALT, BITUMEN, TAR; PYROLIGNEOUS ACID
    • C10C3/00—Working-up pitch, asphalt, bitumen
    • C10C3/002—Working-up pitch, asphalt, bitumen by thermal means
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10C—WORKING-UP PITCH, ASPHALT, BITUMEN, TAR; PYROLIGNEOUS ACID
    • C10C3/00—Working-up pitch, asphalt, bitumen
    • C10C3/06—Working-up pitch, asphalt, bitumen by distillation
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F9/00—Artificial filaments or the like of other substances; Manufacture thereof; Apparatus specially adapted for the manufacture of carbon filaments
    • D01F9/08—Artificial filaments or the like of other substances; Manufacture thereof; Apparatus specially adapted for the manufacture of carbon filaments of inorganic material
    • D01F9/12—Carbon filaments; Apparatus specially adapted for the manufacture thereof
    • D01F9/14—Carbon filaments; Apparatus specially adapted for the manufacture thereof by decomposition of organic filaments
    • D01F9/145—Carbon filaments; Apparatus specially adapted for the manufacture thereof by decomposition of organic filaments from pitch or distillation residues
    • D01F9/155—Carbon filaments; Apparatus specially adapted for the manufacture thereof by decomposition of organic filaments from pitch or distillation residues from petroleum pitch

Definitions

  • This invention relates to injectable compositions of clarithromycin.
  • Lipophilic drugs such as erythromycin and clarithromycin are not administered by intramuscular injection or intravenously because these drugs cause severe pain at the injection site.
  • a variety of approaches have been taken to address this problem, including attempts to derivatize the lipophilic drugs themselves. Nevertheless, there is a continuing need for injectable compositions of lipophilic drugs that do not cause severe pain.
  • the present invention relates to pharmaceutical compositions of clarithromycin for injection.
  • the composition can be delivered by intramuscular or central or peripheral venous routes.
  • the present invention relates to an injectable fat emulsion having a therapeutically effective concentration of clarithromycin which includes a triglyceride oil and a stabilizing agent.
  • compositions of the present invention include compositions comprising an injectable fat emulsion having a therapeutically effective concentration of clarithromycin, a triglyceride oil and a stabilizing agent.
  • the invention also includes compositions which additionally comprise an emulsifier, as well as those containing a tonicity-a justing agent.
  • compositions of the invention are specifically those containing the antibiotic clarithromycin.
  • clarithromycin as used herein is meant 6-0-methyl-erythromycin (see U.S. 4,331,803) and semisynthetic derivatives of clarithromycin known to the art as well as their pharmaceutically acceptable salts and esters.
  • pharmaceutically acceptable salts and esters as used herein is meant those salts and esters 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, commensurate with a reasonable benefit/risk ratio, and effective for their intended use in the chemotherapy and prophylaxis of antimicrobial infections.
  • esters of macrolide antibiotics are the acetate, estolate (lauryl sulfate salt of the propionate ester), ethyl succinate, gluceptate (glucoheptonate), lactobionate, stearate, and hydrochloride forms.
  • acid salts used in the pharmaceutical arts are the following: adipate, alginate, aspartate, benzoate, benzene-sulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, gluconate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene- sulfonate, nicotinate, oxalate, pamoate, pantothenate, pectinate, persulfate, 3-phenylpropionate, pierate, pivalate, propionate, succinate, tartrate, thiocyanate, tos
  • Basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such as decyl,
  • compositions of the invention offer improved solubilization of clarithromycin, higher concentrations are achieved than have previously been attainable.
  • therapeutically effective concentration as used herein is meant the concentration of clarithromycin that is effective to treat or prevent susceptible bacterial or other microbial infections, at a reasonable benefit/risk ratio applicable to any medical treatment, for example 5 mg/ml.
  • the total daily dose of the compositions herein will be decided by the attending physician within the scope of sound medical judgment.
  • the specific total daily dose level for any particular patient will depend upon a variety of factors including age, body weight, general health, sex, diet, time of administration, route of administration (i.e., intramuscular or central or peripheral venous routes), rate of excretion, the severity of the particular disease undergoing therapy, and like factors well known in the medical arts.
  • the preferred therapeutically effective concentration of clarithromycin is from about 2.5 mg/ml to about 10 mg/ml. The most preferred concentration is about 5 mg/ml.
  • triglyceride oil as used herein is meant a triglyceride composition which is liquid at room temperature (22° C) , and which consists primarily of triglycerides of C g to C 18 fatty acids.
  • the triglyceride oil can be short chain (C g to C 12 ) or long chain (C.. to C- 8 ) and preferably C 6 to C 12 aliphatic fatty acids. These triglyceride oils are generally present in a range of from about 2 to about 40%.
  • triglyceride oils of short chain fatty acids is represented by those oils which consist predominantly of glycerol triesters of C- to C- 0 fatty acids.
  • oils can be prepared synthetically by well known techniques, or can be obtained from natural sources by known techniques of thermal or solvent fractionation of suitable natural oils, such as palm oil, to yield fractions rich in the desired low-melting triglycerides.
  • a preferred low-melting, low molecular weight triglyceride oil is a low molecular weight fraction of palm oil which is rich in mixed esters of caprylic (octanoic) and capric (decanoic) acids.
  • Such an oil is commercially available as Neobee ⁇ M-5 oil from PVO International, Inc., of Boonton, New Jersey. Other low-melting cuts of palm oil are also suitable.
  • triglyceride oil consists of triglyceride oils having a high percentage of glycerol triesters of unsaturated or polyunsaturated C ⁇ to C 18 fatty acids.
  • a preferred example of such an oil is safflower oil, which typically has a fatty acid composition of over 90% oleic and linoleic acids. Triglycerides of these acids are liquid at 20°C, while the corresponding saturated triglyceride tristearin is a waxy solid at room temperature and melts at about 72°C.
  • a further preferred example of such an oil is soybean oil.
  • Other low-melting vegetable oils or low-melting fractions of oils which can be obtained by conventional thermal or solvent fractionation, are also suitable.
  • oils may offer a cost advantage in formulating compositions according to this invention, they also exhibit a greater tendency to oxidative deterioration, and may require the addition of oil soluble antioxidants, such as tocopherols.
  • intravenous fat emulsions which are generally prepared from either soybean or safflower oil and provide a mixture of neutral triglycerides containing predominantly unsaturated fatty
  • the major component fatty acids are linoleic, oleic, palmitic, stearic, and linolenic acids.
  • these products can contain egg yolk phospholipids as an emulsifier, and glycerol to adjust tonicity.
  • the emulsified fat particles are generally
  • the triglyceride oil may contain small amounts of mono- and/or diglycerides to enhance solubility of the components or to enhance emulsification.
  • the oil it will be preferable that the oil have a low polarity.
  • the preferred triglyceride oils will be low in the content of mono- and diglycerides, as well as phospholipids, all of which have significant polarity.
  • compositions of the present invention also include at least one stabilizing agent.
  • stabilizing agent as used herein is meant an additive that -1-
  • Stabilizing agents include fatty acids (Co- to C, 2 saturated fatty acids, or unsaturated C 16 to C 18 fatty acids), N-methyl pyrrolidone (NMP), and benzyl alcohol.
  • Preferred fatty acids are oleic decanoic, octanoic and hexanoic acids.
  • Methylene chloride can be utilized, but it must be evaporated off to achieve the final product.
  • the stabilizing agent acts to increase the stability of the emulsion and maintain the suspension for at least six months.
  • the present invention also includes • compositions containing an amulsifier.
  • emulsifier as used herein is meant a compound which prevents the separation of the injectable emulsion into individual lipid and aqueous phases.
  • Suitable emulsifiers include, but are not restricted to, egg yolk phospholipids (approximately 0.5 to 5%); glycodeoxycholic or glycocholic acids or a combination thereof; and non-ionic surfactants (as for example polysorbate, sorbitan monostearate and combinations thereof).
  • compositions of the present invention may also contain minor additives such as compounds to adjust tonicity, as for example glycerol (1-5%) and propylene glycol (1-10%).
  • minor additives such as compounds to adjust tonicity, as for example glycerol (1-5%) and propylene glycol (1-10%).
  • a representative composition of the present invention was prepared as follows:
  • Liposyn ® II 20% 100 ml ..
  • Clarithromycin base 500 mg, available from Abbott Laboratories, Illinois was dissolved in 3 ml NMP (N-methyl pyrrolidone, available from GAF Corp., Wayne N.J.). This
  • compositions of EXAMPLE 2 can generally contain the following relative amounts of ingredients.
  • Neobee ® oil 10-40% decanoic acid 0.5-3% clarithromycin base 0.5-3% egg phosphatide 0.5-3% glycerol 1-4% water q.s.**
  • Solution A was prepared by adding 2.5 gm clarithromycin and 5.6 gm decanoic acid to 100 gm of
  • Neobee oil (a medium chain triglyceride) .
  • the solution was then stirred with heating (approximately 40°C) until dissolved.
  • Solution B was prepared by stirring 6 gm egg phosphatide and 12 gm glycerol into 200 ml of water.
  • Solution B was passed through a Microfluidizer M-llO (Microfluidics Corp.) 3 times.
  • Solution A was then added via a syringe pump at 1 ml/min while the mixture was passed through the microfluidizer. After the addition was completed, the mixture was passed 5 more times through the microfluidizer, adjusted to pH 7.5 with NaOH and diluted to 500 ml with water.
  • the clarithromycin concentration was calculated to be approximately 5 mg/ml.
  • a methylene chloride-containing example of the compositions of the present invention was prepared as follows:
  • Clarithromycin (2.5 gm) and 6 gm egg phosphatide were dissolved in 150 ml methylene chloride. The solution was evaporated to dryness in a rotary evaporator and the residue thin film was taken up, with vortexing, into 200 ml
  • Neobee oil 100 gm was then added via a syringe pump and microfluidizer to the drug-phosphatide mixture as in EXAMPLE 2. The final emulsion was adjusted to pH 7.5 with NaOH and diluted to 500 ml with water.
  • EXAMPLE 2 can be repeated using the solubilizer octanoic acid.
  • Solution A is prepared by adding 2.5 gm clarithromycin base and 4.7 gm octanoic acid to 100 gm of Neobee oil. The solution is then stirred with heating until dissolved.
  • Solution B is prepared by stirring 6 gm egg phosphatide and 12 gm glycerol into 200 ml of water.
  • Solution B is passed through a microfluidizer 3 times.
  • Solution A is then added via a syringe pump while the mixture is passed through the microfluidizer. After the addition is completed, the mixture is passed 5 more times through the microfluidizer, adjusted to pH 7.5 with NaOH and diluted to 500 ml with water.
  • the clarithromycin concentration is calculated to be approximately 5 mg/ml.
  • compositions of the present invention was prepared as follows: Clarithromycin base (5 gm) and soybean oil (20 gm) were mixed to a smooth suspension. Oleic and hexanoic acids (6 gm and 3gm, respectively) were added while stirring and the oil phase mixture heated to 45°C or until clear.
  • egg lecithin 50 gm was dissolved in preheated water (500 ml) and the solution stirred without heat as 12.2 gm NaOH is 50 ml water was added.
  • Glycerin 25 gm was then stirred in and the mixture circulated without cooling (approx. 10-15 min. ) through a Gaulin M-15 homogenizer until 60-65°C and semi-transparent. After transfer of the dispersion to a beaker, and while cooling if necessary to less than 40°C, the above oil phase was gradually blended in using a Silverson mixer at the highest speed possible. Keeping the temperature below 40°C, the mixture was blended an additional 30 minutes.
  • the resulting mixture was then homogenized (30 passes at 6000-7000 p.s.i. at 35-40°C) and the homogenizer rinsed with 450 ml water, the rinse being stirred into the emulsion. After adjusting the pH to 7.7-7.9 with 7% NaOH, the volume was adjusted to 1 liter with water and the emulsion filtered through a 0.2 micron nylon membrane under N 2 gas at about 30 p.s.i.
  • a scratch test was conducted in mice to measure the response to the sensation of irritation, i.e., the pain associated with an injection.
  • ⁇ clarithromycin, NMP, and Liposyn II was administered subcutaneously at a dose of 5 ml/kg to groups of mice (10/group) weighing 16 to 30 g each.
  • a second inventive composition containing the oleic acid/hexanoic acid system of EXAMPLE 5 and a clarithromycin lactobionate standard were similarly tested. The number of times that each mouse scratched the injection site was then counted for exactly five minutes. The results indicate a low scratch response associated with the compounds of the present invention and are summarized in Table 1 below.
  • Clarithromycin in Liposyn II (5 mg/ml) was evaluated for acute vein irritation in rabbits.
  • the test composition was infused into two male and two female rabbits at a rate of 1 ml/minute via the marginal ear vein at a dose volume of 8 ml/kg.
  • the rabbits were observed frequently during and after treatment for signs of local irritation.
  • the injection site appearance at 1 hour, 3 hours and 21 hours was normal with no apparent redness, thus indicating that the composition did not cause local irritation.
  • composition A The antibacterial activity of 5mg/ml compositions of clarithromycin base in Liposyn II for intravenous administration (composition A) was compared to the activity of clarithromycin base lactobionate (composition B) in mouse protection tests.
  • Mice were infected intraperitoneally with 100 5Q doses of Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus pneumoniae (Groups 1, 2 and 3, respectively) and treated one hour after infection by injecting either (A) or (B) intravenously via the tail vein.
  • ED was calculated from cumulative mortalities on the sixth day after infection. The results indicate that the composition has antibacterial activity as shown in Table 2 below.
  • AUC area under curve Mean 31.72
  • composition 24-hr AUC c max ⁇ max (hrs x ug/ml) (ug/ml) (hr)

Abstract

On a mis au point un médicament injectable administré par voie intraveineuse ou intramusculaire, comprenant une concentration thérapeutiquement efficace de clarithromycine, ainsi qu'une huile de triglycéride et un agent stabilisant.
PCT/US1990/003063 1989-05-26 1990-05-25 Composition de clarithromycine injectable WO1990014094A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA002056445A CA2056445A1 (fr) 1989-05-26 1990-05-25 Composition de clarithromycine injectable
KR1019910701690A KR920700655A (ko) 1989-05-26 1990-05-25 주사가능한 클라리트로마이신 조성물

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US35828389A 1989-05-26 1989-05-26
US358,283 1989-05-26

Publications (1)

Publication Number Publication Date
WO1990014094A1 true WO1990014094A1 (fr) 1990-11-29

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ID=23409043

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1990/003063 WO1990014094A1 (fr) 1989-05-26 1990-05-25 Composition de clarithromycine injectable

Country Status (9)

Country Link
EP (1) EP0473707A4 (fr)
JP (1) JP2963537B2 (fr)
KR (1) KR920700655A (fr)
AU (1) AU630469B2 (fr)
CA (1) CA2056445A1 (fr)
GR (1) GR1002177B (fr)
IL (1) IL94516A (fr)
NZ (1) NZ233827A (fr)
WO (1) WO1990014094A1 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2278780A (en) * 1993-05-27 1994-12-14 Sandoz Ltd Macrolide antibiotic emulsions
WO1995026191A1 (fr) * 1994-03-26 1995-10-05 Boehringer Ingelheim Vetmedica Gmbh Solutions injectables de dirithromycine
EP0758549A1 (fr) * 1994-04-26 1997-02-19 Nobuhiro Narita Composition medicinale servant de medicament contre le cancer bronchopulmonaire "non a petites cellules"
US5726181A (en) * 1995-06-05 1998-03-10 Bionumerik Pharmaceuticals, Inc. Formulations and compositions of poorly water soluble camptothecin derivatives
US5932243A (en) * 1993-05-27 1999-08-03 Novartis Ag Galenical formulations
US6017948A (en) * 1998-10-30 2000-01-25 Supergen, Inc. Water-miscible pharmaceutical compositions
WO2003049716A1 (fr) * 2001-12-13 2003-06-19 Ranbaxy Laboratories Limited Formulation topique stable de clarithromycine
WO2005016308A1 (fr) * 2003-08-06 2005-02-24 Sd Pharmaceuticals, Inc. Emulsions huile dans eau contenant des macrolides
DE4447972B4 (de) * 1993-05-27 2007-12-27 Novartis Ag Galenische Formulierungen
US7871632B2 (en) 2004-07-12 2011-01-18 Adventrx Pharmaceuticals, Inc. Compositions for delivering highly water soluble drugs
US8268876B2 (en) 2006-03-08 2012-09-18 Nihon Nohyaku Co., Ltd. Pharmaceutical composition for external use
US8349882B2 (en) 2006-03-08 2013-01-08 Nihon Nohyaku Co., Ltd. Pharmaceutical composition for external use
US8513296B2 (en) 2007-09-05 2013-08-20 Pola Pharma Inc. Pharmaceutical composition
US8952044B2 (en) 2009-08-25 2015-02-10 Pola Pharma Inc. Antimycotic pharmaceutical composition
WO2015068397A1 (fr) 2013-11-08 2015-05-14 株式会社アクティバスファーマ Préparation d'une suspension aqueuse comprenant des nanoparticules d'agent antibactérien macrolide
US9050271B2 (en) 2009-04-09 2015-06-09 Pola Pharma Inc. Antimycotic pharmaceutical composition
US9480678B2 (en) 2007-09-05 2016-11-01 Pola Pharma Inc. Antifungal pharmaceutical composition
US9968591B2 (en) 2007-09-05 2018-05-15 Pola Pharma Inc. Antifungal composition
WO2018185557A1 (fr) * 2017-04-03 2018-10-11 The Center For Digestive Diseases Administration de composés antibiotiques pour le traitement d'infections streptococciques, pour le traitement du psoriasis
US10130610B2 (en) 2009-04-09 2018-11-20 Pola Pharma Inc. Antimycotic pharmaceutical composition

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US6946137B2 (en) * 2001-10-19 2005-09-20 Idexx Laboratories, Inc. Methods for the controlled delivery of pharmacologically active compounds

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IL87219A0 (en) * 1987-08-07 1988-12-30 Abbott Lab Erythromycin formulations for oral administration
US5338761A (en) * 1988-09-29 1994-08-16 Shiseido Company Ltd. Emulsified composition

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JPS61291520A (ja) * 1985-06-19 1986-12-22 Daigo Eiyou Kagaku Kk エリスロマイシン脂肪乳剤

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6565859B1 (en) 1993-05-27 2003-05-20 Novartis Ag Galenical formulations
DE4418115B4 (de) * 1993-05-27 2009-07-23 Novartis Ag Galenische Formulierungen
GB2278780B (en) * 1993-05-27 1998-10-14 Sandoz Ltd Macrolide formulations
DE4447972B4 (de) * 1993-05-27 2007-12-27 Novartis Ag Galenische Formulierungen
US5932243A (en) * 1993-05-27 1999-08-03 Novartis Ag Galenical formulations
GB2278780A (en) * 1993-05-27 1994-12-14 Sandoz Ltd Macrolide antibiotic emulsions
US7025975B2 (en) 1993-05-27 2006-04-11 Novartis Ag Galenical formulations
WO1995026191A1 (fr) * 1994-03-26 1995-10-05 Boehringer Ingelheim Vetmedica Gmbh Solutions injectables de dirithromycine
EP0758549A1 (fr) * 1994-04-26 1997-02-19 Nobuhiro Narita Composition medicinale servant de medicament contre le cancer bronchopulmonaire "non a petites cellules"
EP0758549A4 (fr) * 1994-04-26 1997-07-02 Nobuhiro Narita Composition medicinale servant de medicament contre le cancer bronchopulmonaire "non a petites cellules"
US5955467A (en) * 1995-06-05 1999-09-21 Bionumerik Pharmaceuticals, Inc. Pharmaceutical formulations of poorly water soluble camptothecin analogues and NMP
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JPH04505762A (ja) 1992-10-08
IL94516A (en) 1994-12-29
GR1002177B (en) 1996-03-07
EP0473707A4 (en) 1992-12-09
AU5811090A (en) 1990-12-18
CA2056445A1 (fr) 1990-11-27
AU630469B2 (en) 1992-10-29
IL94516A0 (en) 1991-03-10
NZ233827A (en) 1991-06-25
JP2963537B2 (ja) 1999-10-18
EP0473707A1 (fr) 1992-03-11
GR900100402A (el) 1991-10-10
KR920700655A (ko) 1992-08-10

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