Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-07
2002-07-30
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06426363
ABSTRACT:
The present invention relates to the use of mupirocin or a salt or ester thereof in treating certain bacterial infections, in particular recurrent otitis media and recurrent sinusitis, and to formulations for use in such treatment.
Mupirocin, formerly known as pseudomonic acid, is a therapeutically useful compound which exhibits good antibacterial activity, mainly against Gram-positive bacteria, but also against some Gram-negative bacteria such as
Haemophilus influenzae
and
Moraxella catarrhalis
. It acts as a selective reversible inhibitor of bacterial iso-leucyl t-RNA synthetase, thereby inhibiting bacterial protein synthesis (see Merck Index, 11th edn, 1989, 993 and references therein). The compound has an ester moiety which is susceptible to metabolism, effectively excluding the systemic use of the compound. It is however clinically effective as a topical agent.
Topical antibacterial compositions comprising mupirocin are marketed by SmithKline Beecham under the trade names Bactroban Ointment and Bactroban Nasal. The first product is an ointment comprising a water soluble polyethylene glycol base (see also EP 0 095 897-A, Beecham Group) whilst the second product comprises the calcium salt of mupirocin in a white soft paraffin based ointment containing a glycerin ester (see also EP 0 167 856-A, Beecham Group). More recently, topical creams comprising mupirocin or a salt thereof have been described (PCT/US94/12026, SmithKline Beecham). The formulation comprising the calcium salt of mupirocin in a white soft paraffin based ointment containing a glycerin ester (Bactroban Nasal) is particularly useful when applied to the anterior nares for the prophylactic eradication of the nasal carriage of
Staph aureus
. More recently, it has been found that the impact of such application is limited to the anterior nares. There is no significant reduction in the colonisation (by
H. influenzae, S. pneumonia
and
M. catarrhalis
) of the nasopharynx (unpublished).
A further potential therapeutic use of mupirocin has been described by Nsouli et al (poster presented at the Annual Meeting of the American College of Allergy, Asthma and Immunology, Nov. 10-15, 1995 and published in Annals of Allergy, Asthma and Immunology, January 1996, 76(1), 117). A spray formulation comprising Bactroban Ointment diluted in a 1:9 ratio with a saline solution (Ocean, Fleming & Co) was shown to be effective in reducing the incidence of recurrent paranasal sinusitis when administered twice daily (two ‘puffs’ of spray, estimated to be about 150-200&mgr;l) over a seven month period. It is believed that efficacy of the mupirocin/saline combination is the result of eradication of nasal carriage of pathogenic bacteria associated with the recurrent episodes as the formulation would have no direct access to the sinus mucosa due to a small ostium which separates the nasopharynx from the maxillary sinuses. This dosage regimen may however not be ideal as there is concern that the use of a relatively low dosage over a prolonged period may encourage the development of mupirocin resistant bacteria. Furthermore, there may also be concerns about the desirability of the long term usage of aqueous solutions of mupirocin, given the known susceptibility of mupirocin to degradation in such an environment. There still remains the problem of providing a method of treatment for recurrent sinusitis which is devoid of the concerns mentioned above. In addition, there was no suggestion of other diseases which might be susceptible to similar treatment.
Otitis media is a disease state commonly seen in infants and young children. The acute condition is normally successfully treated with a systemic antibacterial agent such as amoxycillin, optionally in combination with potassium clavulanate.
H. influenzae, S. pneumonia
and
M. catarrhalis
are generally considered to be the most common bacterial pathogens. There however remains the problem of treating the recurrent painful episodes.
Accordingly, in a first aspect, the present invention provides for the use of mupirocin or a pharmaceutically acceptable ester or salt thereof in the manufacture of a medicament for the prophylactic treatment of bacterial infection associated with colonisation of the nasopharynx by pathogenic organisms, and in which the medicament is adapted for administration to, and residence within, the nasopharynx; excluding the use of a 0.2% saline solution of mupirocin for treating recurrent sinusitis, administered at a dosage of less than 1 mg a day, twice daily on a continuing basis.
Typical bacterial infections include recurrent otitis media and recurrent sinusitis.
Accordingly, in a further aspect, the present invention provides for the use of the use of mupirocin or a pharmaceutically acceptable ester or salt thereof in the manufacture of a medicament for the prophylactic treatment of recurrent otitis media.
In addition, the present invention also provides for the use of mupirocin or a pharmaceutically acceptable ester or salt thereof in the manufacture of a medicament for the prophylactic treatment of recurrent sinusitis.
As used herein, the term ‘prophylactic treatment’ includes not only complete elimination of the bacterial infection, for instance recurrent otitis media or recurrent sinusitis, but also a partial elimination of thereof, that is a reduction in the number of acute episodes.
It is believed that the successful treatment of bacterial infections, such as recurrent otitis media and recurrent sinusitis, is associated with the elimination or reduction of nasal carriage of pathogenic bacteria such as
S. aureus, H. influenzae, S. pneumonia
and
M. catarrhalis
, in particular colonisation of the nasospharynx by such organisms.
Accordingly, in a further aspect, the present invention provides for the use of mupirocin or a pharmaceutically acceptable ester or salt in the manufacture of a medicament for reducing or eliminating the nasal carriage of pathogenic organisms associated with recurrent otitis media, which medicament is adapted for nasal administration, in particular, focussed delivery to the nasopharynx.
To lessen the risk of encouraging the development of mupirocin resistant organisms, it is preferred to administer of mupirocin or a pharmaceutically acceptable salt or ester thereof on an intermittent, rather than a continual, basis.
Accordingly, in a further aspect, the present invention provides the use of mupirocin or a pharmaceutically acceptable salt or ester thereof (hereinafter referred to as drug substance) in the manufacture of a medicament adapted for administration to the nasopharynx and which is administered to a patient in need thereof on an intermittent basis.
In a suitable intermittent treatment regimen, drug substance (mupirocin or a pharmaceutically acceptable ester or salt) is administered on a daily basis, for a small number of days, for instance from 2 to 10, suitably 3 to 8, more suitably about 5 days, the administration then being repeated after an interval, for instance, on a monthly basis over a period of months, for instance up to six months.
Less preferably, the drug substance may be administered on a continuing, daily basis, over a prolonged period, for instance several months.
Suitably drug substance is administered twice a day. Suitably, drug substance is administered during the winter months when bacterial infections such as recurrent otitis media and recurrent sinusitis tend to be more prevelant.
Suitably, drug substance is administered at a dosage of from 1 to 10 mg, preferably from 3 to 8, typically about 5 mg, in each nostril, twice a day.
The drug substance is administered to the nasopharynx, in particular the anterior nasopharynx.
Suitable pharmaceutically acceptable salts of mupirocin are well known in the art and include alkali metal salts such as sodium and lithium and alkaline earth metal salts such as calcium, of which the calcium salt is preferred, in particular the crystalline dihydrate form thereof described in EP 0 167 856-A (Beecham Group), as well as other metal salts, for instance silver and Aluminium salt
Hatton Anthony Guy
Henkel Timothy John
Hilton Jane Elizabeth
Scott Hugh
Tallon Teresita Regina Geradine
Fay Zohreh
Gimmi Edward R.
Hecht Elizabeth J.
Kinzig Charles M.
Kwon Brian-Yong S.
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