WO2020141482A1 - Compositions pharmaceutiques comprenant de la mupirocine - Google Patents

Compositions pharmaceutiques comprenant de la mupirocine Download PDF

Info

Publication number
WO2020141482A1
WO2020141482A1 PCT/IB2020/050029 IB2020050029W WO2020141482A1 WO 2020141482 A1 WO2020141482 A1 WO 2020141482A1 IB 2020050029 W IB2020050029 W IB 2020050029W WO 2020141482 A1 WO2020141482 A1 WO 2020141482A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
mupirocin
acceptable salt
pharmaceutically acceptable
pharmaceutical composition
Prior art date
Application number
PCT/IB2020/050029
Other languages
English (en)
Inventor
Sushrut Kulkarni
Jitendra GANGWAL
Ulhas Rameshchandra Dhuppad
Original Assignee
Glenmark Specialty S.A.
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 Glenmark Specialty S.A. filed Critical Glenmark Specialty S.A.
Publication of WO2020141482A1 publication Critical patent/WO2020141482A1/fr

Links

Classifications

    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K9/0046—Ear
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present invention relates to a pharmaceutical composition meant for administering to mucosal surface comprising mupirocin or a pharmaceutical acceptable salt thereof and a process for its preparation.
  • the pharmaceutical composition meant for mucosal surfaces are difficult prepare due the stringent selection of excipients that compatible to epithelial cells as well as to the drug.
  • the mucosal surface in the human composed of epithelial cells that lines various cavities in the body and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue.
  • the pharmaceutical composition administered to the mucosal surface should be safe and non-toxic.
  • Some examples of the mucosal surface is nose, ear, eye or body cavities.
  • the infection caused at mucosal surface at difficult to treat due the sensitivity of the skin in mucosal surface.
  • the composition meant for administering to mucosal surface should be non-toxic, non-irritating, and yet comprising excipients that are compatible to the drug used to treat the infections.
  • One of the bacterial infection caused in eye and ear are due to Staphylococcus genus.
  • Methicillin resistant Staphylococcus aureus (MRSA) infection is a growing concern in medicine and is present in surgical and non-surgical patients (Teweldemedhin et al. BMC Ophthalmology (2017) 17:212).
  • Methicillin- resistant Staphylococcus aureus (MRSA) otorrhea has become an increasing problem with regard to infection through the tympanic membrane perforation and postsurgical infection.
  • Otitis externa is an inflammation of the outer ear and ear canal. It is a common cause of ear ache in humans. This disorder involves inflammation of the skin of the ear canal. The inflammation can be caused by active fungal, viral or bacterial organisms.
  • Ophthalmic MRSA infections can be preseptal cellulitis and/or lid abscess (preseptal cellulitis with lid abscess / preseptal cellulitis without abscess / Lid abscess without mention of cellulitis), conjunctivitis, corneal ulcer, endogenous endophthalmitis, orbital cellulitis with endophthalmitis, blebitis, dacryocystitis, and orbital abscess.
  • Treatment with topical antibiotics is still the most effective medical approach for treating MRSA conjunctivitis (Bartlett et al. “Overview of Methicillin-resistant Staphylococcus aureus (MRSA)”, Contact Lens Spectrum. 2010; 02).
  • MRSA is resistant to methicillin and other beta-lactamase antibiotics because it has an enzyme that attacks the B-lactam ring of the antibiotic. Also, it has become increasingly resistant to cephalosporins and fluoroquinolones. The most important goal for the physician who treat ophthalmic/otic infection to keep in mind in a patient with MRSA is to protect the patient’s vision and ear.
  • the mode of transmission for MRSA can be either through direct contact with a person from the community, community- acquired (CA) MRSA, or in hospitals, hospital acquired (HA) MRSA.
  • Mupirocin Pseudomonic acid A
  • Mupirocin has following structural formula:
  • Mupirocin is useful against superficial skin infections such as impetigo or folliculitis. It is also useful in the treatment of superficial methicillin-resistant Staphylococcus aureus (MRS A) infections. Mupirocin reversibly binds to the isoleucyl t-RNA synthetase in Staphylococcus aureus and Streptococcus, resulting in inhibition of protein synthesis. DNA and cell wall formation are also negatively impacted to a lesser degree.
  • Biological activity of mupirocin is restricted to pH range 4 to 9 as it undergoes rapid hydrolysis and rearrangement in the presence of water, acid and base. Therefore, clinical applications of mupirocin are restricted to the topical treatment of skin infections only.
  • compositions meants for administering to mucosal surfaces such as ophthalmic composition and otic composition are to be dispensed in smaller quantities, and choice of the solvents and excipients are very limited as mupirocin is not compatible in many solvents and excipients. Mupirocin shows degradation in the presence of aqueous medium and some other excipients as well, and further, mupirocin is not soluble in many solvent excipients. Hence, it is extremely important to conduct extensive experiments to determine suitability of the solvents, combination of solvents, or excipients for preparing ophthalmic and otic compositions comprising mupirocin or a pharmaceutically acceptable salt thereof.
  • US 6,001,870 describes nasopharynx administration of mupirocin to treat recurrent sinusitis and recurrent otitis with spray or cream compositions.
  • US 2005/0123575 discloses a spreadable composition containing a hard fat for topical administration. However this product is not fluidy and need spreading which limits its utility as otic drop to be effective in inner ear infections.
  • US 6,013,657 describes a mupirocin composition in a carrier selected from the gourp consisting of oleyl alcohol, castor oil, and a mixture thereof.
  • Furukawa et al. Otol Neurotol, 2008, 29(5):676-8 describe ototopical application of mupirocin ointment in methicillin resistant Staphylococcus aureus otorrhea.
  • Kye Hoon Park et al. Korean J Audiol, 2012, 16(3): 130-133 describe the clinical effectiveness of topical mupirocin ointment (Bactroban®) in reducing early post-tympanostomy tube otorrhea (PTTO).
  • Bactroban® topical mupirocin ointment
  • An otic or ophthalmic compositions are influenced by a variety of factors such as comfort, consistency, accuracy of dosage, type and ease of administration, and timing of delivery etc.
  • ophthalmic composition While the art has produced a variety of compositions for the treatment of ocular infections, there is no United States Food & drug Administration approved antimicrobial drug for treating MRSA. Hence, there is still a need for antimicrobial pharmaceutical ophthalmic compositions.
  • Such compositions would be even more desirable if they comprise a vehicle that readily permits accurate administration of dosages in a convenient form. It is also desirable that the composition be non-irritating and soothing to already irritated ocular and periocular tissues.
  • otic composition In case of otic composition, the infection of the middle ear can cause fluid build up there by drug delivery will be challenging and otic compositions should meet stringent criteria for pH, osmolarity, ionic balance, sterility, endotoxin and/or pyrogen levels.
  • the otic compositions described herein are compatible with the microenvironment of the ear (e.g., the middle ear) and are suitable for administration to humans.
  • the present inventors have found a stable pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof, meant for administering to mucosal surfaces such as otic media and exterior surface of eye.
  • An object of the present invention is to provide a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a stable pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; wherein the composition is meant for otic and/or ophthalmic administration.
  • the present invention relates to a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients thereof.
  • the present invention relates to a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; and a base composition.
  • a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof is meant for administration to a mucosal membrane such as otic externa, otitis media, nasal cavity, exterior surface of eye.
  • the base composition is non-aqueous base comprising one or more pharmaceutically acceptable excipients. In some embodiments, the base composition is aqueous base comprising one or more pharmaceutically acceptable excipients.
  • the base composition is non-aqueous, and the non- aqueous base compsoition comprising one or more excipients selected from propylene glycol, polyethylene glycol, glycofurol, ethanol, glycerol, vitamin E TPGS, isopropyl alcohol, castor oil, almond oil, soya bean oil, and any combination of any of the foregoing.
  • the base composition is aqueous composition
  • the aqueous base compsoition comprising one or more excipients selected from water for injection, propylene glycol, polyethylene glycol, vitamin E TPGS, glycerol, ethanol, isopropyl alcohol, glycofurol, and any combination of any of the foregoing.
  • the present invention is physically and chemically stable at least for a day.
  • the present invention is physically and chemically stable at least for a week.
  • the pharmaceutical composition of the present invention is meant for mucosal administration such as otic and/or ophthalmic.
  • the pharmaceutical compositions of the present invention is meant for otic administration.
  • the present invention relates to a stable otic pharmaceutical composition
  • a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a stable otic pharmaceutical composition
  • a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; wherein the composition is non-aqueous composition.
  • the present invention relates to a stable otic pharmaceutical composition
  • a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; a base composition comprising one or more water-miscible substance(s).
  • the present invention relates to a stable otic pharmaceutical composition
  • a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; a base composition comprising one or more water-miscible substance(s) selected from propylene glycol, polyethylene glycol, castor oil, almond oil, soya bean oil, mineral oil and any combination of any of the foregoing.
  • the present invention relates to a stable otic pharmaceutical composition
  • a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; a base composition comprising propylene glycol and polyethylene glycol in the weight ratio selected from 0:5, 1:5, 1:4, 1 :3, 1 :2, and 1: 1; and the composition optionally comprises a preservative.
  • the present invention relates to a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; a base composition comprising propylene glycol and polyethylene glycol in the weight ratio selected from 1 : 1, 1 :2, 1:3, 1:4, 1:5, and 1 :6; and the composition optionally comprises a preservative.
  • the present invention relates to a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; a base composition comprising glycofurol, and the composition optionally comprises a preservative.
  • the present invention relates to a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; a base composition comprising mineral oil, and the composition optionally comprises a preservative.
  • the present invention relates to a stable otic pharmaceutical composition
  • a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; wherein the composition is aqueous composition.
  • the present invention relates to an aqueous stable otic pharmaceutical composition
  • an aqueous stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof, in which the hydrolytic impurities formed are within acceptable limit of not more than 2%.
  • the present invention relates to a stable non-aqueous water miscible otic pharmaceutical composition
  • a stable non-aqueous water miscible otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a a stable non-aqueous oil based otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition consisting of i) from about 1% w/v to 5% w/v mupirocin or a pharmaceutically acceptable salt thereof; ii) benzalkonium chloride; and iii) propylene glycol up to 100% w/v based on the total volume of the composition; wherein the composition is meant for administering to mucosal surface.
  • the present invention relates to a pharmaceutical composition consisting of i) from about 1% w/v to 5% w/v mupirocin or a pharmaceutically acceptable salt thereof; ii) from about 10% w/v to about 60% w/v of propylene glycol; iii) benzalknoium chloride; iv) water for injection up to 100% w/v based on the total volume of the composition; wherein the composition is meant for otic administration.
  • the present invention relates to a pharmaceutical composition consisiting of: i) from about 1% w/v to 5% w/v mupirocin or a pharmaceutically acceptable salt thereof; ii) benzalknoium chloride; iii) from about 10% w/v to about 60% w/v of propylene glycol; and iv) polyethylene glycol 400 up to
  • composition 100% w/v based on the total volume of the composition; wherein the composition is meant for otic administration.
  • the present invention relates to a pharmaceutical composition consisiting of: i) from about 1% w/v to 5% w/v mupirocin or a pharmaceutically acceptable salt thereof; ii) benzalknoium chloride; iii) from about 10% w/v to about 60% w/v of propylene glycol; and iv) polyethylene glycol 400 up to 100% w/v based on the total volume of the composition; wherein the composition have weight ratio between propylene glycol to polyethylene glycol 400 is from 0: 1 to 1 :0.
  • the weight ratio between propylene glycol to polyethylene glycol 400 is selected from 1: 1, 1:2, 1 :3, 1:4, 1 :5, and 1:6.
  • the present invention relates to a pharmaceutical composition consisting of i) from about 1% w/v to 5% w/v mupirocin or a pharmaceutically acceptable salt thereof; ii) benzalknoium chloride; and iii) glycofurol up to 100% w/v based on the total volume of the composition; wherein the composition is meant for otic administration.
  • the present invention relates to a pharmaceutical composition consisiting of: i) from about 1% w/v to 5% w/v mupirocin or a pharmaceutically acceptable salt thereof; ii) benzalknoium chloride; and iii) polyethylene glycol 400 up to 100% w/v based on the total volume of the composition; wherein the composition is meant for otic administration.
  • the present invention relates to a pharmaceutical composition consisting of i) from about 1% w/v to 5% w/v mupirocin or a pharmaceutically acceptable salt thereof; ii) benzalknoium chloride; and iii) glycofurol up to 100% w/v based on the total volume of the composition; wherein the composition is meant for otic administration.
  • compositions of the present invention is meant for ophthalmic administration.
  • the present invention relates to a topical pharmaceutical ophthalmic composition
  • a topical pharmaceutical ophthalmic composition comprising mupirocin or pharmaceutically acceptable salts (such as a calcium salt thereof) or hydrates thereof.
  • the topical pharmaceutical ophthalmic composition is any composition that is capable of delivering mupirocin or pharmaceutically acceptable salt to the eye can be employed, including solutions, suspensions or emulsion.
  • the pharmaceutical ophthalmic composition of the present invention may also contain excipients, such as ophthalmologically acceptable pH adjusting acids, buffers, tonicity adjusting agents or solubilizers. Additional excipients may include, for example without limitation, chelating agents, surfactants and additional polymeric agents and preservatives. Those skilled in the art will be able to readily appreciate that diverse excipients, such as those set forth in " Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa. can be incorporated into the compositions of this invention.
  • One object of present invention is to provide an ophthalmic pharmaceutical composition
  • an ophthalmic pharmaceutical composition comprising (i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof, (ii) one or more excipients selected from buffering agent, preservative, viscosity modifying agent, tonicity adjusting agent, suspending agent, surfactants, solvent, antioxidant, chelating agent, pH adjusting agent, stabilisers or any combination of any of the foregoing, and (iii) carrier.
  • an ophthalmic pharmaceutical composition comprising(i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof, (ii) suspending agent, (iii) one or more buffering agent, preservative, tonicity adjusting agent, surfactants, solvent, antioxidant, chelating agent, pH adjusting agent or any combination of any of the foregoing, and (iv) carrier.
  • an ophthalmic pharmaceutical composition comprising(i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof, (ii) suspending agent, (iii) one or more buffering agent, preservative, tonicity adjusting agent, surfactants, solvent, antioxidant, chelating agent, pH adjusting agent or any combination of any of the foregoing, and (iv) carrier.
  • the present invention relates to a process for preparing a pharmaceutical composition comprising mupirocin comprising steps of: i) solubilizing mupirocin or a pharmaceutically acceptable salt thereof; and ii) optionally adding additional excipients; wherein the solubilization is done using homogenization and/or stirring.
  • the solubilization process involves homogenization of mupirocin or a pharmaceutically acceptable salt thereof with a non-aquous solvent at 100 to 700 rpm for at least one minute to 1 hour.
  • the solubilization process involves homogenization of mupirocin or a pharmaceutically acceptable salt thereof with a non-aquous solvent at 200 to 500 rpm for at least 10 minutes to 15 minutes.
  • the present invention relates to a method of treating an infection of mucosal surface in a subject in need thereof comprising administering a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; wherein the mucosal surface is otic and/or ophthalmic surface.
  • the present invention relates to a method of preventing an infection of mucosal surface in a subject susceptible to the infection comprising administering a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; wherein the mucosal surface is otic and/or ophthalmic surface.
  • Another aspect of the present invention is a method for treating a mammal (preferably a human patient) having otitis externa, otitis media, a nasal infection, a sinus infection, ophthalmic infection or a combination thereof.
  • the method comprises administering to the mammal a mupirocin composition of the present invention to the affected area, wherein a symptom of otitis externa, otitis media, a nasal infection, a sinus infection or ophthalmic infection is reduced.
  • an effective amount of the mupirocin composition is administered.
  • the human patient may be a child (for instance, a human under 12 years of age), an adolescent (for instance, a human of 13 to 17 years of age), or an adult (18 years of age and up).
  • Another aspect of the present invention is a method for preventing an infection in a subject (preferably a human patient) susceptible to infections in otitis externa, otitis media, a nasal infection, a sinus infection, ophthalmic infection or a combination thereof.
  • the method comprises administering to the subject a mupirocin composition of the present invention to the affected area, wherein a symptom of otitis externa, otitis media, a nasal infection, a sinus infection or ophthalmic infection is reduced.
  • an effective amount of the mupirocin composition is administered.
  • the human patient may be a child (for instance, a human under 12 years of age), an adolescent (for instance, a human of 13 to 17 years of age), or an adult (18 years of age and up).
  • Another object of present invention is to provide a method of treating an ocular infection, which comprises topically applying to the eye a therapeutically effective amount of a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt or hydrates thereof in a concentration of from about 0.1 to about 5 %w/v of mupirocin.
  • Another object of present invention is to provide a method of preventing an ocular infection, which comprises topically applying to the eye a therapeutically effective amount of a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt or hydrates thereof in a concentration of from about 0.1 to about 5 %w/v of mupirocin.
  • Another object of present invention is to provide a method of treating ophthalmic infections commonly associated with at least one of Haemophilus influenza, Staphylococci species but not limited to Methicillin-resistant Staphylococcus aureus (MRSA), Methicillin-sensitive Staphylococcus aureus (MSSA), coagulase-negative staphylococci, Streptococcus pneumonia, Streptococcus pyogenes, Streptococcus viridians and Pseudomonas aeruginosa.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • MSSA Methicillin-sensitive Staphylococcus aureus
  • coagulase-negative staphylococci Streptococcus pneumonia, Streptococcus pyogenes, Streptococcus viridians and Pseudomonas aeruginosa.
  • Ophthalmic infections are, but not limited to, conjunctivitis,
  • ophthalmic infections as listed above can be treated by topically applying to the affected ophthalmic tissue a therapeutically effective amount of a topical ophthalmic pharmaceutical composition containing mupirocin or a pharmaceutically useful salt or hydrates thereof at a concentration of about 2 %.
  • the present invention in an aspect provides an otic pharmaceutical composition.
  • the pharmaceutical composition comprises mupirocin and/or a pharmaceutically acceptable salt thereof as the active ingredient and pharmaceutically acceptable excipients in pre-determined amounts.
  • “ear” refers to the biological structures responsible for hearing and equilibrium in vertebrates, among other things.
  • the term“ear” also includes the visible portions of the biological structures, such as those often present on mammals.
  • otic refers to the ear, in general.
  • compositions of the invention when characterizing the compositions of the invention, means that said compositions are suitable for their application to the eye.
  • treating means: (1) ameliorating, reducing, or decreasing the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with the state, disorder, or condition, (2) delaying, or inhibiting the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (3) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (4) improving or relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
  • preventing or“prevention” include prevention of a pathology, condition, or disease (e.g. preventing the development of one or more symptoms of the mucosal surface such as ophthalmic and/or otic surface).
  • subject means any individual with respect to whom the mupirocin composition is intended to be used, and includes children (up to 12 years of age), adolescents (13 to 17 years of age), and adults (18 years and older).
  • composition and“composition” have their ordinary meaning and can be used interchangeably.
  • stable refers to a minimal change in physical and chemical properties of the composition over time relative to when it is manufactured. Stability over time may be evaluated based on pre-defined criteria including an assay of active and related compounds, impurities and degradation products, appearance, color, viscosity and pH.
  • stabilizers refers to compounds such as any antioxidation agents
  • Stabilizers include but are not limited to agents that will do any of (1) improve the compatibility of excipients with a container, or a delivery system, including a syringe or a glass bottle, (2) improve the stability of a component of the composition, or (3) improve composition stability.
  • a drug is said to be "stabilized" by the presence of a particular material contained in a composition, if a composition comprising all of the same materials in the same relative proportions to each other, excluding the active ingredient or drug, but with the particular material removed, exhibits a loss in potency that is greater than the loss of potency for the original composition when stored at 25° C and 60% relative humidity and/or 40° C and 75% relative humidity for one week, 15 days, 1 month, 2, month, 3 month, 6 months, 1 year and 2 year.
  • the replacement i.e., assessment of stability enhancement
  • the weight percentage of the drug in the composition is not increased, but instead the removed material is effectively replaced by equivalent proportions from the rest of the composition excluding the drug.
  • the comparative composition will contain 0% (w/v) A (the excluded component), 45% (w/v) B, 30% (w/v) C, 15% (w/v) D, and 10% (w/v) E (the active ingredient).
  • aqueous refers to a composition that has from about 8 to about 99% water, based upon 100% total weight of the composition, and in one embodiment is the composition has at least about 95% of water based on total weight of the topical composition. In one embodiment, it is a composition contains at least about 60% by weight water. In another embodiment, the aqueous solvent may include at least about 50%, or, at least about 40%, or at least about 30%, or at least about 20 %, or at least about 10%, or at least about 8% by weight water, based on the total weight of aqueous solvent.
  • therapeutically effective amount or“effective amount” as used herein means the amount of a compound that, when administered to a mammal or patient for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” can vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal or patient to be treated.
  • pharmaceutically acceptable is meant those salts and excipients which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • stable refers to a minimal change in physical and chemical properties of the composition over time relative to when it is manufactured. Stability over time may be evaluated based on pre-defined criteria including assay of active and related compounds, impurities/degradation products, appearance, color, viscosity and pH.
  • Stabilizers include but are not limited to agents that will do any of (1) improve the compatibility of excipients with a container or a delivery system, (2) improve the stability of a component of the composition, or (3) improve composition stability.
  • MIC Minimum Inhibitory Concentration
  • the term“MIC90” as used herein means the lowest concentration of the antibiotic at which 90% of the isolates will be inhibited.
  • the term“MIC50” as used herein means the lowest concentration of the antibiotic at which 50% of the isolates will be inhibited.
  • the term“mucosal membrane” or“mucosal surface” as used herein refers to a membrane/surface that lines various cavities in the body and covers the surface of internal organs including exterior surface of eye. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue.
  • the mucosal membrane includes otic externa, otitis media, nasal cavity, exterior surface of eye.
  • the mupirocin in the topical pharmaceutical composition may be in any form, such as in its base form or a pharmaceutical acceptable salt form.
  • the mupirocin is in the form of its calcium salt (e.g., mupirocin calcium, which is a hemicalcium salt of mupirocin), such as a dihydrate thereof.
  • the mupirocin may be in the form of its dihydrate crystalline calcium hemi-salt (e.g., (aE,2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4 et h y 1 h e x y 1 ] tet rah ydro- 3, 4 dihydroxy-P-methyl-2H-pyran-2-crotonic acid, ester with 9-hydroxynonanoic acid, calcium salt (2: 1), dihydrate).
  • mupirocin or a salt thereof is present in an amount from 0.01 to 5% by weight of the composition.
  • the pharmaceutical composition of the present invention is storage stable and avoids degradation of the mupirocin.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; and a base composition.
  • the pharmaceutical composition comprises base composition that can be in a form selected from an emulsion, suspension, solution, oily solution, oily suspension, or non-aqueous solution.
  • base composition can also be prepared in other known forms.
  • Mupirocin undergoes acid and base catalysed rearrangement through intramolecular opening of the epoxide ring of Pseudomonic acid A, and has shown to possess the trans- fused bicyclic structures, A & B.
  • intramolecular rearrangement of (la) takes place alongwith the loss of the nonanoate ester side chain.
  • Mupirocin is highly unstable and knowns to undergo rapid rearrangement (30 minutes), leading to a 1.6: 1 mixture of the isomeric compounds (A) and (B). Under strongly alkaline conditions, Mupirocin is more stable and undergoes slower rearrangement (18 hours), yielding the same products but in a ratio of 3.7: 1.
  • Epoxy function is of great importance which is disrupted as a result of these degradatation mechanisms and could impact observed biological activity. Hence Mupirocin has to be stabilized and protected from degradation.
  • the amount of mupirocin or pharmaceutically acceptable salt thereof can be in the range of from about 0.01 wt% to about 5 wt% of the pharmaceutical composition.
  • the mupirocin or pharmaceutically acceptable salt thereof concentration is 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%,
  • the therapeutically effective amount refers from about 0.5% w/v to about 5% w/v of mupirocin or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of mupirocin or a pharmaceutically acceptable salt is selected from about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5% based on total volume of
  • the pharmaceutically acceptable excipients comprise one or more humectants, surfactants, stabilizing agents, gelling agents, solubilizers, solvents, co solvents, neutralizing agents, pH adjusting agents or buffering agents, antioxidants, chelating agents, preservatives, tonicity agents and oily components.
  • the pharmaceutical composition comprises mupirocin or a pharmaceutically acceptable salt thereof; and a base composition comprising one or more pharmaceutically acceptable excipients such as propylene glycol, polyethylene glycol, glycofurol, ethanol, glycerol, vitamin E TPGS, isopropyl alcohol, castor oil, almond oil, soya bean oil, water for injection and any combination of any of the foregoing.
  • a base composition comprising one or more pharmaceutically acceptable excipients such as propylene glycol, polyethylene glycol, glycofurol, ethanol, glycerol, vitamin E TPGS, isopropyl alcohol, castor oil, almond oil, soya bean oil, water for injection and any combination of any of the foregoing.
  • the base composition comprises one or more pharmaceutically acceptable excipients selected from propylene glycol, polyethylene glycol, glycofurol, ethanol, glycerol, vitamin E TPGS, isopropyl alcohol, castor oil, almond oil, soya bean oil, and any combination of any of the foregoing.
  • the pharmaceutical composition meant for administering to mucosal surface comprises mupirocin or a pharmaceutically acceptable salt thereof; and a base composition; wherein the mucosal surface is exterior surface of eye, otic externa, otitis media, and nasal cavity.
  • the present invention relates to a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a stable otic pharmaceutical composition
  • a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; wherein the composition is non-aqueous composition.
  • the present invention relates to a stable otic pharmaceutical composition
  • a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; a base composition comprising one or more water-miscible substance(s).
  • the present invention relates to a stable otic pharmaceutical composition
  • a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; a base composition comprising one or more water-miscible substance(s) selected from propylene glycol, polyethylene glycol, castor oil, almond oil, soya bean oil, mineral oil and any combination of any of the foregoing.
  • the present invention relates to a stable otic pharmaceutical composition
  • a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; a base composition comprising propylene glycol and polyethylene glycol in the weight ratio selected from 0:5, 1:5, 1:4, 1 :3, 1 :2, and 1: 1; and the composition optionally comprises a preservative.
  • the present invention relates to a stable otic pharmaceutical composition
  • a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; a base composition comprising glycofurol, and the composition optionally comprises a preservative.
  • the present invention relates to a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; a base composition comprising mineral oil, and the composition optionally comprises a preservative.
  • the present invention relates to a stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; wherein the composition is aqueous composition.
  • the present invention relates to an aqueous stable otic pharmaceutical composition
  • an aqueous stable otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof, in which the hydrolytic impurities formed are within acceptable limit of not more than 2%.
  • the present invention relates to a stable non-aqueous water miscible otic pharmaceutical composition
  • a stable non-aqueous water miscible otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a a stable non-aqueous oil based otic pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a topical pharmaceutical ophthalmic composition
  • a topical pharmaceutical ophthalmic composition comprising mupirocin or a pharmaceutically acceptable salt thereof.
  • the present invention provides a topical pharmaceutical ophthalmic composition comprising (i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (ii) buffer. In an embodiment, the present invention provides a topical pharmaceutical ophthalmic composition comprising (i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (ii) tonicity adjusting agent.
  • the present invention provides a topical pharmaceutical ophthalmic composition comprising (i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof (ii) buffer and (iii) tonicity adjusting agent.
  • the present invention provides a topical pharmaceutical ophthalmic composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) one or more excipients.
  • the present invention provides a topical pharmaceutical ophthalmic composition
  • a topical pharmaceutical ophthalmic composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) stabilizer.
  • the present invention provides a topical ophthalmic composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) Tonicity adjusting agent.
  • the present invention provides a topical ophthalmic composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) buffer.
  • the present invention provides a topical ophthalmic composition
  • a topical ophthalmic composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof (iii) tonicity adjusting agent and (iv) buffer.
  • the present invention provides a topical ophthalmic composition
  • a topical ophthalmic composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) one or more excipients selected from buffering agent, preservative, tonicity adjusting agent, viscosity enhancing agent, suspending agent, surfactants, solvent, antioxidants, chelating agent, penetration enhancer or any combination of any of the foregoing.
  • the present invention provides a topical pharmaceutical ophthalmic liquid composition
  • a topical pharmaceutical ophthalmic liquid composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) buffer.
  • the composition may comprise a tonicity adjusting agent.
  • the composition may contain one or more additional excipients selected from preservative, viscosity enhancing agent, suspending agent surfactants, solvent, antioxidants, chelating agent, pH adjusting agent, penetration enhancer or combination thereof.
  • the present invention provides a topical pharmaceutical ophthalmic aqueous liquid composition
  • a topical pharmaceutical ophthalmic aqueous liquid composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) one or more excipients.
  • the present invention provides a topical ophthalmic aqueous liquid composition
  • a topical ophthalmic aqueous liquid composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) tonicity adjusting agent.
  • the present invention provides a topical ophthalmic aqueous liquid composition
  • a topical ophthalmic aqueous liquid composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) buffer.
  • the present invention provides a topical ophthalmic aqueous liquid composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof (iii) tonicity adjusting agent and (iv) buffer.
  • the present invention provides a topical ophthalmic aqueous liquid composition comprising (i) carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) one or more excipients selected from buffering agent, preservative, tonicity adjusting agent, viscosity enhancing agent, suspending agent surfactants, solvent, antioxidants, chelating agent, pH adjusting agent, penetration enhancer or any combination of any of the foregoing.
  • the present invention provides a topical pharmaceutical ophthalmic aqueous liquid composition
  • a topical pharmaceutical ophthalmic aqueous liquid composition comprising (i) water and/or water miscible solvents as carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) one or more excipients.
  • the present invention provides a topical ophthalmic aqueous liquid composition
  • a topical ophthalmic aqueous liquid composition comprising (i) water and/or water miscible solvents as carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) one or more excipients selected from buffering agent, preservative, tonicity adjusting agent, viscosity enhancing agent, suspending agent surfactants, solvent, antioxidants, chelating agent, pH adjusting agent, penetration enhancer or any combination of any of the foregoing.
  • the present invention provides a topical ophthalmic solution comprising (i) water and/or water miscible solvents as carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) one or more excipients.
  • the present invention provides a topical ophthalmic solution comprising (i) water and/or water miscible solvents as carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) one or more excipients selected from buffering agent, preservative, tonicity adjusting agent, surfactants, solvent, antioxidants, chelating agent, pH adjusting agent or any combination of any of the foregoing.
  • the topical ophthalmic solution can be colloidal.
  • the present invention provides a topical ophthalmic suspension comprising (i) water and/or water miscible solvents as carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) excipients.
  • the present invention provides a topical ophthalmic suspension comprising (i) water and/or water miscible solvents as carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) suspending agent
  • the present invention provides a topical ophthalmic suspension comprising (i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (ii) one or more excipients selected from suspending agent, buffering agent, preservative, surfactants, solvent, antioxidants, chelating agent, pH adjusting agent or any combination of any of the foregoing.
  • the present invention provides a topical ophthalmic suspension comprising (i) water and/or water miscible solvents as carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) one or more excipients selected from suspending agent, viscosity enhancing gent, tonicity adjusting agent, buffering agent, preservative, surfactants, solvent, antioxidants, chelating agent, pH adjusting agent or any combination of any of the foregoing.
  • the composition may be a microsuspension or nanosuspension, flocculated or deflocculated.
  • suspension composition may be in the form of flocculated form.
  • the present invention provides a topical ophthalmic composition in the form of an emulsion comprising (i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (ii) one or more excipients.
  • the present invention provides a topical ophthalmic composition in the form of an emulsion comprising (i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (ii) one or more excipients selected from suspending agent, buffering agent, preservative, viscosity enhancing gent, tonicity adjusting agent, surfactants, solvent, antioxidants, chelating agent, pH adjusting agent or any combination of any of the foregoing.
  • the present invention provides a topical ophthalmic composition in the form of an emulsion comprising (i) water and/or water miscible solvents as carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) excipients.
  • the present invention provides a topical ophthalmic composition in the form of an emulsion comprising (i) water and/or water miscible solvents as carrier (ii) mupirocin or a pharmaceutically acceptable salt or hydrates thereof and (iii) one or more excipients selected from buffering agent, preservative, viscosity enhancing gent, tonicity adjusting agent, suspending agent, surfactants, solvent, antioxidants, chelating agent, pH adjusting agent or any combination of any of the foregoing.
  • the ophthalmic composition comprising in the form of an emulsion comprising (i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof, (ii) oil component, (iii) one or more excipients selected from buffering agent, preservative, surfactants, viscosity enhancing gent, tonicity adjusting agent, suspending agent, solvent, antioxidant, chelating agent, pH adjusting agent or any combination of any of the foregoing, and (iv) water.
  • the present invention provides a pharmaceutical composition suitable for topical administration to an eye, the composition comprising: mupirocin or a pharmaceutically acceptable salt or hydrates thereof in therapeutically effective amount for treatment and/or prophylaxis of a gram-positive bacterial infection of at least one tissue of the eye.
  • the present invention provides a pharmaceutical composition suitable for topical administration to an eye, the composition comprising: mupirocin or a pharmaceutically acceptable salt or hydrates thereof in therapeutically effective amount for treatment and/or prophylaxis of a gram-positive bacterial infection of at least one tissue of the eye, and at least one ophthalmically acceptable excipient.
  • the present invention provides a pharmaceutical composition suitable for topical administration to an eye, the composition comprising: mupirocin or a pharmaceutically acceptable salt or hydrates thereof in therapeutically effective amount for treatment and/or prophylaxis of a gram-positive bacterial infection of at least one tissue of the eye, and at least one ophthalmically acceptable excipient that reduces a rate of removal of the composition from the eye by lacrimation, such that the composition has an effective residence time in the eye of about 5 minutes to about 24 hours.
  • compositions suitable for topical administration to an eye comprising: mupirocin or a pharmaceutically acceptable salt or hydrates thereof in therapeutically effective amount for treatment and/or prophylaxis of a gram-positive bacterial infection of one or more tissues of the eye, and at least one ophthalmically acceptable excipient that reduces a rate of removal of the composition from the eye by lacrimation such that a concentration of muprocin or its calcium salt in lacrimal fluid of the eye is maintained above the MIC90 for at least about 5 minutes following topical application to the eye.
  • concentration of muprocin or its calcium salt in lacrimal fluid of the eye is maintained above the MIC90 for at least about 10, about 20, about 30, about 20, about 40, about 50, about 60 and 120 minutes.
  • compositions suitable for topical administration to an eye comprising: mupirocin or a pharmaceutically acceptable salt or hydrates thereof in therapeutically effective amount for treatment and/or prophylaxis of a gram-positive bacterial infection of one or more tissues of the eye, and at least one ophthalmically acceptable excipient that reduces a rate of removal of the composition from the eye by lacrimation such that a concentration of muprocin or its calcium salt in lacrimal fluid of the eye is maintained above the MIC50 for at least about 5 minutes following topical application to the eye.
  • concentration of muprocin or its calcium salt in lacrimal fluid of the eye is maintained above the MIC50 for at least about 10, about 20, about 30, about 20, about 40, about 50, about 60 and 120 minutes.
  • This composition may improve ocular bioavailability by increasing the duration of contact with corneal layer and reducing the frequency of administration.
  • In-situ gelling delivery systems for the ocular administration of drugs improve the treatment of diseases of the anterior segment of the eye by simple, safe, and reproducible drug administration.
  • a composition of the present invention can have a viscosity in the range from about 5 to about 100,000 centipoise (“cp”) or mPa*s (or alternatively, from about 10 to about 50,000, or from about 10 to about 20,000, or from about 10 to about 10,000, or from about 10 to about 1,000, or from about 100 to about 10,000, or from about 100 to about 20,000, or from about 100 to about 50,000 or from about 500 to about 10,000, or from about 500 to about 20,000 cp).
  • cp centipoise
  • mPa*s or alternatively, from about 10 to about 50,000, or from about 10 to about 20,000, or from about 10 to about 10,000, or from about 10 to about 1,000, or from about 100 to about 10,000, or from about 100 to about 20,000, or from about 100 to about 50,000 or from about 500 to about 10,000, or from about 500 to about 20,000 cp).
  • gel composition releases an active over an extended period, preferably longer than about two hours. In one embodiment, composition the present invention releases active ingredient for more than about four hours.
  • the ophthalmic composition is isotonic. In another preferred embodiment, the ophthalmic composition is buffered. In yet another preferred embodiment, the ophthalmic composition is isotonic and buffered.
  • present invention provides an ophthalmic liquid preparation comprising mupirocin or a pharmacologically acceptable salt thereof or a hydrate thereof, which is stable within a pH range giving no irritation to eyes.
  • the pH of such composition s will typically be from about 5 to about 8.5 e.g. about 7.0 to about 7.4.
  • the pH range in the composition is about pH 6.6 to about pH 7.0.
  • the composition of the present invention is having a pH of about 7-8.
  • Suitable humectants include, but are not limited to, guanidine, urea, glycolic acid and glycolate salts (e.g. ammonium and quaternary alkyl ammonium), lactic acid and lactate salts (e.g.
  • aloe vera in any of its variety of forms (e.g., aloe vera gel), allantoin, urazole, polyhydroxy alcohols such as sorbitol, glycerol, hexanetriol, propylene glycol, butylene glycol, and hexylene glycol, polyethylene glycols, sugars and starches, sugar and starch derivatives (e.g., alkoxylated glucose), hyaluronic acid, lactamide monoethanol amine and acetamide monoethanolamine. Also suitable are derivatives, esters, salts and combinations of the same.
  • Suitable surfactants include, but are not limited to, anionic, cationic, nonionic, zwitterionic, amphoteric and ampholytic surfactants, as well as mixtures of these surfactants.
  • Non-limiting examples of surfactants include polysorbates, such as polyoxyethylene (20) sorbitan monostearate (Tween 60) and poly(oxyethylene) (20) sorbitan monooleate (Tween 80); poly(oxyethylene) (POE) fatty acid esters; poly(oxyethylene) alkylyl ethers, such as poly(oxyethylene) cetyl ether, poly(oxyethylene) palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether; sucrose esters, partial esters of sorbitol and its anhydrides, such as sorbitan monolaurate and sorbitan monolaurate; mono or diglycerides, isoceteth-20, sodium methyl cocoyl taurate, sodium methyl
  • Tonicity adjusting agents include, for example one or more salts having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, ammonium sulfate, sodium nitrate, sodium sulfate.
  • pharmaceutically acceptable sugar such as, but not limited to dextrose, glycerin, mannitol and sorbitol.
  • the osmolarity of the composition is adjusted to be in the range of about 250 to about 375 mOsmol/L. In a preferred aspect, the osmolarity of the composition is adjusted to between about 280 to about 300 mOsmol/L. In one embodiment, the opthalmic pharmaceutical composition includes from about 0.1 to about 20% (w/v) of tonicity adjusting agent, based upon total weight of topical composition . Viscosity modifying agent or a bioadhesive agent or gelling agent include, but are not limited to, hydrophilic polymers.
  • polymers examples include polyvinyl alcohol, poloxamers, acrylic acid/butyl acrylate copolymer, acrylic acid polymer, poly(methylmethacrylate), polyacrylamide, polycarbophil, carbomers (homopolymer of acrylic acid is crosslinked with an allyl ether pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene), such as Carbomer 974P, Carbopol® 934, Carbopol® 940, Carbopol® 941, Carbopol® 980 and Carbopol® 981, acrylamide / sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 (available as Sepineo P 600 from SEPPIC Inc.
  • polysaccharides polysaccharides, cellulose derivatives, gellan gum, xanthan gum, carrageenan (e.g., kappa-carrageenan and iota-carrageenan), alginate gums, polyoxyethylene-polyoxypropylene block copolymer (poloxamer 407), amine -bearing polymers such as chitosan, tetra- substituted ethylene diamine block copolymers of ethylene oxide and propylene oxide (e.g., poloxamine 1307), polyethylene oxide, dextran, cellulose ethers, such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methylhydroxy ethylcellulose, methylhydroxy propylcellulose, hydroxye
  • Suspending agents include, but are not limited to, polymers.
  • Suitable polymers include, but are not limited to, a cellulose ether, such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methylhydroxy ethylcellulose, methylhydroxy propylcellulose, hydroxyethylcarboxy methylcellulose, carboxymethylcellulose, carboxymethylhydroxy ethylcellulose, and cationic celluloses, carbomer (homopolymer of acrylic acid is crossl inked with an allyl ether pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene), such as Carbomer 974P, Carbopol® 934, Carbopol® 940, Carbopol® 941, Carbopol® 980 and Carbopol® 981, acrylamide / sodium acryloyldimethylt
  • polyethylene glycol having molecular weight of 1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG 10,000), locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate,, quince seed extract, tragacanth gum, guar gum, cationic guars, hydroxypropyl guar gum, starch, amine bearing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid and hyaluronic acid or their salts such as sodium alginate and sodium hyaluronate; chemically modified starches, carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers such as polycarbophil
  • the viscosity enhancing agent and suspending agent can be same or different.
  • Gelling agents can be used in the compositions to increase the retention time of the drug gradient over the inner surface of ear.
  • Suitable gelling agents include, but are not limited to, a cellulose ether, such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethyl cellulose, carboxymethylcellulose, carboxymethylhydroxyethylcellulose, and cationic celluloses, carbomer (homopolymer of acrylic acid is crosslinked with an allyl ether pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene), such as Carbopol® 934, Carbopol® 940, Carbopol® 941, Carbopol
  • polyethylene glycol having molecular weight of 1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG 10,000), locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guar gum, cationic guars, hydroxypropyl guar gum, starch, amine -bearing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid and hyaluronic acid or their salts such as sodium alginate and sodium hyaluronate; chemically modified starches, carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic
  • the gelling agent may be present in amounts ranging from about 0.05 to about 50% w/v, more specifically from about 0.05 to about 25% w/v.
  • the gelling agent may be present in an amount ranging from about 0.05% w/v to about 10% w/v.
  • tonicity agents are added to the compositions described herein in an amount as to provide a practical osmolality of an composition of about 100 mOsm/kg to about 1000 mOsm/kg, from about 200 mOsm/kg to about 800 mOsm/kg, from about 250 mOsm/kg to about 500 mOsm/kg, or from about 250 mOsm/kg to about 350 mOsm/kg or from about 280 mOsm/kg to about 320 mOsm/kg.
  • the present invention relates to a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; and the base composition; wherein the osmolity of the composition is from about 100 mOsm/L to about 1000 mOsm/kg.
  • the present invention relates to a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; and the base composition; wherein the osmolity of the composition is from about 300 mOsm/L to about 1000 mOsm/kg.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; and the base composition; wherein the osmolity of the composition is from about 400 mOsm/L to about 900 mOsm/kg and the composition is meant for administering to otic externa, otitis media, nasal cavity, and exterior surface of eye.
  • the compositions described herein have a practical osmolarity of about 100 mOsm/L to about 1000 mOsm/L, about 200 mOsm/L to about 800 mOsm/L, about 250 mOsm/L to about 500 mOsm/L, about 250 mOsm/L to about 350 mOsm/L, about 280 mOsm/L to about 320 mOsm/L or about 250 mOsm/L to about 320 mOsm/L.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; and the base composition; wherein the osmolity of the composition is from about 100 mOsm/L to about 1000 mOsm/L.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; and the base composition; wherein the osmolity of the composition is from about 300 mOsm/L to about 1000 mOsm/L.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; and the base composition; wherein the osmolity of the composition is from about 400 mOsm/L to about 900 mOsm/L.
  • the deliverable osmolarity of any composition described herein is designed to be isotonic with the targeted otic structure.
  • otic compositions described herein are formulated to provide a delivered osmolarity at the target site of action of about 250 to about 320 mOsm/L, and preferably about 270 to about 320 mOsm/L.
  • otic compositions described herein are formulated to provide a delivered osmolality at the target site of action of about about 250 to about 320 mOsm/kg H2O; or an osmolality of about 270 to about 320 mOsm/kg H2O.
  • the deliverable osmolarity/osmolality of the compositions i.e., the osmolarity/osmolality of the composition in the absence of gelling or thickening agents (e.g., thermoreversible gel polymers)
  • the osmolarity/osmolality of the composition in the absence of gelling or thickening agents is adjusted, for example, by the use of appropriate salt concentrations (e.g., concentration of potassium or sodium salts) or the use of tonicity agents which renders the compositions compatible upon delivery at the target site.
  • the compositions described herein provide a deliverable osmolarity (e.g., at a target site that causes minimal disturbance to the environment and causes minimum discomfort (e.g., vertigo)) to a mammal upon administration.
  • One object of present invention is to provide an ophthalmic pharmaceutical composition
  • an ophthalmic pharmaceutical composition comprising (i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof, (ii) one or more excipients selected from buffering agent, preservative, viscosity modifying agent, tonicity adjusting agent, suspending agent, surfactants, solvent, antioxidant, chelating agent, pH adjusting agent, stabilisers or any combination of any of the foregoing, and (iii) carrier.
  • suitable tonicity agents include, but are not limited to any pharmaceutically acceptable sugar, salt or any combinations or mixtures thereof, such as, but not limited to dextrose, glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes.
  • Useful otic compositions include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • compositions also include one or more pH adjusting agents or buffering agents.
  • pH adjusting agents or buffers include, but are not limited to hydrochloric acid, sodium hydroxide, citric acid, acetate, bicarbonate, ammonium chloride, citrate, phosphate, pharmaceutically acceptable salts thereof and combinations or mixtures thereof.
  • the pH adjusting agent may be present in amount sufficient to adjust the pH to 4.5-6.0. Generally, 0.1-0.5% by weight of the pH adjusting agent is used in an amount on the total weight of the pharmaceutical composition.
  • one or more buffers when utilized in the compositions of the present invention, they are combined, e.g., with a pharmaceutically acceptable vehicle and are present in the final composition, e.g., in an amount ranging from about 0.1% to about 20%, from about 0.5% to about 10%.
  • the amount of buffer included in the gel compositions are an amount such that the pH of the gel composition does not interfere with the body's natural buffering system.
  • diluents are also used to stabilize mupirocin because they can provide a more stable environment.
  • Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.
  • Stabilizer may be the sodium lauryl sulfate, Tween, Span, phosphatidylcholine with one or more, in order to improve the stability of the water-soluble dispersion.
  • the stabilizer agents may comprise from 0.5 to 5% by weight of the total weight of the ear drops.
  • diluents are also used to stabilize compounds because they can provide a more stable environment.
  • Salts dissolved in buffered solutions are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.
  • Stabilizer may be the sodium lauryl sulfate, Tween, Span, phosphatidylcholine, polyethylene glycol monostearate, and alkyl aryl polyether alcohol type polymers such as tyloxapol in order to improve the stability of the water-soluble dispersion; preferably, the stabilizer agents may comprise from 0.5 to 5% (w/v) of the total volume of the composition.
  • the ear drop composition described herein has a pH that allows for sterilization (e.g, by filtration or aseptic mixing or heat treatment and/or autoclaving (e.g., terminal sterilization) of a drop composition without degradation of the pharmaceutical agent (e.g., otic agent) or the excipients comprising the drop.
  • the buffer pH is designed to maintain the pH of the composition at 7-8 during the process of sterilization.
  • the drop composition described herein has a pH that allows for terminal sterilization (e.g, by heat treatment and/or autoclaving) of a drop composition without degradation of the pharmaceutical agent (e.g., otic agent) or the excipients comprising the drop.
  • the buffer pH is designed to maintain pH of the composition at 7-8 at elevated temperatures. Any appropriate buffer is used depending on the otic agent used in the composition. In some instances, since pKa of TRIS decreases as temperature increases at approximately - 0.03/ °C.
  • compositions of the present invention may contain one or more optional co-solvents such as, without limitation, volatile organic solvents (e.g. alcohols such as ethanol, propanol or butanol), benzoyl alcohol, non-volatile organic solvents (e.g.
  • amides such as pyrrolidones; polyol ethers such as glycol ethers; polyols such as glycols; and derivatives thereof) and water or mixtures thereof.
  • a surfactant or other appropriate co-solvent in the composition include polysorbate 20, 60, and 80, polyoxyethylene/polyoxypropylene surfactants (e.g. Pluronic F-68, F-84 and P-103), cyclodextrin, tyloxapol, other agents known to those skilled in the art, or a combination thereof.
  • co-solvents are employed at a level of from 0.01% to 2% by weight of the final composition.
  • the composition may also contain an antioxidant.
  • the amount of antioxidant if present, will typically range from about 0.005% to about 3.0% by weight of the composition. Illustrative ranges include from about 0.01% to about 2.5% by weight antioxidant, from about 0.05% to about 2% by weight antioxidant, and from about 0.1% to about 1.5% by weight antioxidant. Illustrative amounts of antioxidant include 0.01%, 0.025%, 0.05%, 0.075%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% and 1% by weight. In one embodiment, the amount of antioxidant comprised within the composition is 0.01% by weight. In another embodiment, the amount of antioxidant comprised within the composition is 0.2% by weight.
  • Suitable antioxidants include, for example, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tertiary butyl hydroquinone, propyl gallate, .alpha.-tocopherol, sodium metabisulfite, and the like.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • tertiary butyl hydroquinone propyl gallate
  • .alpha.-tocopherol sodium metabisulfite
  • sulfur-containing antioxidants such as sodium metabisulfite, glutathione, N-acetylcysteine, thioproline, and taurine.
  • compositions comprise an antioxidant selected from the list consisting of a sulfite compound, BHT, sodium selenite, DL-alpha tocopherol, a combination of dithioerythreitol and DL-alpha tocopherol, and sodium erythorbate.
  • Sulfurous acid salts and organic esters are also preferred, such as bisulfites, pyrosulfites, metabisulfites, and sulfites.
  • the composition may further contain one or more preservatives in an amount typically ranging from about 0.01% to about 2.0% by weight of the composition.
  • the preservative can include, but is not limited to, paraben such as methyl paraben, propyl paraben and long chain paraben; phenoxyethanol and benzalkonium chloride. Other known preservatives can also be used in the pharmaceutical composition of the present invention.
  • the composition may further contain one or more preservatives in an amount typically ranging from about 0.01% to about 2.0% by weight of the composition.
  • Illustrative preservatives include, for example, phenoxyethanol, methyl paraben, propyl paraben, butyl paraben, benzyl alcohol, and the like.
  • the preservative may be methyl benzoate, ethyl benzoate, benzyl benzoate, or hydroxyethyl dimethyl hydantoin.
  • the preservative may comprise 0.01 to 0.15 wt% of the total weight of the ear drops.
  • Suitable chelating agents include, but are not limited to, ethylenediamine tetracetic acid (EDTA), commercially available both as the free acid and as various salts, for example, disodium EDTA, tetrasodium EDTA, dipotassium EDTA, and calcium disodium EDTA.
  • EDTA ethylenediamine tetracetic acid
  • Other commercial chelators include the naturally occurring amino acid L-cysteine, HSCPb CH(NH 2 )C0 2 H, and its acetylated derivative N-acetyl- L-cysteine, HSCH 2 -CH(NHC0CH 3 )C0 2 H, commonly referred to as NAC.
  • stabilizers that are useful in the auris-acceptable compositions disclosed herein include, for example, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinyl pyrrolidones, polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture absorbing polymers, and combinations thereof.
  • amide analogues of stabilizers are also used.
  • the chosen stabilizer changes the hydrophobicity of the composition (e.g., oleic acid, waxes), or improves the mixing of various components in the composition (e.g., ethanol), controls the moisture level in the formula (e.g., PVP or polyvinyl pyrrolidone), controls the mobility of the phase (substances with melting points higher than room temperature such as long chain fatty acids, alcohols, esters, ethers, amides etc. or mixtures thereof; waxes).
  • some of these stabilizers are used as solvents/co solvents (e.g., ethanol).
  • stabilizers are present in sufficient amounts to inhibit the degradation of the otic agent.
  • stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
  • Suitable oily components can include, but is not limited to, peanut oil, palm oil, palmkernel oil, cotton seed oil, miglyol oil, almond oil, corn oil, Sesame oil, mineral oil, squalene, soyabean oil, olive oil, isopropyl myristate, isopropyl palmitate, and isopropyl sterate.
  • Other known emulsifying agents can also be used in the pharmaceutical composition of the present invention.
  • stabilizers that are useful in the ophthalmic-acceptable compositions disclosed herein include, for example, fatty acids, fatty alcohols,, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture-absorbing polymers, sugars, sugar alcohols and combinations thereof.
  • amide analogues of stabilizers are also used.
  • the chosen stabilizer changes the hydrophobicity of the composition (e.g., oleic acid, waxes), or improves the mixing of various components in the composition (e.g., ethanol), controls the moisture level in the formula (e.g., polyvinyl pyrrolidones (PVP)), controls the mobility of the phase (substances with melting points higher than room temperature such as long chain fatty acids, alcohols, esters, ethers, amides etc. or mixtures thereof; waxes).
  • PVP polyvinyl pyrrolidones
  • some of these stabilizers are used as solvents/co solvents (e.g., ethanol).
  • stabilizers are present in sufficient amounts to inhibit the degradation of the ophthalmic agent.
  • stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1 % to about 1 % w/v methionine, (c) about 0.1 % to about 2% w/v monothioglycerol, (d) about 1 uiM to about 10 mM EDTA, (e) about 0.01 % to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
  • Suitable oily components can include, but is not limited to, peanut oil, palm oil, palmkernel oil, cotton seed oil, miglyol oil, almond oil, corn oil, Sesame oil, mineral oil, squalene, soyabean oil, olive oil, isopropyl myristate, isopropyl palmitate, and isopropyl stearate.
  • Other known emulsifying agents can also be used in the pharmaceutical composition of the present invention.
  • the carrier can selected from water, non-aqueous solvents, and organic solvents, oily vehicles.
  • the nonaqueous solvent includes, but is not limited to, propylene glycol, glycerol, PEG 300, and PEG 400.
  • the organic solvent includes, but is not limited to, ethanol, and isopropyl alcohol.
  • Other known fluid medium can also be used in the pharmaceutical composition of the present invention.
  • the mixtures are preferably formulated as aqueous solutions.
  • the non aqueous solvent includes water optinally containing propylene glycol, glycerol, PEG 300, and PEG 400.
  • the mixture of solvents used in the composition of the present invention comprises propylene glycol and polyethylene glycol, and the weight ratio between propylene glycol to polyethylene glycol is selected from 0:5, 1 :5, 1 :4, 1 :3, 1 :2, and 1 : 1 ; and the composition optionally comprises a preservative.
  • Oily vehicles such as glycol stearate, glyceryl isostearate, sorbitane sesquioleate, sorbitane isostearate and triisostearate, sorbitan oleate and polyglyceryl- 3 polyricinoleate, tyloxapol (polymer of the alkyl aryl polyether alcohol type), liquid lecithin, peanut oil, palm oil, palmkernel oil, cotton seed oil, miglyol oil, almond oil, corn oil, sesame oil, mineral oil, squalene, soyabean oil, olive oil, isopropyl myristate, iso propyl palmitate, iso propyl sterate and / or oleic acid/ ethyl oleate, enanthic acid, pelargonic acid, undecylenic acid, arachidonic acid, caprylic acid, caproic acid, capric acid.
  • tyloxapol polymer of the alky
  • Oily vehicle components of the composition includes one or more materials that are practically insoluble or insoluble in water and which are liquid at room temperature of 22°C.
  • the oily vehicles may be selected from one or more ingredients from the group consisting of fish-liver oil, long-chain triglycerides (wherein each side chain has 14-18 carbons, such as peanut oil, sesame oil, coconut oil; sunflower oil, corn oil, olive oil, cotton seed oil, or derivatives thereof), hydrocarbons like mineral oil, light mineral oil, squalene, and squalane, fatty alcohols (such as octyldodecanol and isostearyl alcohol), and fatty acids (such as isostearic acid and oleic acid), propylene glycol diesters, medium-chain triglycerides (such as those wherein each side chains has 8-10 carbons; e.g., capric/caprylic acid triglycerides).
  • fish-liver oil long-chain triglycerides (wherein
  • the present invention provides ophthalmic solution compositions of mupirocin comprising a cyclodextrin as a solubilizing agent and / or stabilizing agent cyclodextrins are cyclic oligosaccharides containing 6, 7, or 8 glucopyranose units, referred to as .alpha. -cyclodextrin, .beta. -cyclodextrin, or .gamma. -cyclodextrin respectively. Cyclodextrins have a hydrophilic exterior, which enhances water-soluble, and a hydrophobic interior which forms a cavity.
  • Cyclodextrins have three free hydroxyl groups for each glucopyranose unit, or 18 hydroxyl groups on .alpha. -cyclodextrin, 21 hydroxyl groups on .beta.-cyclodextrin, and 24 hydroxyl groups on .gamma. -cyclodextrin.
  • cyclodextrin ingredient in the compositions of the present invention may be any pharmaceutically acceptable cyclodextrin.
  • Many cyclodextrins are known, including, but not limited to those classified as b-cyclodextrin derivatives, g-cyclodextrin derivatives and sulfated cyclodextrin derivatives.
  • a preferred cyclodextrin is hydroxypropyl -b-cyclodextrin.
  • the amount of cyclodextrin ingredient included in the compositions of the present invention will depend on the concentration of mupirocin.
  • the amount of cyclodextrin should be enough to solubilize mupirocin so that the composition is administered to a patient as a solution.
  • the amount of cyclodextrin contained in the compositions of the present invention will be about 0.1 to 30%, preferably about 1 to 25%, and most preferably about 5 to 10%.
  • a pharmaceutical composition is partially-alcoholic.
  • inclusion of a percentage of alcohol in the composition will aid in the solubility of the components.
  • Alcohols useful in the present invention include methanol, ethanol, and isopropanol, among others.
  • provided herein are methods for sterilization of otic compositions that prevent degradation of polymeric components (e.g., thermosetting and/or gelling components) and/or the active agent during the process of sterilization.
  • degradation of the active agent e.g., any therapeutic otic agent described herein
  • the choice of an appropriate gelling agent and/or thermosetting polymer allows for sterilization of compositions described herein by filtration.
  • an appropriate thermosetting polymer and an appropriate copolymer e.g., a gelling agent
  • a specific pH range for the composition allows for high temperature sterilization of compositions described with substantially no degradation of the therapeutic agent or the polymeric excipients.
  • An advantage of the methods of sterilization provided herein is that, in certain instances, the compositions are subjected to terminal sterilization via autoclaving without any loss of the active agent and/or excipients and/or polymeric components during the sterilization step and are rendered substantially free of microbes and/or pyrogens.
  • the present invention provides solution compositions of mupirocin.
  • the present compositions contain a cyclodextrin as a solubilizing agent and / or stabilizing agent.
  • Cyclodextrins are cyclic oligosaccharides containing 6, 7, or 8 glucopyranose units, referred to as .alpha.-cyclodextrin, .beta.-cyclodextrin, or .gamma. -cyclodextrin respectively. Cyclodextrins have a hydrophilic exterior, which enhances water-soluble, and a hydrophobic interior which forms a cavity. In an aqueous environment, hydrophobic portions of other molecules often enter the hydrophobic cavity of cyclodextrin to form inclusion compounds. Additionally, cyclodextrins are also capable of other types of nonbonding interactions with molecules that are not inside the hydrophobic cavity.
  • Cyclodextrins have three free hydroxyl groups for each glucopyranose unit, or 18 hydroxyl groups on .alpha.-cyclodextrin, 21 hydroxyl groups on .beta.-cyclodextrin, and 24 hydroxyl groups on .gamma.-cyclodextrin.
  • One or more of these hydroxyl groups can be reacted with any of a number of reagents to form a large variety of cyclodextrin derivatives, including hydroxypropyl ethers, sulfonates, and sulfoalkylethers. Shown below is the structure of .beta.-cyclodextrin and the hydroxypropyl-.beta.
  • the cyclodextrin ingredient in the compositions of the present invention may be any pharmaceutically acceptable cyclodextrin.
  • Many cyclodextrins are known, including, but not limited to those classified as b-cyclodextrin derivatives, g-cyclodextrin derivatives and sulfated cyclodextrin derivatives.
  • a preferred cyclodextrin is hydroxypropyl -b-cyclodextrin.
  • the amount of cyclodextrin ingredient included in the compositions of the present invention will depend on the concentration of mupirocin.
  • the amount of cyclodextrin should be enough to solubilize mupirocin so that the composition is administered to a patient as a solution.
  • the amount of cyclodextrin contained in the compositions of the present invention will be about 0.1 to 30%, preferably about 1 to 25%, and most preferably about 5 to 10%.
  • One of the embodiment is and aqueous emulsion compositions containing mupirocin or a pharmaceutical acceptable salt thereof from about 0.1 to about 5 % w/v of, glycerin from about 0.5 to about 3.5 % w/v; castor oil from about 1.0 to about 10.0 w/v; Polysorbate 80 from about 0.05 to about 1.0 w/v; Cremophore from about 0.05 to about 5.0 w/v; hydroxyethyl cellulose from about 0.1 to about 0.5 w/v; disodium EDTA from about 0.05 to about 0.1 w/v; Benzalkonium Chloride from about 0.005 to about 0.01 w/v; Sodium Chloride from about 0.5 to about 0.9 w/v; Sodium hydroxide and/or Hydrochloric acid in an amount sufficient to adjust pH of from about 3 to about 10; water for injection to make a final volume of the composition.
  • One of the embodiment is and aqueous suspension compositions containing mupirocin or a pharmaceutical acceptable salt thereof from about 0.1 to about 5 % w/v; Polysorbate 80 from about 0.05 to about 1.0 w/v; Cremophore from about 0.05 to about 5.0 w/v; hydroxyethyl cellulose from about 0.1 to about 0.5 w/v; disodium EDTA from about 0.05 to about 0.1 w/v; Benzalkonium Chloride from about 0.005 to about 0.01 w/v; Sodium Chloride from about 0.5 to about 0.9 w/w; Sodium hydroxide and/or Hydrochloric acid in an amount sufficient to adjust pH of about 3 to about 10; water for injection to make a final volume of the composition.
  • One of the embodiment is and aqueous solution compositions containing mupirocin or a pharmaceutical acceptable salt thereof from about 0.1 to about 5 % w/v; Hydroxypropyl Beta cyclodexrtin (HPPCD) from about 1.0 to about 20.0 w/v; Propylene Glycol from about 1.0 to about 10.0 w/v; Polysorbate 80 from about 0.05 to about 1.0 w/v; disodium EDTA from about 0.05 to about about 0.1 w/v; Benzalkonium Chloride from about 0.005 to about 0.01 w/v; Sodium Chloride from about 0.5 to about 0.9 w/v; Sodium hydroxide and/or Hydrochloric acid in an amount sufficient to adjust pH of from about 3 to about 10; water for injection to make a final volume of the composition.
  • HPPCD Hydroxypropyl Beta cyclodexrtin
  • HPPCD Hydroxypropyl Beta cyclodexrtin
  • One of the embodiment is and oil solution compositions containing mupirocin or a pharmaceutical acceptable salt thereof from about 0.1 to about 5 % w/v; tocopherol from about 0.002 to about 0.1 w/v; parabens from about 0.001 to about 0.01 w/v; trglyceride oil and/or medium chain fatty acid and /or non-aqueosu solvent to make a final volume of the composition.
  • One of the embodiment is and oil suspension compositions containing mupirocin or a pharmaceutical acceptable salt thereof from about 0.1 to about 5 % w/v; tocopherol from about 0.002 to about 0.1 w/v; parabens from about 0.001 to about 0.01 w/v; surfactant from about 0.01 to about 5 w/v trglyceride oil and/or medium chain fatty acid to make a final volume of the composition.
  • One of the embodiment is and non-aqueous solution compositions containing mupirocin or a pharmaceutical acceptable salt thereof from about 0.1 to about 5 % w/v; bnzalkonium Chloride from about 0.005 to about 0.01 w/v; disodium EDTA from about 0.05 to about 0.1 w/v and organic solvent to make a final volume of the composition.
  • the composition of the present invention comprises a solution compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), surfactant of about 0.001 to about 5% (w/v), buffer of about 0.01 to about 10% (w/v), preservative of about 0.005 to about 5% (w/v), tonicity adjusting agent of about 0.1 to about 20% (w/v), chelating agent of about 0.01 to about 2% (w/v), antioxidant of about 0.01 to about 2% (w/v), pH adjusting agent in an amount sufficient to adjust pH of about 5 to about 8.5 and optionally a polymer of about 0.1 to about 5% (w/v).
  • the composition of the present invention comprises a solution compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), polyoxyl hydrogenated Castor oil of about 1.0 to about 5% (w/v), tromethamine of about 0.01 to about 5% (w/v), boric acid of about 0.005 to about 5% (w/v), sodium chloride of about 0.1 to about 10% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • the composition of the present invention comprises a solution compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), propylene glycol of about 1.0 to about 20% (w/v), mannitol of about 0.1 to about 10% (w/v), disodium EDTA of about 0.01 to about 5% (w/v), dibasic sodium phosphate of about 0.01 to about 5% (w/v), monobasic sodium phosphate of about 0.01 to about 5% (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • the composition of the present invention comprises a solution compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), polyethylene glycol (PEG-400) of about 1.0 to about 20% (w/v), sodium chloride of about 0.1 to about 5% (w/v), sodium borate of about 0.1 to about 3% (w/v), boric acid of about 0.1 to about
  • the composition of the present invention comprises a solution compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), polyethylene glycol (PEG-400) of about 1.0 to about 20% (w/v), glycerin of about 0.1 to about 5% (w/v), citric acid of about 0.001 to about 2% (w/v), sodium citrate of about 0.01 to about 5% (w/v), sodium chloride of about 0.1 to about 5 % (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • PEG-400 polyethylene glycol
  • glycerin of about 0.1 to about 5% (w/v)
  • citric acid of about 0.001 to about 2% (w/v)
  • sodium citrate of about 0.01 to about 5% (w/v)
  • sodium chloride of
  • the composition of the present invention comprises a solution compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5 % w/v, polyethylene glycol (PEG-400) of about 1.0 to about 20% (w/v), glycerin of about 0.1 to about 5% (w/v), citric acid of about 0.001 to about 2% (w/v), sodium chloride of about 0.1 to about 5% (w/v), sodium citrate of about 0.01 to about 5% (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • PEG-400 polyethylene glycol
  • glycerin of about 0.1 to about 5% (w/v)
  • citric acid of about 0.001 to about 2%
  • sodium chloride of about 0.1 to about 5% (w/v)
  • sodium citrate of about 0.01 to about
  • an ophthalmic pharmaceutical suspension composition comprising (i) mupirocin or a pharmaceutically acceptable salt or hydrates thereof, (ii) suspending agent, (iii) one or more buffering agent, preservative, surfactants, solvent, antioxidant, chelating agent, pH adjusting agent or any combination of any of the foregoing, and (iv) water.
  • the composition of the present invention comprises a suspension compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), surfactant of about 0.001 to about 5% (w/v) polymer of about 0.1 to about 5% (w/v), buffer of about 0.01 to about 10% (w/v), preservative of about 0.005 to about 5% (w/v), tonicity adjusting agent of about 0.1 to about 20% (w/v), chelating agent of about 0.01 to about 2% (w/v), antioxidant of about 0.01 to about 2% (w/v), pH adjusting agent in an amount sufficient to adjust pH of about 5 to about 8.5.
  • the composition of the present invention comprises a suspension compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), sodium carboxymethylcellulose of about 0.1 to about 5% w/v, ethoxylated octylphenol of about 0.001 to about 5% (w/v), sodium chloride of about 0.1 to about 5% (w/v), dibasic sodium phosphate of about 0.01 to about 5% (w/v), monobasic sodium phosphate of about 0.01 to about 5% (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), sodium carboxymethylcellulose of about 0.1 to about 5% w/v, ethoxylated octylphenol
  • the composition of the present invention comprises a suspension compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), hydroxyethyl cellulose of about 0.1 to about 5% (w/v), polysorbate 80 of about 0.001 to about 5% (w/v), sodium chloride of about 0.1 to about 5% (w/v), dibasic sodium phosphate of about 0.01 to about 5% (w/v), monobasic sodium phosphate of about 0.01 to about 5% (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), hydroxyethyl cellulose of about 0.1 to about 5% (w/v), polysorbate 80 of about 0.001 to about 5% (w/
  • the composition of the present invention comprises a suspension compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), povidone of about 0.1 to about 5% (w/v), ethoxylated octylphenol of about 0.001 to about 5% (w/v), sodium chloride of about 0.1 to about 5% (w/v), sodium borate of about 0.01 to about 5% (w/v), boric acid of about 0.01 to about 5% (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), povidone of about 0.1 to about 5% (w/v), ethoxylated octylphenol of about 0.001 to about 5% (w/
  • the composition of the present invention comprises a suspension compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), polycarbophil of about 0.1 to about 5% (w/v), poly(propylene oxide)- poly( ethylene oxide) block copolymer of about 0.001 to about 5% (w/v), sodium chloride of about 0.1 to about 5% (w/v), citric acid of about 0.01 to about 5% (w/v), sodium citrate of about 0.01 to about 5% (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), polycarbophil of about 0.1 to about 5% (w/v), poly(propylene oxide)- poly( ethylene oxide) block copo
  • the composition of the present invention comprises a suspension compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), carbomer of about 0.1 to about 5% (w/v), tyloxapol 0.001 to about 5% (w/v), sodium chloride of about 0.1 to about 5% (w/v), disodium EDTA 0.01 to about 5% (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • the composition of the present invention comprises
  • mupirocin or a pharmaceutically acceptable salt or hydrates thereof, (ii) oil component, (iii) one or more buffering agent, preservative, surfactants, solvent, antioxidant, chelating agent, pH adjusting agent or any combination of any of the foregoing, and (iv) water.
  • the composition of the present invention comprises a emulsion compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), soyabean oil of about 1 to about 20% (w/v), polyoxyl hydrogenated Castor oil of about 1 to about 5% (w/v), ethoxylated octylphenol of about 0.001 to about 5% (w/v), dibasic sodium phosphate of about 0.01 to about 5% (w/v), monobasic sodium phosphate of about 0.01 to about 5% (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • soyabean oil of about 1 to about 20% (w/v)
  • polyoxyl hydrogenated Castor oil of about 1 to about 5% (w/v)
  • ethoxylated octylphenol
  • the composition of the present invention comprises a emulsion compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), soyabean oil of about 1 to about 20% (w/v), soya lecithin of about 1 to about 5% (w/v), disodium EDTA 0.01 to about 5% (w/v), dibasic sodium phosphate of about 0.01 to about 5% (w/v), monobasic sodium phosphate of about 0.01 to about 5% (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • soyabean oil of about 1 to about 20% (w/v)
  • soya lecithin of about 1 to about 5% (w/v)
  • the composition of the present invention comprises a emulsion compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), mineral oil of about 1 to about 20% (w/v), polysorbate of about 0.001 to about 5% (w/v), propylene glycol of about 1.0 to about 20% (w/v), sodium chloride of about 0.1 to about 5% (w/v), citric acid of about 0.001 to about 2% (w/v), sodium citrate of about 0.01 to about 5% (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5.
  • the composition of the present invention comprises a emulsion compositions containing mupirocin or a pharmaceutical acceptable salt or hydrate thereof of about 0.1 to about 5% (w/v), mineral oil of about 1 to about 20% (w/v), polysorbate of about 0.001 to about 5% (w/v), peg 400 of about
  • One of the embodiment is a solution compositions containing mupirocin or a pharmaceutical acceptable salt or hydrates thereof of about 0.1 to about 5% (w/v), hydroxypropyl beta cyclodexrtin (HPPCD) of about 1 to about 20% (w/v), propylene glycol of about 1 to about 10% (w/v), polysorbate 80 of about 0.05 to about 1% (w/v), disodium EDTA of about 0.05 to about 0.1% (w/v), benzalkonium chloride of about 0.0005 to about 0.1% (w/v), sodium chloride of about 0.5 to about 0.9% (w/v), sodium hydroxide and/or hydrochloric acid in an amount sufficient to adjust pH of about 5 to about 8.5, water for injection to make a final volume of the composition.
  • HPPCD hydroxypropyl beta cyclodexrtin
  • HPPCD hydroxypropyl beta cyclodexrtin
  • HPPCD hydroxypropyl beta cyclod
  • the ophthalmic composition described herein has a pH that allows for sterilization (e.g, by filtration or aseptic mixing or heat treatment and/or autoclaving (e.g., terminal sterilization) of an ophthalmic composition without degradation of the mupirocin or the excipients comprising the composition.
  • the buffer pH is designed to maintain pH of the composition in the range of about 5.0 to about 8.5 during the process of sterilization (e.g., high temperature autoclaving).
  • Degradation of a mupirocin is reduced by the use of an appropriate combination of a buffer and other excipients (such as antioxidants and preservatives) as described herein.
  • excipients such as antioxidants and preservatives
  • An advantage of the methods of sterilization provided herein is that, in certain instances, the compositions are subjected to terminal sterilization via autoclaving without any loss of the active agent and/or excipients and/or polymeric components during the sterilization step and are rendered substantially free of microbes and/or pyrogens.
  • compositions of any of the aspects of the present invention can be suitably packaged in glass or plastic containers of suitable size, preferably in plastic containers.
  • suitable plastic may be high density polyethylene (HDPE), low density polyethylene (LDPE), polypropylene (PP) and polyethylene terephthalate (PET).
  • the size of the container will depend on the application. For example mupirocin eye-drops may be packaged in sizes of 0.5 ml up to 30 ml.
  • composition of present invention is filled into blow/fill/seal (BFS) unit dose vials.
  • BFS blow/fill/seal
  • the ophthalmic pharmaceutical composition of the present invention is storage stable and avoids degradation of the mupirocin.
  • the present invention relates to a method of treating an infection of mucosal surface in a subject in need thereof comprising administering a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; wherein the mucosal surface is otic and/or ophthalmic surface.
  • the present invention relates to a method of preventing an infection of mucosal surface in a subject susceptible to the infection comprising administering a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof; wherein the mucosal surface is otic and/or ophthalmic surface.
  • the present invention provides a method for treating an otic condition in a patient in need thereof with mupirocin, the method comprising administering mupirocin or a pharmaceutically acceptable salt or hydrates thereof as the only active 2% w/v in a composition at a pH greater than 5.0 and pH ⁇ 8.5 and containing one or more excipients.
  • a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof and a base composition for the treatment of a bacterial infection of mucosal surface in a subject.
  • a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof and a base composition for the prevention of a bacterial infection of mucosal surface in a subject.
  • a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof and a base composition comprising one or more excipient selected from propylene glycol, polyethylene glycol, glycofurol, ethanol, glycerol, vitamin E TPGS, isopropyl alcohol, castor oil, almond oil, soya bean oil, and any combination of any of the foregoing, for treating a bacterial infection of mucosal surface in a subject.
  • a pharmaceutical composition comprising mupirocin or a pharmaceutically acceptable salt thereof and a base composition comprising one or more excipient selected from propylene glycol, polyethylene glycol, glycofurol, ethanol, glycerol, vitamin E TPGS, isopropyl alcohol, castor oil, almond oil, soya bean oil, and any combination of any of the foregoing, for preventing a bacterial infection of mucosal surface in a subject.
  • the present invention provides a method for treating an ocular condition in a patient in need thereof with mupirocin, the method comprising administering mupirocin or a pharmaceutically acceptable salt or hydrates thereof as the only active 2% w/v in a composition at a pH greater than 5.0 and pH ⁇ 8.5 and containing one or more excipients.
  • present invention relates to a method of treating ophthalmic infections commonly associated with at least one of Haemophilus influenza, Staphylococci species but not limited to Methicillin-resistant
  • Staphylococcus aureus Methicillin-sensitive Staphylococcus aureus, Staphylococci aureus, coagulase-negative staphylococci, Streptococcus pneumonia, Streptococcus pyogenes, Streptococcus viridians and Pseudomonas aeruginosa.
  • present invention relates to a method of treating ophthalmic infections commonly associated with at least one of Haemophilus influenza, Staphylococci species but not limited to Methicillin-resistant
  • Staphylococcus aureus Methicillin-sensitive Staphylococcus aureus, coagulase- negative staphylococci, Streptococcus pneumonia, Streptococcus pyogenes, Streptococcus viridians, and Pseudomonas aeruginosa which comprises topically applying to the affected ophthalmic tissue a therapeutically effective amount of a topical ophthalmic pharmaceutical composition containing mupirocin or a pharmaceutically useful hydrate or salt or hydrates thereof at a concentration of about 2%
  • a method of treating ophthalmic infections which comprises topically applying to the eye a pharmaceutical composition comprising mupirocin or a pharmaceutically useful salt or hydrate thereof in a concentration of from about 0.1 to about 2% (w/v) of mupirocin.
  • present invention comprises a method of treating ocular infection conjunctivitis, Blepharitis, endophthalmitis, dacryocystitis, scleritis and keratitis which comprises instilling a composition comprising therapeutically effective amount of mupirocin.
  • a method of treating conjunctivitis infections attributable to a pathogenic staphylococci species which comprises instilling an antibiotic composition in the affected eye to eradicate said pathogenic staphylococci species, said composition comprising a therapeutically effective amount of mupirocin.
  • a method of treating Blepharitis infections attributable to a pathogenic staphylococci species which comprises instilling an antibiotic composition in the affected eye to eradicate said pathogenic staphylococci species, said composition comprising a therapeutically effective amount of a mupirocin.
  • a method of treating keratitis infections attributable to a pathogenic staphylococci species which comprises instilling an antibiotic composition in the affected eye to eradicate said pathogenic staphylococci species, said composition comprising a therapeutically effective amount of a mupirocin.
  • a method of treating endophthalmitis infections attributable to a pathogenic staphylococci species which comprises instilling an antibiotic composition in the affected eye to eradicate said pathogenic staphylococci species, said composition comprising a therapeutically effective amount of a mupirocin and a pharmaceutically acceptable vehicle therefor.
  • a method of treating dacryocystitis infections attributable to a pathogenic staphylococci species which comprises instilling an antibiotic composition in the affected eye to eradicate said pathogenic staphylococci species, said composition comprising a therapeutically effective amount of a mupirocin and a pharmaceutically acceptable vehicle therefor.
  • a method of treating ophthalmic infections which comprises topically applying to the eye a therapeutically effective amount of a pharmaceutical composition comprising mupirocin or a pharmaceutically useful salt or hydrate thereof in a concentration of from about 0.1 to about 5% (w/v) of mupirocin.
  • the drop compositions are capable of being administered inside or on or near the outer surface of the ear via syringe and needle.
  • the drop compositions are capable of being administered inside or on or near the outer surface of the tympanic membrane via a syringe.
  • the drop compositions are capable of being administered inside or on or near the outer surface of the tympanic membrane via a dropper.
  • the drop compositions are administered onto the external auditory canal.
  • the compositions are administered via a pump device or another device capable of delivering the compositions onto or near the outer surface of the tympanic membrane, onto the external auditory canal, or a combination thereof.
  • Example 1 Pre-formulation studies for otic compositons of mupirocin
  • Mupirocin base containing compositions F1-F17 The observation after 7 days were captured in inference column of TABLE 1.
  • Pharmaceutical compositions of FI to F9 are physically stable at 20-25°C.
  • F13, and F16 were not physically stable, as they were showing precipitation and/or color change.
  • some compositions were 5 prepared using Vitamin E TPGS and water for injection, however, mupirocin was not soluble in the vehicle containing vitamin E TPGS and water for injection, and one more composition was prepared using glycerol as a solvent, mupirocin did not show solubility in glycerol.
  • Mupirocin E is Pseudomonic acid-F / N; Mupirocin D is Pseudomonic acid-D; Mupirocin B is Pseudomonic acid-B; and Mupirocin C is Pseudomonic acid-C
  • Example 2 Otic compositions of mupirocin
  • compositions of example 2 were prepared by solubilizing 5 benzylkonium chloride in propylene glycol/polyethylene glycol by stirring at 300 rpm for 5-10 minutes and mupirocin was added under stirring at 300 rpm to the above solution and the polyethylene glycol 400 was further added to make up volume.
  • the composition of example 2 was tested for stability at elevated temperature at 80 °C.
  • the F19 composition was prepared by solubilizing mupirocin in castor oil using High shear 10 homogeniser at around 10,000 rpm for 2 mins at room temperature. Stability evaluation of compositions F6, F8, F18 and F19 at elevated temperature
  • pH and osmolality of the compositons F8 and F6 were tested after aqueous dilution 1 : 1.
  • Example 3 Otic compositions of mupirocin calcium
  • compositions of example 3 were prepared by solubilizing mupirocin calcium in propylene glycol and glycofurol respectively, and making up volume using QS excipient under stirring at 300 rpm.
  • the composition of F28 was prepared by dispersing mupirocin calcium in mineral oil using high shear homogeniser at 30000 rpm for 2.5 mins.
  • the composition of F27 was prepared by dissolving sodium chloride in water for injection, and part of this solution was used for solubilizing hydroxyethyl cellulose at 500 rpm for around 30 minutes.
  • the polysorbate 80 and benzoylkonium chloride were further added to the dispersion 10 by stirring at 500 rpm at around 10-15 minutes.
  • Mupirocin calcium was added and suspended using high shear homogenizer at 30000 rpm for about 2.5 minutes. The remaining part of the sodium chloride solution was mixed to the mupirocin containing dispersion.
  • composition F28 was stable and showed less impurity profile as compared to other composition at elevated temperature. pH and osmolality of the compositons F20, F22, and F27 were tested after aqueous dilution 1: 1.

Landscapes

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

Abstract

La présente invention concerne une composition pharmaceutique destinée à l'administration à une surface mucosale, comprenant de la mupirocine ou un sel pharmaceutiquement acceptable de celle-ci et un procédé pour sa préparation. En outre, la présente invention concerne un procédé de traitement et/ou de prévention d'infections mucosales par administration otique et/ou ophtalmique.
PCT/IB2020/050029 2019-01-04 2020-01-03 Compositions pharmaceutiques comprenant de la mupirocine WO2020141482A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN201921000418 2019-01-04
IN201921000418 2019-01-04
IN201921010005 2019-03-14
IN201921010005 2019-03-14

Publications (1)

Publication Number Publication Date
WO2020141482A1 true WO2020141482A1 (fr) 2020-07-09

Family

ID=71407001

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2020/050029 WO2020141482A1 (fr) 2019-01-04 2020-01-03 Compositions pharmaceutiques comprenant de la mupirocine

Country Status (1)

Country Link
WO (1) WO2020141482A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008094002A1 (fr) * 2007-01-31 2008-08-07 Tds Pharm. Co., Ltd. Préparation d'hydrogel comprenant des médicaments actifs pour le traitement de blessures
CN102335122A (zh) * 2011-06-21 2012-02-01 北京协和药厂 一种莫匹罗星软膏及其制备方法
WO2012052472A1 (fr) * 2010-10-20 2012-04-26 Laboratorios Ojer Pharma S.L. Composition topique pharmaceutique de mupirocine
CN102885763A (zh) * 2012-10-29 2013-01-23 杭州朱养心药业有限公司 一种新颖的莫匹罗星软膏剂药物组合物
CN108186660A (zh) * 2018-03-29 2018-06-22 刘春霞 一种消肿西药软膏

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008094002A1 (fr) * 2007-01-31 2008-08-07 Tds Pharm. Co., Ltd. Préparation d'hydrogel comprenant des médicaments actifs pour le traitement de blessures
WO2012052472A1 (fr) * 2010-10-20 2012-04-26 Laboratorios Ojer Pharma S.L. Composition topique pharmaceutique de mupirocine
CN102335122A (zh) * 2011-06-21 2012-02-01 北京协和药厂 一种莫匹罗星软膏及其制备方法
CN102885763A (zh) * 2012-10-29 2013-01-23 杭州朱养心药业有限公司 一种新颖的莫匹罗星软膏剂药物组合物
CN108186660A (zh) * 2018-03-29 2018-06-22 刘春霞 一种消肿西药软膏

Similar Documents

Publication Publication Date Title
US11052095B2 (en) D2O stabilized pharmaceutical formulations
ES2461617T3 (es) Composiciones farmacéuticas acuosas que contienen complejos borato-polioles
US6277829B1 (en) Process for preparing of aqueous formulation for opthalmic use
AU2009225931B9 (en) Aqueous pharmaceutical compositions containing borate-polyol complexes
US20120093876A1 (en) Ophthalmic Formulations, Methods Of Manufacture And Methods of Normalizing Meibomian Gland Secretions
Dubey et al. Formulation and evaluation of stimuli-sensitive hydrogels of timolol maleate and brimonidine tartrate for the treatment of glaucoma
JP2011006348A (ja) ドライアイ治療剤
EA034839B1 (ru) Офтальмологический раствор
US20210177890A1 (en) Composition containing chlorine dioxide and methods for using same
JP2023058566A (ja) 安定なペプチド組成物
JP4773721B2 (ja) 第四級化アンモニウムシクロデキストリン化合物
WO2020141482A1 (fr) Compositions pharmaceutiques comprenant de la mupirocine
WO2022023822A1 (fr) Composition ophtalmique stable de posaconazole
AU2010236505B2 (en) Aqueous ophthalmic compositions containing anionic therapeutic agents
Bandyopadhyay et al. Development of ophthalmic formulations
JP2008156290A (ja) 眼科用組成物
Ghosh et al. Chemistry, manufacturing, and control of ophthalmic formulations
JP2019189607A (ja) 眼科組成物
US20080015250A1 (en) Ultraviolet absorbing ophthalmic compositions
JP7191524B2 (ja) 眼科組成物
Maiti et al. Ocular Preservatives: Risks and Recent Trends in Its Application in Ocular Drug Delivery (ODD)
WO2024105689A1 (fr) Nouvelle composition ophtalmique
EP3761986A1 (fr) Procédés d'utilisation et compositions pharmaceutiques d'un inhibiteur de syk sélectif
JP2004043516A (ja) 眼科用剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20735987

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20735987

Country of ref document: EP

Kind code of ref document: A1