[go: up one dir, main page]

WO2006079896A2 - Formulations stables de polyol d'agents antibacteriens a base d'oxazolidinone - Google Patents

Formulations stables de polyol d'agents antibacteriens a base d'oxazolidinone Download PDF

Info

Publication number
WO2006079896A2
WO2006079896A2 PCT/IB2006/000117 IB2006000117W WO2006079896A2 WO 2006079896 A2 WO2006079896 A2 WO 2006079896A2 IB 2006000117 W IB2006000117 W IB 2006000117W WO 2006079896 A2 WO2006079896 A2 WO 2006079896A2
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
linezolid
gel
amino
alkyl
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.)
Ceased
Application number
PCT/IB2006/000117
Other languages
English (en)
Other versions
WO2006079896A3 (fr
Inventor
Lorraine Elisabeth Pena
Pamela Jean Secreast
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.)
Pharmacia and Upjohn Co LLC
Original Assignee
Pharmacia and Upjohn Co LLC
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 Pharmacia and Upjohn Co LLC filed Critical Pharmacia and Upjohn Co LLC
Publication of WO2006079896A2 publication Critical patent/WO2006079896A2/fr
Publication of WO2006079896A3 publication Critical patent/WO2006079896A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the present invention relates to stable polyol formulations of an oxazolidinone antibacterial agent, wherein the agent is solubilized in the formulation.
  • the invention also relates to compositions, such as gels, hydrogels, soft elastic capsules, and films which include or contain such polyol formulations, and the use of such compositions in the delivery of the oxazolidinone antibacterial agent to a subject.
  • U.S. Patent No. 5,688,792 discloses one set of such oxazolidinone antibacterial agents, including (S)-N-[[3-[3-fluoro-4-(4- morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, referred to herein as "linezolid.”
  • linezolid Treatment of infections by administration to the skin of a mammal of a pharmaceutical formulation of an oxazolidinone antibacterial agent in the form of a solution, suspension, or emulsion is disclosed in WO 03/030906 (PHARMACIA & UPJOHN COMPANY).
  • oxazolidinones such as linezolid
  • linezolid tend to crystallize out of typical polyol formulations over time.
  • the present invention relates to a gel formulation suitable for topical administration comprising: an oxazolidinone antibiotic drug solubilized in a polyol solvent system comprising a polyol solvent, a thickening agent, and water, in which the oxazolidinone drug remains solubilized in the solvent system for at least 3 hours at a temperature from 15°C to 30°C.
  • the present invention also relates to a method of treating an infection by gram- positive bacteria in a mammal in need of such treatment, comprising topically administering a therapeutically effective amount of the gel formulation of the present invention to such mammal.
  • the present invention in one aspect, is a polyol formulation of an oxazolidinone antibacterial agent.
  • the oxazolidinone antibacterial agent is suitably any one of a number of oxazolidinone compounds having therapeutically and/or prophylactically useful antibiotic activity.
  • oxazolidinone compounds having therapeutically and/or prophylactically useful antibiotic activity.
  • oxazolidinone compounds having therapeutically and/or prophylactically useful antibiotic activity.
  • oxazolidinone compounds having therapeutically and/or prophylactically useful antibiotic activity.
  • oxazolidinone compounds having therapeutically and/or prophylactically useful antibiotic activity.
  • oxazolidinone compounds having therapeutically and/or prophylactically useful antibiotic activity.
  • Among such compounds are those disclosed in the following patents, each of which is incorporated by reference herein: U.S. Patent No. 5,164,510 (Brickner); U.S. Patent No. 5,231,188 (Brickner); U.S.
  • Oxazolidinone antibacterial agents exhibit antibacterial activity against gram- positive organisms.
  • the oxazolidinone antibacterial agent included in the formulations and used in the methods of the present invention preferably exhibit antibacterial activity against gram-positive organisms of at least one of the following genera: Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis), Streptococcus (e.g., Streptococcus viridans, Streptococcus pneumoniae), Enterococcus (e.g., Enterococcus fecalis, Enterococcus faecium), Bacillus, Corynebacterium, Chlamydia and Neisseria.
  • Staphylococcus e.g., Staphylococcus aureus, Staphylococcus epidermidis
  • Streptococcus e.g., Streptococcus viridans, Streptococcus
  • Oxazolidinone antibacterial agents are also generally effective against anaerobic organisms such as those of the genera Bacteroides and Clostridia, and against acid-fast organisms such as those of the genus Mycobacterium.
  • the oxazolidinone antibacterial agent is a compound of formula (I), below:
  • R 1 is selected from (a) H, (b) C 1-8 allcyl optionally substituted with at least one substituent, preferably with from one to three substituents, independently selected from F, Cl, OH, C 1-8 alkoxy, C 1-8 acyloxy, C 1-8 benzyloxy, and C 3-6 cycloalkyl, (c) amino, (d) mono- and di(C 1-8 alkyl)amino and (e) C 1-8 alkoxy;
  • R 2 and R 3 are each independently selected from H, F and Cl;
  • R 4 is H or CH 3 ;
  • R 5 is selected from H, CH 3 , CN, CO 2 R 1 and (CH 2 ) m R 6 , where R 1 is as defined above, R 6 is selected from H, OH, OR 1 , OCOR 1 , NHCOR 1 , amino, mono- and di(C 1-8 alkyl)amino; and m is 1 or 2;
  • R 6 is O or S; n is O, 1 or 2; and
  • X is O, S, SO, SO 2 , p-toluenesulfonyl, SNR 7 or S(O)NR 7 , wherein R 7 is selected from H and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with one or more substituents, preferably with from one to three substituents, independently selected from F, Cl, OH, C 1-8 alkoxy, amino, and C 1-8 mono- or di(C 1-8 alkyl)amino group; or a pharmaceutically acceptable salt thereof.
  • the oxazolidinone antibacterial drug of Formula I is preferably (5)-N-[[3-[3- fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide, also referred to herein by its generic name, "linezolid.”
  • Linezolid has the structure shown in formula (II): and is in commercial use as a medicament under the trademark Zyvox® of Pharmacia and Upjohn Company. Linezolid exhibits strong antibacterial activity against gram-positive organisms of all of the genera of such organisms listed above.
  • the concentration of the oxazolidinone antibacterial agent in the gel formulation of the present invention is preferably high enough that it is capable of delivering an amount of the antibacterial agent above that is greater than or equal to the MIC 90 for the agent to target tissue, after being topically applied.
  • the MIC 90 is the minimum inhibitory concentration for 90% of the target organisms, in this instance infective gram-positive bacteria.
  • the active agent is linezolid
  • the MICg 0 is about 4 ⁇ g/ml.
  • the concentration of the oxazolidinone antibacterial agent in the gel formulation is also preferably low enough that the antibacterial agent does not crystallize out of the formulation within 3 hours, more preferably within 6 hours, more preferably within 12 hours, more preferably within 24 hours, even more preferably within 1 year, even more preferably within 2 years of production of the formulation.
  • the concentration of oxazolidinone antibacterial agent in the gel formulation of the present invention is preferably 0.05% to 2%, more preferably 0.1% to 1%, even more preferably 0.1% to 0.5% by weight of the total weight of the gel formulation.
  • the polyol of the formulation of the present invention is preferably a polyol or polyol combination which does not cause irritation when applied to the skin of a mammal.
  • Suitable polyols include glycerine, propylene glycol, dipropylene glycol, hexylene glycol, butylene glycol, and liquid polyethylene glycols, such as polyethylene glycol 200 to 600, and glycerol.
  • the polyol is preferably selected from the group consisting of propylene glycol, dipropylene glycol, butylene glycol, and polyethylene glycol.
  • the polyol is more preferably propylene glycol or a combination of propylene glycol and a polyethylene glycol.
  • the polyol is polyethylene glycol, it is preferably polyethylene glycol 400.
  • the thickening agent of the polyol gel formulation of the present invention enhances the viscosity of the formulation.
  • a wide variety of thickening agents are known to those skilled in the art of the present invention, which are suitable for use as the thickening agent in the formulations of the present invention.
  • the thickening agent may be an organic thickening agent or an inorganic thickening agent, more preferably an organic thickening agent.
  • the thickening agent is an organic thickening agent, it is preferably a polymeric thickening agent.
  • Polymeric thickening agents suitable for use in the present gel formulations include cellulose, cellulose derivatives, starches, gums, pectin, casein, gelatin, phyco colloids, and synthetic polymers.
  • alginates and salts and derivatives thereof including sodium alginate and propylene glycol alginate, acacia, carrageenan, guar gum, karaya gum, locust bean gum, tragacanth, and xanthan gum.
  • the polymeric thickening agent is a polymer of acrylic acid, it is preferably a carbomer.
  • the thickening agent is a carbomer or a cellulose or a cellulose derivative, or a mixture of a carbomer and either cellulose or a cellulose derivative.
  • the thickening agent is cellulose or a cellulose derivative, it is preferably HPMC.
  • the term "carbomer” as used herein refers to synthetic, high molecular weight crosslinked homopolymers of acrylic acid. Certain carbomers are particularly useful in formulations, such as the polyol gel formulations of the present invention, which contain high amounts of solvent, such as polyols or water. Examples of such carbomers include carbomer 910, 934, 940, 941, 980, 981, and 1343, and Carbopol® UltrezTM 10, all of which are commercially available from Noveon (Cleveland, OH).
  • the polyol gel formulation includes an inorganic thickening agent.
  • Suitable inorganic thickening agents include bentonite, magnesium aluminum silicate and colloidal silicon dioxide.
  • the amount of thickening agent included in the polyol gel formulations of the present invention may vary and depends, for example, on the particular thickening agent and polyol used, and on the quantity of oxazolidinone to be included in the formulation. Generally speaking, the thickening agent is employed in an amount to provide a formulation with the desired viscosity. The thickening agent is preferably employed in an amount ranging from about 0.1% to about 20%, preferably about 0.1% to about 10%, more preferably from about 0.1% to about 3%, even more preferably from 0.15% to 1%.
  • the polyol formulation of the present invention further comprises a crystallization inhibitor, preferably, a crystallization inhibitor which inhibits the crystallization of the oxazolidinone in the polyol gel formulation.
  • the crystallization inhibitor preferably further acts as a thickening agent in the formulation.
  • the crystallization inhibitor is preferably cellulose or a cellulose derivative, such as carboxymethylcellulose (“CMC”), ethylcellulose, hydroxyethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (“HPMC”), macrocrystalline cellulose, and powdered cellulose, or a salt of a cellulose.
  • CMC carboxymethylcellulose
  • HPMC hydroxypropyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • the crystallization inhibitor is most preferably HPMC.
  • the polyol formulation of the present invention further comprises a neutralizing agent.
  • neutralizing agent refers to a material that may be used to modify the pH of a composition, for example, from an acidic pH to a more basic pH, or from a basic pH to a more acidic pH, to bring the pH of the formulation closer to a neutral pH.
  • Components of the polyol formulations of the present invention such as carbomeric thickening agents, tend to be acidic.
  • suitable neutralizing agents are preferably those which modify the pH of the polyol formulations of the present invention from an acidic to a more basic pH.
  • neutralizing agents are known to those skilled in the art for inclusion in this embodiment of the formulations of the present invention, including ammonium hydroxide, sodium hydroxide, potassium hydroxide, diethanolamine, diisopropanolamine, triethanolamine, aminomethylpropanol, and TRIS.
  • the neutralizing agent is preferably sodium hydroxide.
  • the pH of the polyol formulation is preferably a pH at which the oxazolidinone agent is stable, and at which the formulation does not cause pain or damage skin when applied thereto.
  • the pH is preferably between 4 and 8, more preferably between 5 and 7, even more preferably between 5 and 6.
  • the amount of neutralizing agent included in this embodiment of the polyol formulations of the present invention will depend upon a number of different factors, including the particular neutralizing and thickening agents employed, the quantity of thickening agent to be neutralized, and the desired pH of the formulation.
  • polyol formulations of the present invention further comprise a preservative.
  • Suitable preservatives include benzyl alcohol, benzoic acid and salts thereof, quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylamonium bromide and cetylpyridim ' um chloride; imidazolidinyl urea; parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, and salts thereof; phenoxyethanol; chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol; phenylethyl alcohol; disodium EDTA; and sorbic acid and salts thereof.
  • quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylamonium bromide and cetylpyridim ' um chloride
  • imidazolidinyl urea parabens such as methylparaben, ethylparaben, propyl
  • the preservative is preferably a paraben or benzyl alcohol, most preferably methylparaben, propylparaben, or a combination of the above.
  • the quantity of preservative used in this embodiment of the polyol formulations of the present invention is preferably an amount sufficient to inhibit microbial growth in the formulation.
  • the amount of preservative in the formulation is preferably 0.01% to 10%, more preferably 0.02% to 5%, even more preferably 0.02% to 1% of the total weight of the formulation.
  • Formulations and methods of the present invention are suitable for use in the treatment of skin infections. Specific types of skin infections that are suitably treated with formulations and methods of the present invention include acne and soft-tissue infections, such as infections caused by staphylococci or streptococci.
  • the method of the present invention comprises topically administering the formulation of the present invention to a subject.
  • the formulation is administered to the subject in order to treat or prevent a gram-positive bacteria infection.
  • the infection can be due to any gram-positive bacteria; but, is preferably due to an infection by one or more bacteria of a genus selected from the group consisting of: Staphylococcus, Streptococcus, Enterococcus, Bacillus, Corynebacterium, Chlamydia and Neisseria.
  • the genus is Staphylococcus
  • the species of bacteria is preferably Staphylococcus aureus or Staphylococcus epidermidis.
  • the species of bacteria is preferably Streptococcus viridans or Streptococcus pneumoniae.
  • the species is preferably Enterococcus fecalis or Enterococcus faecium.
  • Treatment of the infection according to the method of the present invention preferably comprises administering a sufficient amount of the oxazolidinone antibacterial drug to the affected area to either kill the gram-positive bacteria present therein and/ or to stop them from growing to a point where the subject's natural defense mechanism can reduce or eradicate the bacteria.
  • Prevention according to the method of the present invention preferably comprises preventing an infection by gram-positive bacteria, or preventing a minor infection of such bacteria from growing into a larger infection. Prevention of infection is a particularly important step in preparing a subject for surgery.
  • the oxazolidinone antibacterial agent can be used either individually or in combination with another oxazolidinone antibacterial agent, whether both agents are included in the same formulation or administered separately. Further, the oxazolidinone antibacterial agent can be used in combination with other antibacterial agents, whether administered separately or whether both are included in the formulation of the present invention, hi addition, the formulation of the present invention can be used with non-antibacterial agents in treating infections, whether the non- antibacterial agents are administered separately or included in the formulation.
  • the exact dosage and frequency of administration of the polyol gel formulations of the present invention depends upon the particular oxazolidinone antibiotic agent used, the particular condition being treated, the severity of the condition being treated; the age, weight, and general physical condition of the particular patient; and other medication the particular patient may be taking. Such factors are well known to those skilled in the art and can be more accurately determined by the patient's response to the particular treatment administered.
  • the polyol gel formulations of the present application are preferably formulated for direct application to the skin, or incorporated into a matrix designed to be applied to the skin, such as a hydrogel or other wound dressing matrix.
  • wound dressing matrices are described in various references, including US Pat. Nos. 6,476,104 (Nakamura et al); 6,180,132 (Huang et al); 6,333,054 (Rogozinski); 6,348,212 (Hymes et al); 5,686,425 (Lee); 5,736,113 (Lee); 6,455,065 (Hymes); and EP 0 552 151 (THE DOW CHEMICAL COMPANY).
  • the polyethylene glycol 400 and propylene glycol were added to 2.5 L of purified water and mixed.
  • Carbomer was added and mixed into the solution until a substantially homogenious dispersion was formed.
  • the resulting linezolid gel formulation was found to have a viscosity of 13,600 cps.
  • the linezolid in the gel formulation was found to retain its potency after 8 weeks at 30°C, 40°C, and even 50°C. However, after long term storage at room temperature (about 22°C), and at 25 0 C, 30 0 C, and 40 0 C, needle-like crystalline precipitates developed in the gel formulation.
  • Linezolid gel and placebo gel formulations were prepared according to the formulae in Table 3, below, using the procedure described below.
  • Example 2 The same procedure was used to make the formulations as was used in Example 2, above, except that the temperature of the mixture produced in step 2 was elevated to 70°C before the addition of linezolid in step 3, and mixed at that temperature until the linezolid was dissolved. Hydroxypropylmethyl cellulose (“HPMC”) was added to the resulting mixture, prior to step 4, and mixed until the solution became clear. The solution had cooled to 4O 0 C by the time the carbomer was added in step 4.
  • HPMC Hydroxypropylmethyl cellulose
  • the linezolid gel formulations prepared as described above were tested for short term and long term stability, as described in Example 2, above.
  • the linezolid in the 0.5% and 1% gel formulations prepared as described in the present example was found to retain its potency after 3 months at 25 0 C and 5O 0 C. All the gel formulations were also found to be physically stable at both temperatures. No precipitates or crystals were observed in the
  • the three gel solutions were applied twice daily to the dorsal skin of 4 female fz rats for each formulation tested.
  • the skin of each rat was inspected daily for irritancy (i.e., erythema and edema), and transepidermal water loss ("TEWL”), a measure of water efflux through the skin, was measured before and after the 4 day treatment regimens.
  • TEWL transepidermal water loss
  • the rats were fitted with a modified cardboard Elizabethan collar to prevent ingestion of the topical treatment.
  • Blood samples were taken 3 hours after doses 5 (day 3) and 7 (day 4) for plasma drug analysis. Terminal skin biopsies were taken for histological examination. Assay results are shown in Table 4, below.
  • the TEWL measurements shown in Table 4, indicate no change relative to basal levels, thus indicating no impact of the formulation on the integrity of the dermal membrane of any of the animals tested.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a trait à des formulations stables en gel de médicaments antibiotiques à base d'oxazolidinone, tel que le linézolide, aptes à une administration topique. Des formulations en gel de la présente invention comporte un médicament antibiotique à base d'oxazolidinone solubilisé dans un système solvant de polyol comprenant un solvant polyol, un agent épaississant, et de l'eau. Le médicament à base d'oxazolidinone reste solubilisé dans des formulations en gel de la formulation de la présente invention pour au moins 3 heures à une température comprise entre 15 °C et 30 °C. L'invention a également trait à des procédés d'administration topique des formulations en gel de la présente invention pour le traitement ou la prévention d'infection par des bactéries gram positif.
PCT/IB2006/000117 2005-01-27 2006-01-17 Formulations stables de polyol d'agents antibacteriens a base d'oxazolidinone Ceased WO2006079896A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US64756105P 2005-01-27 2005-01-27
US60/647,561 2005-01-27

Publications (2)

Publication Number Publication Date
WO2006079896A2 true WO2006079896A2 (fr) 2006-08-03
WO2006079896A3 WO2006079896A3 (fr) 2007-01-11

Family

ID=36740872

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/000117 Ceased WO2006079896A2 (fr) 2005-01-27 2006-01-17 Formulations stables de polyol d'agents antibacteriens a base d'oxazolidinone

Country Status (1)

Country Link
WO (1) WO2006079896A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2275061A1 (fr) 2009-07-15 2011-01-19 Otos Tech Co., Ltd. Casque de soudure incluant un dispositif anti-colmatage pour contrôler de manière sélective et pratique les opérations de soudure et opérations de meulage
GB2487773A (en) * 2011-02-04 2012-08-08 Aidance Skincare & Topical Solutions Llc Biocompatible putty formulation for chronic and acute wounds
WO2021184339A1 (fr) * 2020-03-20 2021-09-23 Merck Sharp & Dohme Corp. Composé d'oxazolidinone et procédés d'utilisation de celui-ci comme agent antibactérien

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE90195T1 (de) * 1988-02-18 1993-06-15 Upjohn Co Minoxidil-gel.
AU5294393A (en) * 1992-10-06 1994-04-26 Upjohn Company, The Topical pharmaceutical compositions
AR031135A1 (es) * 2000-10-10 2003-09-10 Upjohn Co Composiciones de antibiotico topico para el tratamiento de infecciones oculares
WO2003030906A1 (fr) * 2001-10-11 2003-04-17 Pharmacia & Upjohn Company Traitement d'infections par administration cutanee d'oxazolidinones

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2275061A1 (fr) 2009-07-15 2011-01-19 Otos Tech Co., Ltd. Casque de soudure incluant un dispositif anti-colmatage pour contrôler de manière sélective et pratique les opérations de soudure et opérations de meulage
GB2487773A (en) * 2011-02-04 2012-08-08 Aidance Skincare & Topical Solutions Llc Biocompatible putty formulation for chronic and acute wounds
GB2487773B (en) * 2011-02-04 2014-09-17 Aidance Skincare & Topical Solutions Llc Topical antibiotic formulations
WO2021184339A1 (fr) * 2020-03-20 2021-09-23 Merck Sharp & Dohme Corp. Composé d'oxazolidinone et procédés d'utilisation de celui-ci comme agent antibactérien
US12435077B2 (en) 2020-03-20 2025-10-07 Merck Sharp & Dohme Llc Oxazolidinone compound and methods of use thereof as an antibacterial agent

Also Published As

Publication number Publication date
WO2006079896A3 (fr) 2007-01-11

Similar Documents

Publication Publication Date Title
JP3526887B2 (ja) 消炎鎮痛外用貼付剤
US5116621A (en) Anti-inflammatory analgesic patch
US4678666A (en) Topical anti-inflammatory compositions
AU2010204986B2 (en) Transdermal administration of tamsulosin
TWI667028B (zh) 抗微生物聚醯胺組合物及乳腺炎治療
CN108349968A (zh) 抗菌治疗剂和预防剂
JP2001521887A (ja) Ｎｓａｉ薬送達用局所組成物
CN109431966B (zh) 依达拉奉药物组合物
KR101307650B1 (ko) 구역에 대한 경피 방법 및 패치
KR20230050475A (ko) 고농도 생물 발효 히알루론산 나트륨으로 구성된 국소성 중합체 기지 합성물 및 그 사용
WO2006079896A2 (fr) Formulations stables de polyol d'agents antibacteriens a base d'oxazolidinone
WO2001000226A1 (fr) Pommade ophtalmique pour traiter les maladies infectieuses
US11844861B2 (en) Topical Montelukast formulations
US12233055B2 (en) Topical Montelukast formulations
US20100003325A1 (en) Composition and method for treatment of warts
ES2357662T3 (es) Preparaciones para el cuidado de la piel que contienen mupirocina y dipropionato de betametasona.
JP7523439B2 (ja) 活性医薬成分の安定性向上のための製剤、方法、ｋｉｔ、及び剤形
WO2024184792A1 (fr) Systèmes d'administration transdermique de médicament pour l'administration d'une quantité thérapeutiquement efficace d'apixaban et d'autres anticoagulants oraux directs
CN116059383A (zh) 一种氟比洛芬盐凝胶及其抗结晶剂
KR20070071534A (ko) 비스테로이드성 항염증제가 함유된 경피 투여제
KR20000066357A (ko) 케토롤락 외용제제
BR112015023445B1 (pt) Composições de poliamida antimicrobiana e tratamento de mastite
MXPA05005078A (en) Pharmaceutical composition having a higher ciprofloxacin bioavailability
BRPI0713002A2 (pt) composições tópicas

Legal Events

Date Code Title Description
DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase

Ref document number: 06701066

Country of ref document: EP

Kind code of ref document: A2

WWW Wipo information: withdrawn in national office

Ref document number: 6701066

Country of ref document: EP