US20020035160A1 - Antibacterial composition for topical administration containing antibiotic - Google Patents
Antibacterial composition for topical administration containing antibiotic Download PDFInfo
- Publication number
- US20020035160A1 US20020035160A1 US09/380,530 US38053099A US2002035160A1 US 20020035160 A1 US20020035160 A1 US 20020035160A1 US 38053099 A US38053099 A US 38053099A US 2002035160 A1 US2002035160 A1 US 2002035160A1
- Authority
- US
- United States
- Prior art keywords
- composition
- ointment
- compound
- gum
- white
- 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.)
- Granted
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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- 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
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
-
- 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
- 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
- A61P31/02—Local antiseptics
Definitions
- the present invention relates to pharmaceutical compositions for use in dermatological, ophthalmologic, otolaryngologic, dental/oral surgical and urogenital fields, and more specifically to the use of penem antibiotics for topical administration.
- Ointments are used for topical administration to treat various diseases due to their convenience of administration and portability.
- Therapeutic agents comprising antibiotics in an ointment base are useful for treating local inflammatory or pyogenic diseases caused by bacterial infection. There is a demand for these ointments, with a number being available.
- ointments containing aminoglycoside, tetracycline and chloramphenicol antibiotics are commonly used for inflammatory or pyogenic diseases in dermatological, ophthalmologic, otolaryngologic, dental/oral surgical and urogenital fields.
- tetracycline antibiotics such as tetracycline hydrochloride ointments and chloramphenicol antibiotics such as chloramphenicol ointments
- Ointments containing tetracycline hydrochloride as a tetracycline antibiotic and hydrocortisone acetate are commercially available for dental/oral surgical application.
- the active component in antibiotic ointments should be incorporated in a stable form.
- Japanese Patent Publication (Kokoku) No. 12728/89 describes a composition for topical administration as an external dental agent.
- a magnesium compound is employed to a hydrogel comprising minocycline or a pharmaceutically acceptable salt thereof as a tetracycline antibiotic in a water-soluble polymer compound and a polyhydric alcohol to stabilize the antibiotic.
- penem compounds are non-natural ⁇ -lactam compounds designed based on the concept of combining the structures of penicillin and cephalosporin (e.g. see Woodward, R. B., In Recent Advances in the Chemistry of ⁇ -Lactam Antibiotics; Elks, J., Ed; The Chemical Society; London, 1977; Spec. No. 28, pp. 167-180, Japanese Patent Public Disclosure (Kokai) Nos.
- the penem compounds are reported to show potent antibacterial activity on not only methicillin-sensitive Staphylococcus aureus (MSSA), Streptococcus pyrogenes and Streptococcus pneumoniae but also gram-positive bacteria less susceptible to conventional ⁇ -lactam agents such as penicillin-resistant Streptococcus pneumoniae (PRSP), stomatic Streptococcus spp. and Enterococcus sp. by virtue of the novel skeleton called penem ring.
- MSSA methicillin-sensitive Staphylococcus aureus
- PRSP penicillin-resistant Streptococcus pneumoniae
- stomatic Streptococcus spp. stomatic Streptococcus spp.
- Enterococcus sp. by virtue of the novel skeleton called penem ring.
- the broad-spectrum antibacterial activity covers gram-negative bacteria such as Haemophilus influenzae and anaerobics such as the gen
- penem compounds like other ⁇ -lactam compounds, are generally chemically labile to hydrolysis, oxidation, photoisomerization, etc., and no composition for topical administration has been known that exhibits their excellent efficacy against inflammatory or pyogenic diseases, or diseases caused by infection with resistant bacteria.
- an active component has to be mixed homogeneously throughout a semisolid base.
- an active component is in the form of crystals or a crystalline powder like penem antibiotics, it is difficult to achieve overall homogeneity simply by dispersing the component in a base. Therefore, the component must first be ground into fine particles or dissolved in solvent, before being kneaded with a base into an ointment. Pulverization of the component is necessary also in view of the resulting texture of the formulation.
- the inventors conducted extensive studies to develop a method to topically administer penem antibiotics and pharmaceutically acceptable salts thereof which have a broad-spectrum and a potent antibacterial activity as well as being highly safe. As a result, the inventors have developed a highly safe antibacterial composition for topical administration in which the active component is incorporated in a stable form. The present invention has been accomplished based on the finding.
- the present invention relates to an antibacterial composition for topical administration comprising a penem antibiotic or a pharmaceutically acceptable salt thereof incorporated in a non-aqueous base.
- very unstable penem antibiotics can be stably incorporated in a non-aqueous base such as hydrophobic polymer compounds to provide an antibacterial composition which can be widely used in dermatological, ophthalmologic, otolaryngologic, dental/oral surgical and urogenital fields.
- Antibacterial compositions of the present invention may further contain various additives such as water-soluble or hydrophilic polymer compounds conferring thickening effects to provide various compositions for intended uses without affecting the stability of active components.
- the composition of the present invention is basically a viscous liquid or paste-like composition comprising a penem antibiotic or a pharmaceutically acceptable salt thereof incorporated in a non-aqueous base, and it is typically formulated into an ointment. It is important that the base of a non-aqueous type is used to ensure the stability of the penem antibiotic.
- Penem antibiotics used in the present invention are not specifically limited provided that they are antibacterially active, compatible to lesions and safe in view of irritability, sensitizing effect and oral toxicity, and that they are pharmaceutically acceptable. They may be either in the form of a free carboxylic acid or a pharmaceutically acceptable salt including salts with alkali or alkali earth metals such as sodium, potassium, calcium, magnesium or amino acids such as lysine or ammonium salts.
- Examples of such compounds other than the above Compound 1 include those in which the substituent at position 3 is 1,4-dioxane-2-yl, ethylsulphanyl, 3-tetrahydrofurylmethyl, methoxymethyl or ((aminocarbonyl)oxy)methyl or the like.
- the content of such a compound in the composition may be appropriately determined depending on the nature of the compound, the disease to be treated or other factors.
- Compound 1 is incorporated at 10% by weight or less, normally 0.1 to 5% by weight expressed as free anhydride on the basis of the whole composition.
- the active component In order to formulate a penem antibiotic into an ointment, the active component must be incorporated into the composition in such a manner as to ensure the stability of the active component while assuring applicability or usability. In the present invention, proper stability can be ensured for penem antibiotics by using a non-aqueous base.
- non-aqueous base is a base which is substantially free from water.
- typical examples of non-aqueous bases are hydrophobic polymer compounds generally classified as hydrophobic ointment bases, such as oleaginous ointment bases consisting of hydrophobic polymers commonly used for ointments.
- Oleaginous ointment bases include, for example, hydrocarbon gel, paraffin, liquid paraffin, white petrolatum, petrolatum, microcrystalline wax, plant oils (vegetable oils), carnauba wax, beewax, stearic acid, stearyl alcohol, cacao butter, cetanol, hard fat, white ointment, simple ointment and ceresin.
- emulsion bases which are free from any aqueous phase or film coating- or matrix -bases which are free from any aqueous phase.
- Emulsion ointment bases free from aqueous phase include hydrophilic petrolatum and purified lanolin.
- Film coatings and matrix bases free from any aqueous phase include acrylic resins which are commercially available under the trade name Eudragit (aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer S, ethyl acrylate-methyl methacrylate copolymer emulsion, available from Röhm Pharma, Germany) optionally in combination with plasticizers.
- Eudragit aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer S, ethyl acrylate-methyl methacrylate copolymer emulsion, available from Röhm Pharma, Germany
- One or more of these bases are preferably used. Especially preferred are hydrocarbon gel, white petrolatum and Eudragit.
- hydrophilic bases in general nor many of the emulsion ointment bases, i.e. those comprising an aqueous phase, such as hydrophilic ointment and absorptive ointment will provide ointments which are capable of maintaining the activity of incorporated active components.
- composition of the present invention When the composition of the present invention is embodied as a pharmaceutical composition directly administered to a local site in the mouth for treating periodontitis, a high degree of viscosity will be required to provide a prolonged effect at the target site.
- additives such as gelatinizers, thickening agents, viscosifiers, viscosity enhancers and elasticizers may be optionally added.
- Additives for this purpose include water-soluble or hydrophilic polymer compounds such as carmellose, carmellose sodium, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, sodium polyacrylate, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, xanthan gum, tragacanth gum, guar gum, locust bean gum, arabic gum, chitosan, sodium alginate, starches, gelatins, hydrophobically modified-hydroxypropylmethylcellulose (Sangelose, available from Sankyo Chemical).
- water-soluble or hydrophilic polymer compounds such as carmellose, carmellose sodium, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, sodium polyacrylate, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, xanthan gum
- the water-soluble or hydrophilic polymer compounds may also be employed to facilitate the absorption of secreted fluids from body tissues and prevent any contamination at the location.
- Suitable plasticizers include triacetine, diacetyl ethylene glycol, diethyl sebacate, diethyl phthalate, dibutyl phthalate, diisopropyl adipate, dibutyl succinate.
- Suitable surfactants include polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, Polysorbate, sucrose esters of fatty acids.
- Suitable flavoring agents include sodium, saccharin or the like.
- Stabilizers such as calcium disodium edetate or the like may also be used as judged appropriate.
- composition of the present invention may further contain appropriate amounts of perfumes such as menthol, carboxylic acids, anethole, eugenol, methyl salicylate, limonene, ocimene, citronellol, methyl acetate, methyl eugenol, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, rosemary oil, cinnamon oil, eucalyptus oil and pimento oil alone or in combination.
- perfumes such as menthol, carboxylic acids, anethole, eugenol, methyl salicylate, limonene, ocimene, citronellol, methyl acetate, methyl eugenol, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, rosemary oil, cinnamon oil, eucalyptus oil and pimento oil alone or in combination.
- higher alcohols higher fatty acids, shellac-ethylcellulose, ethylcellulose, carnauba wax, hydroxypropylmethylcellulose acetate succinate and solubilizing agents therefor may be used alone or in combination to effect control of the release of the active component from the base or to mask the odor of the active component.
- composition of the present invention comprise a base selected from those which have been confirmed in terms of their stability, and hence, which may be applied by various application methods without being limited to any specific one.
- the ointment is suitable for any one of topical external application on the skin for the treatment of acne, urogenital application, oral application for the treatment of infectious periodontitis or the like.
- the process of the invention is characterized in that a non-aqueous base is provided without any use of water in its preparation which would otherwise affect the stability of the active component.
- the process for preparing the composition of the present invention is described in detail below.
- composition of the present invention i.e., dispersion method, fusion method and slolubilizing method.
- a homogeneous dispersion of the active component in a non-aqueous base is prepared by thoroughly grinding, pulverizing and kneading the active component, to make suitable the crystalline active component for topical administration.
- a preferred particle diameter of the active component is preferably 500 ⁇ m or less, normally 100 ⁇ m or less.
- the active component is mixed and thoroughly triturated with a portion of the base using an ointment slab and an ointment spatula or a mortar and a pestle. Subsequently, the rest of the base and other additives are added and trituration is continued until overall homogeneity is achieved.
- machines such as three roller machines, roll mills, kneaders, grinders or mixers are used. These machines may be used optionally under a reduced pressure or under heating. In such a case, the optimal stirring speed will be between 25 and 100 rpm and a preferred vacuum level ranges from 60 to 80 cmHg. A suitable heating temperature is between 35 to 60° C. depending on the stability of the active component. If necessary, the resulted particles may be screened.
- the active component is readily soluble in water, and its activity is lowered by hydrolysis, the active component is first wet-triturated in a non-aqueous base such as a small amount of liquid paraffin. Subsequently, the other components are successively admixed in an order that increases the ability of the component to solubilize the active component, to thereby finally accomplish overall homogeneity. Fusion may be carried out under heating and stirring, if necessary. A suitable heating temperature is between 35 to 60° C. depending on the stability of the active component.
- An ointment jar and a water bath may be used for small scale production, while machines such as a three roller machine, grinders and mixers will be used in a water bath for large scale production.
- an optimal stirring speed is between 25 to 100 rpm and a preferred vacuum level is 60 to 80 cmHg. Particles may be filtered or screened, if necessary.
- the solubilizing method comprises the use of a non-aqueous solvent compatible with the non-aqueous base since the active component is readily soluble in water and its activity is lowered by hydrolysis.
- a solution of the active component in methanol or ethanol is kneaded with a non-aqueous base, optionally under heating or stirring.
- a suitable heating temperature is between 35 to 60° C. depending on the stability of the active component.
- the solution in which the active component has been dissolved is mixed and thoroughly triturated with a portion of the base, then further triturated with the rest of the base and other additives to provide overall homogeneity.
- Mixing or trituration is performed with an ointment slab and an ointment spatula or a mortar and a pestle for small scale production.
- a three roller machine, roller mills, kneaders, grinders and mixers or the like are used for large scale production. These machines may be used optionally under reduced pressure and an optimal agitation speed is between 25 to 100 rpm and the vacuum level is preferably 60 to 80 cmHg.
- particles may be filtered or screened.
- the methods described above are preferably carried out under conditions which are free from not only water but also any other external factors which may potentially affect the stability of the active component.
- external factors include, for example, high temperatures, light and oxygen, which would all cause a deterioration in the active component.
- the step of filling the composition into a container should also be carried out under conditions which are free from any of the stated external factors.
- the shape of the container should be capable of preventing contact with such external factors and also be able to properly maintain the stability of the active component of the composition.
- Specific examples include bottles or jars made from glass, plastics and synthetic resins, or tubes made from metals, plastics and laminates.
- a screw cap is used to effect closure for bottles and jars, or folding a metal tube filled from its bottom end or contact-bonding a similarly filled plastic tube between hot plates, or contact-bonding a similarly filled laminate tube under heat such as high frequency or supersonic wave can also be employed.
- the shape of the container may be selected depending on the intended use.
- the container may have a shape which enables, for example, direct application or injection of the composition at various body sites.
- One example is a container designed to discharge the composition by a piston-like rod from an injection cylinder or a syringe made from plastic or synthetic resin.
- Compound 1 was mixed with hydrocarbon gel to overall homogeneity to give the desired composition.
- Compound 1 was mixed with hydrocarbon gel to overall homogeneity to give the desired composition.
- Compound 1 was mixed with hydrocarbon gel to overall homogeneity to give the desired composition.
- Compound 1 was mixed with white petrolatum to overall homogeneity to give the desired composition.
- Compound 1 was mixed with purified lanolin to overall homogeneity to give the desired composition.
- Compound 1 was mixed with a dispersion of carmellose sodium in hydrocarbon gel to give the desired composition.
- This composition is particularly suitable for oral application as a therapeutic agent for periodontal diseases.
- Compound 1 was mixed with a dispersion of xanthan gum in hydrocarbon gel to give the desired composition.
- This composition is suitable for oral application as a therapeutic agent for periodontal diseases.
- Compound 1 was wet-kneaded with liquid paraffin and then mixed with hydrocarbon gel to overall homogeneity to give the desired composition.
- Hydrocarbon gel was added in portions into a solution of Compound 1 in ethanol and mixed to overall homogeneity to give the desired composition.
- a plastic container filled with a composition containing Compound 1 prepared according to the 5 formulations of Examples 1, and 4 to 7 was sealed with a screw cap.
- the container was stored at 40° C., 75% relative humidity (RH) for 1 month or 2 months or at room temperature for 1 month. Any observable change in the appearance of the composition was evaluated, and at the same time, the potency of the antibiotic was determined by high-performance liquid chromatography, from which the residual retention (%) to the initial potency was calculated.
- Conditions for high-performance liquid chromatography were as follows. A stainless steel high-performance liquid chromatography column charged with octadecylsilylated silica gel was used. Column temperature was maintained at 40° C.
- the mobile phase consisted of Solution A containing 45 mM potassium dihydrogenphosphate, 5 mM sodium monohydrogenphosphate and 5 mM tetra-n-butylammonium bromide and Solution B comprising a 1:1 mixture of Solution A and acetonitrile. The mobile phase initially contained 16% of Solution B, then once analysis was started, Solution B was gradually increased to 70% over 54 minutes. The flow rate was controlled so that the retention time of Compound 1 was 24 minutes.
- the detector used was a UV spectrophotometer at a wavelength of 240 nm.
- Control 1 Component % by weight Compound 1 2.5 1) Hydrophilic ointment 97.5
- Control 1 was mixed with hydrophilic ointment to overall homogeneity to give the composition of Control 1.
- Control 2 Component % by weight Compound 1 2.5 1) Absorptive ointment 97.5
- Compound 1 was mixed with absorptive ointment to overall homogeneity to give the composition of Control 2.
- compositions in which Compound 1 was admixed into a non-aqueous bases according to the present invention were stable, and their stability was not affected even by addition of a water-soluble polymer compound.
- very unstable penem antibiotics can be formulated into a stable composition by using hydrophobic polymer compounds as bases without the stability of the active component being compromised by further addition of water-soluble polymer compounds, to thereby provide antibacterial compositions which can be widely used in dermatological, ophthalmologic, otolaryngologic, dental/oral surgical and urogenital fields.
Abstract
Description
- The present invention relates to pharmaceutical compositions for use in dermatological, ophthalmologic, otolaryngologic, dental/oral surgical and urogenital fields, and more specifically to the use of penem antibiotics for topical administration.
- Ointments are used for topical administration to treat various diseases due to their convenience of administration and portability.
- Therapeutic agents comprising antibiotics in an ointment base are useful for treating local inflammatory or pyogenic diseases caused by bacterial infection. There is a demand for these ointments, with a number being available.
- For example, ointments containing aminoglycoside, tetracycline and chloramphenicol antibiotics are commonly used for inflammatory or pyogenic diseases in dermatological, ophthalmologic, otolaryngologic, dental/oral surgical and urogenital fields. Specific examples include commercially available dermatological agents for pyogenic diseases, based on aminoglycoside antibiotics such as kanamycin monosulfate ointments, tetracycline antibiotics such as tetracycline hydrochloride ointments and chloramphenicol antibiotics such as chloramphenicol ointments, as well as commercially available ophthalmic ointments based on macrolide antibiotics such as pimaricin formulations. Ointments containing tetracycline hydrochloride as a tetracycline antibiotic and hydrocortisone acetate are commercially available for dental/oral surgical application.
- The active component in antibiotic ointments should be incorporated in a stable form. Japanese Patent Publication (Kokoku) No. 12728/89 describes a composition for topical administration as an external dental agent. In this composition, a magnesium compound is employed to a hydrogel comprising minocycline or a pharmaceutically acceptable salt thereof as a tetracycline antibiotic in a water-soluble polymer compound and a polyhydric alcohol to stabilize the antibiotic.
- On the other hand, penem compounds are non-natural β-lactam compounds designed based on the concept of combining the structures of penicillin and cephalosporin (e.g. see Woodward, R. B., In Recent Advances in the Chemistry of β-Lactam Antibiotics; Elks, J., Ed; The Chemical Society; London, 1977; Spec. No. 28, pp. 167-180, Japanese Patent Public Disclosure (Kokai) Nos. 207387/86, 162694/88, 222486/85 and 119486/79), with the aim of creating a new range of antibiotics which have the broad antibacterial spectrum and high safety of penicillin antibiotics and cephem antibiotics belonging to β-lactam antibiotics combined with the potent antibacterial activity and high stability to β-lactamase of carbapenem antibiotics. Currently, sodium (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-7-oxo-3-[(R)-2-tetrahydrofuryl]-4-thia-1-azabicyclo[3.2.0]hepto-2-ene-2-carboxylate 2.5 hydrate (faropenem sodium, hereinafter referred to as Compound 1) is orally administated as a therapeutic agent for use in various infections. The penem compounds are reported to show potent antibacterial activity on not only methicillin-sensitiveStaphylococcus aureus (MSSA), Streptococcus pyrogenes and Streptococcus pneumoniae but also gram-positive bacteria less susceptible to conventional β-lactam agents such as penicillin-resistant Streptococcus pneumoniae (PRSP), stomatic Streptococcus spp. and Enterococcus sp. by virtue of the novel skeleton called penem ring. The broad-spectrum antibacterial activity covers gram-negative bacteria such as Haemophilus influenzae and anaerobics such as the genus Bacteroides (Antibiotics & Chemotherapy, Vol. 13, No. 10, pp. 74-80, 1997). They are also reported to exhibit potent antibacterial activity on not only pathogenic bacteria of periodontitis such as Porphyromonas gingivalis (Chemotherapy, Vol. 42, S-1, pp. 38-50, 1994) but also other strains which are becoming increasingly resistant, that cause dental infections (Chemotherapy, Vol. 45, No. 11, pp. 965-971, 1997).
- However, penem compounds, like other β-lactam compounds, are generally chemically labile to hydrolysis, oxidation, photoisomerization, etc., and no composition for topical administration has been known that exhibits their excellent efficacy against inflammatory or pyogenic diseases, or diseases caused by infection with resistant bacteria.
- Furthermore, in formulating ointments, an active component has to be mixed homogeneously throughout a semisolid base. When an active component is in the form of crystals or a crystalline powder like penem antibiotics, it is difficult to achieve overall homogeneity simply by dispersing the component in a base. Therefore, the component must first be ground into fine particles or dissolved in solvent, before being kneaded with a base into an ointment. Pulverization of the component is necessary also in view of the resulting texture of the formulation.
- However, no technique for use of a penem compound as a component of an ointment has hitherto been known.
- Under the circumstances described above, the inventors conducted extensive studies to develop a method to topically administer penem antibiotics and pharmaceutically acceptable salts thereof which have a broad-spectrum and a potent antibacterial activity as well as being highly safe. As a result, the inventors have developed a highly safe antibacterial composition for topical administration in which the active component is incorporated in a stable form. The present invention has been accomplished based on the finding.
- Accordingly, the present invention relates to an antibacterial composition for topical administration comprising a penem antibiotic or a pharmaceutically acceptable salt thereof incorporated in a non-aqueous base.
- According to the present invention, very unstable penem antibiotics can be stably incorporated in a non-aqueous base such as hydrophobic polymer compounds to provide an antibacterial composition which can be widely used in dermatological, ophthalmologic, otolaryngologic, dental/oral surgical and urogenital fields.
- Antibacterial compositions of the present invention may further contain various additives such as water-soluble or hydrophilic polymer compounds conferring thickening effects to provide various compositions for intended uses without affecting the stability of active components.
- The composition of the present invention is basically a viscous liquid or paste-like composition comprising a penem antibiotic or a pharmaceutically acceptable salt thereof incorporated in a non-aqueous base, and it is typically formulated into an ointment. It is important that the base of a non-aqueous type is used to ensure the stability of the penem antibiotic.
- Penem antibiotics used in the present invention are not specifically limited provided that they are antibacterially active, compatible to lesions and safe in view of irritability, sensitizing effect and oral toxicity, and that they are pharmaceutically acceptable. They may be either in the form of a free carboxylic acid or a pharmaceutically acceptable salt including salts with alkali or alkali earth metals such as sodium, potassium, calcium, magnesium or amino acids such as lysine or ammonium salts. Examples of such compounds other than the above Compound 1 include those in which the substituent at position 3 is 1,4-dioxane-2-yl, ethylsulphanyl, 3-tetrahydrofurylmethyl, methoxymethyl or ((aminocarbonyl)oxy)methyl or the like. The content of such a compound in the composition may be appropriately determined depending on the nature of the compound, the disease to be treated or other factors. For example, Compound 1 is incorporated at 10% by weight or less, normally 0.1 to 5% by weight expressed as free anhydride on the basis of the whole composition.
- In order to formulate a penem antibiotic into an ointment, the active component must be incorporated into the composition in such a manner as to ensure the stability of the active component while assuring applicability or usability. In the present invention, proper stability can be ensured for penem antibiotics by using a non-aqueous base.
- As used herein, “non-aqueous” base is a base which is substantially free from water. Thus, typical examples of non-aqueous bases are hydrophobic polymer compounds generally classified as hydrophobic ointment bases, such as oleaginous ointment bases consisting of hydrophobic polymers commonly used for ointments. Oleaginous ointment bases include, for example, hydrocarbon gel, paraffin, liquid paraffin, white petrolatum, petrolatum, microcrystalline wax, plant oils (vegetable oils), carnauba wax, beewax, stearic acid, stearyl alcohol, cacao butter, cetanol, hard fat, white ointment, simple ointment and ceresin.
- Included in the non-aqueous bases used in the present invention are some emulsion bases which are free from any aqueous phase or film coating- or matrix -bases which are free from any aqueous phase. Emulsion ointment bases free from aqueous phase include hydrophilic petrolatum and purified lanolin. Film coatings and matrix bases free from any aqueous phase include acrylic resins which are commercially available under the trade name Eudragit (aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer S, ethyl acrylate-methyl methacrylate copolymer emulsion, available from Röhm Pharma, Germany) optionally in combination with plasticizers.
- One or more of these bases are preferably used. Especially preferred are hydrocarbon gel, white petrolatum and Eudragit.
- Neither hydrophilic bases in general nor many of the emulsion ointment bases, i.e. those comprising an aqueous phase, such as hydrophilic ointment and absorptive ointment will provide ointments which are capable of maintaining the activity of incorporated active components.
- When the composition of the present invention is embodied as a pharmaceutical composition directly administered to a local site in the mouth for treating periodontitis, a high degree of viscosity will be required to provide a prolonged effect at the target site. In such a case, additives such as gelatinizers, thickening agents, viscosifiers, viscosity enhancers and elasticizers may be optionally added. Additives for this purpose include water-soluble or hydrophilic polymer compounds such as carmellose, carmellose sodium, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, sodium polyacrylate, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, xanthan gum, tragacanth gum, guar gum, locust bean gum, arabic gum, chitosan, sodium alginate, starches, gelatins, hydrophobically modified-hydroxypropylmethylcellulose (Sangelose, available from Sankyo Chemical). One or more of these compounds can be added at a proportion of 0.1 to 10% by weight, preferably 0.5 to 10% by weight on the basis of the whole composition to further enhance the thickening effect at the target site.
- The water-soluble or hydrophilic polymer compounds may also be employed to facilitate the absorption of secreted fluids from body tissues and prevent any contamination at the location.
- As long as the purposes and effects of the present invention are not compromised, other components such as conventional plasticizers, surfactants, perfumes, flavoring agents or other additives may be optionally employed in an amount which does not influence the stability of the active component.
- Suitable plasticizers include triacetine, diacetyl ethylene glycol, diethyl sebacate, diethyl phthalate, dibutyl phthalate, diisopropyl adipate, dibutyl succinate. Suitable surfactants include polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, Polysorbate, sucrose esters of fatty acids. Suitable flavoring agents include sodium, saccharin or the like. Stabilizers such as calcium disodium edetate or the like may also be used as judged appropriate.
- The composition of the present invention may further contain appropriate amounts of perfumes such as menthol, carboxylic acids, anethole, eugenol, methyl salicylate, limonene, ocimene, citronellol, methyl acetate, methyl eugenol, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, rosemary oil, cinnamon oil, eucalyptus oil and pimento oil alone or in combination.
- If necessary, higher alcohols, higher fatty acids, shellac-ethylcellulose, ethylcellulose, carnauba wax, hydroxypropylmethylcellulose acetate succinate and solubilizing agents therefor may be used alone or in combination to effect control of the release of the active component from the base or to mask the odor of the active component.
- The composition of the present invention comprise a base selected from those which have been confirmed in terms of their stability, and hence, which may be applied by various application methods without being limited to any specific one. For example, the ointment is suitable for any one of topical external application on the skin for the treatment of acne, urogenital application, oral application for the treatment of infectious periodontitis or the like.
- In accordance with the present invention, it is also provided processes for preparing the composition of the invention.
- The process of the invention is characterized in that a non-aqueous base is provided without any use of water in its preparation which would otherwise affect the stability of the active component. The process for preparing the composition of the present invention is described in detail below.
- Three basic alternatives can be mentioned as methods for preparing the composition of the present invention, i.e., dispersion method, fusion method and slolubilizing method.
- In the dispersion method, a homogeneous dispersion of the active component in a non-aqueous base is prepared by thoroughly grinding, pulverizing and kneading the active component, to make suitable the crystalline active component for topical administration. A preferred particle diameter of the active component is preferably 500 μm or less, normally 100 μm or less. For small scale production, the active component is mixed and thoroughly triturated with a portion of the base using an ointment slab and an ointment spatula or a mortar and a pestle. Subsequently, the rest of the base and other additives are added and trituration is continued until overall homogeneity is achieved. For large scale production, machines such as three roller machines, roll mills, kneaders, grinders or mixers are used. These machines may be used optionally under a reduced pressure or under heating. In such a case, the optimal stirring speed will be between 25 and 100 rpm and a preferred vacuum level ranges from 60 to 80 cmHg. A suitable heating temperature is between 35 to 60° C. depending on the stability of the active component. If necessary, the resulted particles may be screened.
- In the fusion method, since the active component is readily soluble in water, and its activity is lowered by hydrolysis, the active component is first wet-triturated in a non-aqueous base such as a small amount of liquid paraffin. Subsequently, the other components are successively admixed in an order that increases the ability of the component to solubilize the active component, to thereby finally accomplish overall homogeneity. Fusion may be carried out under heating and stirring, if necessary. A suitable heating temperature is between 35 to 60° C. depending on the stability of the active component. An ointment jar and a water bath may be used for small scale production, while machines such as a three roller machine, grinders and mixers will be used in a water bath for large scale production. During the process, an optimal stirring speed is between 25 to 100 rpm and a preferred vacuum level is 60 to 80 cmHg. Particles may be filtered or screened, if necessary.
- The solubilizing method comprises the use of a non-aqueous solvent compatible with the non-aqueous base since the active component is readily soluble in water and its activity is lowered by hydrolysis. For example, a solution of the active component in methanol or ethanol is kneaded with a non-aqueous base, optionally under heating or stirring. A suitable heating temperature is between 35 to 60° C. depending on the stability of the active component. The solution in which the active component has been dissolved is mixed and thoroughly triturated with a portion of the base, then further triturated with the rest of the base and other additives to provide overall homogeneity. Mixing or trituration is performed with an ointment slab and an ointment spatula or a mortar and a pestle for small scale production. For large scale production, a three roller machine, roller mills, kneaders, grinders and mixers or the like are used. These machines may be used optionally under reduced pressure and an optimal agitation speed is between 25 to 100 rpm and the vacuum level is preferably 60 to 80 cmHg. Optionally, particles may be filtered or screened.
- The methods described above are preferably carried out under conditions which are free from not only water but also any other external factors which may potentially affect the stability of the active component. Such external factors include, for example, high temperatures, light and oxygen, which would all cause a deterioration in the active component.
- The step of filling the composition into a container should also be carried out under conditions which are free from any of the stated external factors. Namely, the shape of the container should be capable of preventing contact with such external factors and also be able to properly maintain the stability of the active component of the composition. Specific examples include bottles or jars made from glass, plastics and synthetic resins, or tubes made from metals, plastics and laminates. To seal the container, a screw cap is used to effect closure for bottles and jars, or folding a metal tube filled from its bottom end or contact-bonding a similarly filled plastic tube between hot plates, or contact-bonding a similarly filled laminate tube under heat such as high frequency or supersonic wave can also be employed.
- The shape of the container may be selected depending on the intended use. Thus, in addition to the shapes mentioned above, the container may have a shape which enables, for example, direct application or injection of the composition at various body sites. One example is a container designed to discharge the composition by a piston-like rod from an injection cylinder or a syringe made from plastic or synthetic resin.
- The following examples further illustrate the present invention using Compound 1 without, however, limiting the same thereto.
-
Component % by weight Compound 1 2.51) Hydrocarbon gel2) 97.5 - Compound 1 was mixed with hydrocarbon gel to overall homogeneity to give the desired composition.
-
Component % by weight Compound 1 6.23) Hydrocarbon gel2) 93.8 - Compound 1 was mixed with hydrocarbon gel to overall homogeneity to give the desired composition.
-
Component % by weight Compound 1 12.44) Hydrocarbon gel 87.6 - Compound 1 was mixed with hydrocarbon gel to overall homogeneity to give the desired composition.
-
Component % by weight Compound 1 2.5 White petrolatum 97.5 - Compound 1 was mixed with white petrolatum to overall homogeneity to give the desired composition.
-
Component % by weight Compound 1 2.5 Purified lanolin 97.5 - Compound 1 was mixed with purified lanolin to overall homogeneity to give the desired composition.
-
Component % by weight Compound 1 2.5 Carmellose sodium 2.0 Hydrocarbon gel 95.5 - Compound 1 was mixed with a dispersion of carmellose sodium in hydrocarbon gel to give the desired composition. This composition is particularly suitable for oral application as a therapeutic agent for periodontal diseases.
-
Component % by weight Compound 1 2.5 Xanthan gum 2.0 Hydrocarbon gel 95.5 - Compound 1 was mixed with a dispersion of xanthan gum in hydrocarbon gel to give the desired composition. This composition is suitable for oral application as a therapeutic agent for periodontal diseases.
-
Component % by weight Compound 1 2.5 Liquid paraffin 0.2 Hydrocarbon gel 97.3 - Compound 1 was wet-kneaded with liquid paraffin and then mixed with hydrocarbon gel to overall homogeneity to give the desired composition.
-
Component % by weight Compound 1 2.5 Ethanol 0.1 Hydrocarbon gel 97.4 - Hydrocarbon gel was added in portions into a solution of Compound 1 in ethanol and mixed to overall homogeneity to give the desired composition.
- Stability test of penem-containing composition
- A plastic container filled with a composition containing Compound 1 prepared according to the 5 formulations of Examples 1, and 4 to 7 was sealed with a screw cap. The container was stored at 40° C., 75% relative humidity (RH) for 1 month or 2 months or at room temperature for 1 month. Any observable change in the appearance of the composition was evaluated, and at the same time, the potency of the antibiotic was determined by high-performance liquid chromatography, from which the residual retention (%) to the initial potency was calculated.
- Conditions for high-performance liquid chromatography were as follows. A stainless steel high-performance liquid chromatography column charged with octadecylsilylated silica gel was used. Column temperature was maintained at 40° C. The mobile phase consisted of Solution A containing 45 mM potassium dihydrogenphosphate, 5 mM sodium monohydrogenphosphate and 5 mM tetra-n-butylammonium bromide and Solution B comprising a 1:1 mixture of Solution A and acetonitrile. The mobile phase initially contained 16% of Solution B, then once analysis was started, Solution B was gradually increased to 70% over 54 minutes. The flow rate was controlled so that the retention time of Compound 1 was 24 minutes. The detector used was a UV spectrophotometer at a wavelength of 240 nm.
- As controls, the following formulations using hydrophilic bases were also tested in the same manner.
Control 1 Component % by weight Compound 1 2.51) Hydrophilic ointment 97.5 - Compound 1 was mixed with hydrophilic ointment to overall homogeneity to give the composition of Control 1.
Control 2 Component % by weight Compound 1 2.51) Absorptive ointment 97.5 - Compound 1 was mixed with absorptive ointment to overall homogeneity to give the composition of Control 2.
- Results are shown in Table 1.
TABLE 1 Composition No. (Control No.) 1 2 3 4 5 (1) (2) Formu- Compound 1 2.5 2.5 2.5 2.5 2.5 2.5 2.5 lation Hydrocarbon gel 97.5 95.5 95.5 0 0 0 0 (% by White peterolatum 0 0 0 97.5 0 0 0 weight) Purified lanolin 0 0 0 0 97.5 0 0 Hydrophilic ointment 0 0 0 0 0 97.5 0 Absorptive ointment 0 0 0 0 0 0 97.5 Carmellose Sodium 0 2.0 0 0 0 0 0 Xanthan gum 0 0 2.0 0 0 0 0 Stability Initial appearance White Yellowish Yellowish Yellowish Pale White White test Semisolid white white white greenish Semisolid Semisolid results Semisolid Semisolid Semisolid yellow Semisolid Storage for Appearance Yellowish Yellowish Slightly Slightly Yellow Pale Bright 1 month at after storage white white pale pale Semisolid yellow yellow 40° C., 75% RH Semisolid Semisolid yellow yellow Semisolid Semisolid Semisolid Semisolid Storage for Appearance Yellowish Yellowish Slightly Slightly Yellow Pale Dark 2 months at after storage white white pale pale Semisolid yellow reddish 40° C., 75% RH Semisolid Semisolid yellow yellow Semisolid yellow Semisolid Semisolid Semisolid Potency 100 97 100 100 92 0 0 retention (%) Storage for Appearance White Yellowish Yellowish Yellowish Pale Pale Bright 1 month at after storage Semisolid white white white greenish yellow reddish room Semisolid Semisolid Semisolid yellow Semisolid yellow temperature Semisolid Semisolid Potency 100 100 100 100 100 47 26 retention (%) - As shown in Table 1, combinations of Compound 1 with non-aqueous bases such as hydrocarbon gel, white petrolatum and purified lanolin provided stable compositions, and their stability was not adversely affected even by the addition of water-soluble polymer compounds such as carmellose sodium and xanthan gum as thickening agents. In contrast, when a water-absorbing ointment or hydrophilic ointment with hydrophilicity was used as a base, the active component was inactivated after storage at 40° C. for 2 months, or even after storage at room temperature for 1 month, and the properties of the composition were changed with a significant decrease in the residual titer of Compound 1 to generate many decomposition products including hydrolyzates, hydrolytic isomerization products and cleavage products of Compound 1.
- Thus, the compositions in which Compound 1 was admixed into a non-aqueous bases according to the present invention were stable, and their stability was not affected even by addition of a water-soluble polymer compound.
- A similar stability was observed when the composition according to the formulation of Example 1 was stored at room temperature for 3 years.
- Advantageous effects of the Invention
- According to the present invention, very unstable penem antibiotics can be formulated into a stable composition by using hydrophobic polymer compounds as bases without the stability of the active component being compromised by further addition of water-soluble polymer compounds, to thereby provide antibacterial compositions which can be widely used in dermatological, ophthalmologic, otolaryngologic, dental/oral surgical and urogenital fields.
Claims (10)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/062,720 US20020142040A1 (en) | 1998-01-13 | 2002-02-05 | Antibacterial composition for topical administration containing antibiotic |
US10/758,217 US20040151743A1 (en) | 1998-01-13 | 2004-01-16 | Antibacterial composition for topical administration containing antibiotic |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4845/1998 | 1998-01-13 | ||
JP484598 | 1998-01-13 | ||
JP10-004845 | 1998-01-13 | ||
PCT/JP1999/000068 WO1999036098A1 (en) | 1998-01-13 | 1999-01-12 | Antibacterial composition for topical administration containing antibiotics |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1999/000068 A-371-Of-International WO1999036098A1 (en) | 1998-01-13 | 1999-01-12 | Antibacterial composition for topical administration containing antibiotics |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/062,720 Division US20020142040A1 (en) | 1998-01-13 | 2002-02-05 | Antibacterial composition for topical administration containing antibiotic |
Publications (2)
Publication Number | Publication Date |
---|---|
US20020035160A1 true US20020035160A1 (en) | 2002-03-21 |
US6365635B1 US6365635B1 (en) | 2002-04-02 |
Family
ID=11595031
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/380,530 Expired - Fee Related US6365635B1 (en) | 1998-01-13 | 1999-01-12 | Antibacterial composition for topical administration containing antibiotic |
US10/062,720 Abandoned US20020142040A1 (en) | 1998-01-13 | 2002-02-05 | Antibacterial composition for topical administration containing antibiotic |
US10/758,217 Abandoned US20040151743A1 (en) | 1998-01-13 | 2004-01-16 | Antibacterial composition for topical administration containing antibiotic |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/062,720 Abandoned US20020142040A1 (en) | 1998-01-13 | 2002-02-05 | Antibacterial composition for topical administration containing antibiotic |
US10/758,217 Abandoned US20040151743A1 (en) | 1998-01-13 | 2004-01-16 | Antibacterial composition for topical administration containing antibiotic |
Country Status (7)
Country | Link |
---|---|
US (3) | US6365635B1 (en) |
EP (1) | EP0966974B1 (en) |
KR (1) | KR20000076105A (en) |
CN (1) | CN1133428C (en) |
AT (1) | ATE283707T1 (en) |
DE (1) | DE69922296T2 (en) |
WO (1) | WO1999036098A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100179170A1 (en) * | 2006-12-05 | 2010-07-15 | Lisa Claire Du Toit | Heterogeneously configured multiparticulate gastrointestinal drug delivery system |
WO2014025412A1 (en) * | 2012-08-06 | 2014-02-13 | Isp Investments Inc. | Eco-friendly non-aqueous antimicrobial composition comprising tropolone with 1,3-propanediol and/or sorbitan caprylate |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1142573B1 (en) * | 1999-09-17 | 2006-01-11 | Daiichi Asubio Pharma Co., Ltd. | Pharmaceutical compositions comprising faropenem sodium and a diamineacetate compound for improving gastrointestinal absorption |
PT1138333E (en) * | 1999-10-12 | 2004-07-30 | Daiichi Suntory Pharma Co Ltd | ORAL PHARMACEUTICAL COMPOSITION |
HU228233B1 (en) * | 1999-12-28 | 2013-02-28 | Teikoku Seiyaku Co | Antipruritic agents for external use |
JP4653282B2 (en) * | 2000-05-23 | 2011-03-16 | 昭和薬品化工株式会社 | Minocycline-containing composition |
EP1399128B1 (en) | 2001-06-15 | 2006-08-30 | Innovent Technology Limited | Composition for the treatment of diseases which affect animals' hooves |
US7220431B2 (en) | 2002-11-27 | 2007-05-22 | Regents Of The University Of Minnesota | Methods and compositions for applying pharmacologic agents to the ear |
US8778889B2 (en) * | 2003-03-10 | 2014-07-15 | The United States Of America As Represented By The Secretary Of The Army | Antimicrobial decapeptide oral hygiene treatment |
US7494980B2 (en) * | 2003-03-10 | 2009-02-24 | The United States Of America As Represented By The Secretary Of The Army | Antimicrobial peptide and methods of use thereof |
US20050123576A1 (en) * | 2003-12-03 | 2005-06-09 | Ilana Lavon | Mupirocin compositions for topical use, an improved process of making same and methods of using same |
US20060029674A1 (en) * | 2004-04-09 | 2006-02-09 | Sever Nancy E | Stable amorphous Cefdinir |
US20060069079A1 (en) * | 2004-09-27 | 2006-03-30 | Sever Nancy E | Stable amorphous cefdinir |
JP4526042B2 (en) * | 2005-04-08 | 2010-08-18 | 国立大学法人三重大学 | External preparation for wound treatment |
US20090275746A1 (en) * | 2006-07-28 | 2009-11-05 | Hetero Drugs Limited | Solid faropenem free acid |
EP2328590A1 (en) * | 2008-08-18 | 2011-06-08 | Nanotherapeutics, Inc. | Topical hydrogel composition |
US20130245060A1 (en) * | 2010-10-08 | 2013-09-19 | Helperby Therapeutics Limited | Novel composition |
US20170239277A1 (en) * | 2016-02-23 | 2017-08-24 | Cmpd Licensing, Llc | Compositions and methods for treating an infection |
US11278590B2 (en) | 2015-08-05 | 2022-03-22 | Cmpd Licensing, Llc | Compositions and methods for treating nail infections |
US11690815B2 (en) | 2015-08-05 | 2023-07-04 | Cmpd Licensing Llc | Hyperkeratotic skin condition treatments and compositions |
US10898455B2 (en) | 2016-01-07 | 2021-01-26 | Cmpd Licensing, Llc | Urea cream formulations |
US10898491B2 (en) | 2015-12-18 | 2021-01-26 | Cmpd Licensing, Llc | Compositions and methods for treating an infection |
US11793783B2 (en) | 2015-08-05 | 2023-10-24 | Cmpd Licensing, Llc | Compositions and methods for treating an infection |
US11684567B2 (en) | 2015-08-05 | 2023-06-27 | Cmpd Licensing, Llc | Compositions and methods for treating an infection |
US11202788B2 (en) | 2019-08-22 | 2021-12-21 | Nanopharmaceutics, Inc. | Topical doxycycline hydrogel with improved long-term stability |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4168314A (en) * | 1977-11-17 | 1979-09-18 | Merck & Co., Inc. | 6-(1'-Hydroxyethyl)-2-aminoethylthio-pen-2-em-3-carboxylic acid |
EP0003960B1 (en) | 1978-02-02 | 1983-06-29 | Ciba-Geigy Ag | 6-substituted thia-aza-compounds, their preparation and pharmaceutical compositions containing them |
IL58576A (en) | 1978-12-18 | 1985-12-31 | Bristol Myers Co | 2-substituted and 2,6-disubstituted penem compounds,their preparation and pharmaceutical compositions containing them |
JPS5625110A (en) | 1978-12-18 | 1981-03-10 | Bristol Myers Co | Antibacterial |
US4282150A (en) | 1978-12-18 | 1981-08-04 | Bristol-Myers Company | 2,6-Disubstituted penem compounds |
US4272437A (en) | 1978-12-18 | 1981-06-09 | Bristol-Myers Company | Antibacterial agents, and 4-thio azetidinone intermediates |
US4683226A (en) * | 1979-08-01 | 1987-07-28 | Schering Corporation | 6-hydroxyalkyl-2-(substituted-thio)penem-3-carboxylic acids |
US4411906A (en) * | 1981-11-25 | 1983-10-25 | Schering Corporation | (5R,6S,8R)-6-(1-Hydroxyethyl)-2-(2-fluoroethylthio)-penem-3-carboxylates |
US4650794A (en) * | 1982-04-29 | 1987-03-17 | Merck & Co., Inc. | 6-(1-hydroxyethyl)-2-carbamimidoyl-pen-2-em-3-carboxylic acids |
US4388310A (en) * | 1982-03-01 | 1983-06-14 | Merck & Co., Inc. | 6-Amido-2-S-oxides of substituted 2-organothio-pen-2-em-3-carboxylic acids |
US4743598A (en) * | 1982-12-06 | 1988-05-10 | Schering Corporation | Antibacterial 2-(azacycloalkyl) penems |
US4701320A (en) | 1984-11-29 | 1987-10-20 | Lederle (Japan), Ltd. | Composition stably containing minocycline for treating periodontal diseases |
JPH0234325B2 (en) | 1985-11-22 | 1990-08-02 | Sansutaa Kk | SHISHUSHITSUKANCHIRYOYOSOSEIBUTSU |
JPS61130228A (en) * | 1984-11-29 | 1986-06-18 | Sunstar Inc | Composition stably blended with minocycline |
JPH075463B2 (en) * | 1985-03-09 | 1995-01-25 | サントリー株式会社 | Antibacterial agent |
JP2526046B2 (en) | 1986-12-26 | 1996-08-21 | サントリー株式会社 | Penem derivative, its manufacturing method and its use |
JP2852687B2 (en) * | 1990-04-27 | 1999-02-03 | 富山化学工業株式会社 | Sustained-release oral ointment for periodontal pockets |
CZ282086B6 (en) * | 1990-08-20 | 1997-05-14 | Suntory Limited | Antibacterially active penem esters and antibiotic preparations containing thereof |
ES2244529T3 (en) * | 1991-02-01 | 2005-12-16 | Daiichi Suntory Pharma Co., Ltd. | ORAL ANTIBACTERIAL COMPOSITIONS AND METHOD FOR IMPROVING GASTROINTESTINAL ABSORPTION OF ANTIBIOTICS OF PENEMO OR CARBAPENEMO. |
JP3132863B2 (en) | 1991-10-24 | 2001-02-05 | 富山化学工業株式会社 | Sustained-release oral ointment |
US5654451B1 (en) * | 1993-01-14 | 2000-02-22 | Magainin Pharma | Amino acids and peptides having modified c-terminals and modified n-terminals |
JP2913241B2 (en) | 1993-01-29 | 1999-06-28 | 富山化学工業株式会社 | Sustained-release oral ointment |
US5858408A (en) | 1994-07-20 | 1999-01-12 | Toyama Chemical Co., Ltd. | Sustained-release oral ointment |
US5795909A (en) * | 1996-05-22 | 1998-08-18 | Neuromedica, Inc. | DHA-pharmaceutical agent conjugates of taxanes |
-
1999
- 1999-01-12 WO PCT/JP1999/000068 patent/WO1999036098A1/en not_active Application Discontinuation
- 1999-01-12 EP EP99900173A patent/EP0966974B1/en not_active Expired - Lifetime
- 1999-01-12 CN CNB998001392A patent/CN1133428C/en not_active Expired - Fee Related
- 1999-01-12 DE DE69922296T patent/DE69922296T2/en not_active Expired - Fee Related
- 1999-01-12 AT AT99900173T patent/ATE283707T1/en not_active IP Right Cessation
- 1999-01-12 US US09/380,530 patent/US6365635B1/en not_active Expired - Fee Related
- 1999-01-12 KR KR1019997008193A patent/KR20000076105A/en not_active Application Discontinuation
-
2002
- 2002-02-05 US US10/062,720 patent/US20020142040A1/en not_active Abandoned
-
2004
- 2004-01-16 US US10/758,217 patent/US20040151743A1/en not_active Abandoned
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100179170A1 (en) * | 2006-12-05 | 2010-07-15 | Lisa Claire Du Toit | Heterogeneously configured multiparticulate gastrointestinal drug delivery system |
WO2014025412A1 (en) * | 2012-08-06 | 2014-02-13 | Isp Investments Inc. | Eco-friendly non-aqueous antimicrobial composition comprising tropolone with 1,3-propanediol and/or sorbitan caprylate |
US9226882B2 (en) | 2012-08-06 | 2016-01-05 | Isp Investments Inc. | Eco-friendly non-aqueous antimicrobial composition comprising tropolone with 1,3-propanediol and/or sorbitan caprylate |
Also Published As
Publication number | Publication date |
---|---|
CN1256633A (en) | 2000-06-14 |
WO1999036098A1 (en) | 1999-07-22 |
KR20000076105A (en) | 2000-12-26 |
US20020142040A1 (en) | 2002-10-03 |
DE69922296T2 (en) | 2005-10-27 |
US20040151743A1 (en) | 2004-08-05 |
EP0966974A1 (en) | 1999-12-29 |
EP0966974B1 (en) | 2004-12-01 |
EP0966974A4 (en) | 2003-05-21 |
DE69922296D1 (en) | 2005-01-05 |
US6365635B1 (en) | 2002-04-02 |
ATE283707T1 (en) | 2004-12-15 |
CN1133428C (en) | 2004-01-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6365635B1 (en) | Antibacterial composition for topical administration containing antibiotic | |
US10849847B2 (en) | Compositions and methods for treating rosacea and acne | |
CN1051453C (en) | Compositions of clindamycin and benzoyl peroxide for acne treatment | |
JP2005511642A (en) | Formulations containing cephalosporin compounds and their use in the treatment of bacterial infections in dogs and cats | |
IE902307A1 (en) | Stable, cosmetically acceptable topical gel formulation and¹method of treatment for acne | |
JP2004511561A (en) | Pharmaceutical composition | |
US4923862A (en) | Topical preparation containing ofloxacin | |
US20040208906A1 (en) | Pharmaceutical composition for topical administration | |
EP1142573B1 (en) | Pharmaceutical compositions comprising faropenem sodium and a diamineacetate compound for improving gastrointestinal absorption | |
CA2429205C (en) | Dermatological formulations | |
CN113194943B (en) | Pharmaceutical composition containing cefotaxime sulbactam or cefotaxime tazobactam with stability and antibacterial activity | |
EP1112750A9 (en) | Drug composition for topical administration | |
KR101019769B1 (en) | Antibacterial Medicinal Composition of Enhanced Oral Absorptivity | |
JP2020512997A (en) | Topical doxycycline composition | |
Radwanski et al. | Pharmacokinetic drug interaction study: administration of ceftibuten concurrently with the antacid mylanta double-strength liquid or with ranitidine | |
AU2021211317A1 (en) | External preparation containing rapamycin | |
JPH01193387A (en) | Method for stabilizing azulene compound | |
JPS61183228A (en) | Drug preparation for external use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: SUNTORY LIMITED, JAPAN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:NOMURA, MASAAKI;SUMIKAWA, HIROMI;SUGITA, OSAMU;REEL/FRAME:010253/0490 Effective date: 19990830 |
|
FEPP | Fee payment procedure |
Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
AS | Assignment |
Owner name: DAIICHI SUNTORY PHARMA CO., LTD., JAPAN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SUNTORY LIMITED;REEL/FRAME:013868/0759 Effective date: 20030314 |
|
FPAY | Fee payment |
Year of fee payment: 4 |
|
REMI | Maintenance fee reminder mailed | ||
LAPS | Lapse for failure to pay maintenance fees | ||
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20100402 |