Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
1999-09-02
2002-04-02
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C514S192000, C424S405000
Reexamination Certificate
active
06365635
ABSTRACT:
FIELD OF THE INVENTION
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.
PRIOR ART
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 &bgr;-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 &bgr;-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 &bgr;-lactam antibiotics combined with the potent antibacterial activity and high stability to &bgr;-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-sensitive
Staphylococcus aureus
(MSSA),
Streptococcus pyrogenes
and
Streptococcus pneumoniae
but also gram-positive bacteria less susceptible to conventional &bgr;-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 &bgr;-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.
SUMMARY OF THE INVENTION
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.
DETAILED DESCRIPTION OF THE INVENTION
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 en
Nomura Masaaki
Sugita Osamu
Sumikawa Hiromi
Fubara Blessing
Nixon & Vanderhye
Page Thurman K.
Suntory Limited
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