Patent Application
20150119371
The present invention relates to pharmaceutical compositions. In particular, this invention relates to sterile, storage-stable topically administrable otic pharmaceutical compositions comprising one or more antibiotic(s) and one or more steroidal anti-inflammatory agent(s) and a process for preparation thereof.
U.S. Pat. Nos. 6,284,804 and 6,359,016 discloses topically administrable sterile ophthalmic and otic suspensions of Ciprofloxacin and Dexamethasone, marketed by Alcon under tradename CiproDex® for treatment of acute otitis media and acute otitis externa, containing nonionic polymer, a nonionic surfactant and an ionic tonicity agent. The nonionic polymer incorporated in these suspensions is hydroxyethyl cellulose in an amount of 0.2% weight (wt.)
U.S. Pat. Nos. 5,843,930 and 5,965,549 discloses non-ototoxic, non-irritating and non-sensitizing aqueous otic suspension for the treatment of acute otitis externa and otitis media, particularly otorrhea. The composition comprises nonionic polymer, a nonionic surfactant and a nonionic tonicity agent. The '549 patent teaches that “aqueous solutions of ionic polymers such as carbopol and sodium carboxymethylcellulose were found to have undesirable viscosity variability with ionic level and pH” (see Col. 5, lines 17-21). For compatibility with ciprofloxacin hydrochloride solubility, such agents were preferably non-ionic and unaffected by pH and ionic level (see Col. 5, lines 14-16). The composition comprises ciprofloxacin in an amount effective for antibacterial action; a non-ionic viscosity augmenter unaffected by pH and ionic level in an amount effective for augmenting viscosity of the composition to a viscosity greater than that of water; and water sufficient to produce a liquid composition. The viscosity augmenter is chosen from the group consisting of methylcellulose, polyvinyl alcohol, and glycerine (see Col. 2, lines 52-56).
U.S. Pat. No. 6,066,292 provides method for sterilizing a pharmaceutical suspension of a water-insoluble pharmaceutical like steroids including Hydrocortisone and Dexamethasone by preparation of three pre-mixes comprising i) a first sterile pre-mix of heat-sterilized aqueous solution of a viscosity enhancer (b) a second pre-mix having sterile-filtered aqueous solution of a mixture of a pharmaceutically-active compound (c) third sterile pre-mix containing heat-sterilized mixture of water, a water-insoluble pharmaceutical, and at least a partial amount of an sodium chloride to provide a sub-saturated solution, and adding under aseptic conditions an aqueous surfactant (d) combining all three pre-mixes in sterile fashion to achieve a sterile suspended pharmaceutical formulation like sterile suspension of Ciprofloxacin and Hydrocortisone. The viscosity enhancers used in this composition, such as polyvinyl alcohol or lecithin is non-ionic in nature.
While there are compositions available, still there remains a need to develop sterile, storage-stable topically administrable otic pharmaceutical composition comprising antiinflammatory agent(s) and antibiotic agent(s) having excellent physical stability and are characterized by their easy and ready resuspendability.
The present inventors have now found that sterile storage-stable topically administrable otic pharmaceutical compositions comprising one or more antibiotic(s), one or more steroidal anti-inflammatory agent(s) and one or more ionic polymer(s) provides excellent physical stability and are characterized by their easy and ready resuspendability.
The present invention is directed to a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising one or more antibiotic(s) and one or more steroidal anti-inflammatory agent(s).
In one aspect, the present invention provides sterile, storage-stable topically administrable otic pharmaceutical compositions comprising:
(a) one or more antibiotic(s),
(b) one or more steroidal anti-inflammatory agent(s),
(c) one or more Ionic polymer(s).
In yet another aspect, the present invention provides a pharmaceutical composition comprising fixed dose combination comprising one or more antibiotic(s) and one or more steroidal anti-inflammatory agent(s).
In yet another aspect, the present invention provides a pharmaceutical composition comprising fixed dose combination comprising one or more antibiotic(s), one or more steroidal anti-inflammatory agent(s) and one or more Ionic polymer(s).
In yet another aspect, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(a) one or more antibiotic(s);
(b) one or more steroidal anti-inflammatory agent(s);
(c) one or more ionic polymer(s), wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg.
In yet another aspect, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(a) one or more antibiotic(s);
(b) one or more steroidal anti-inflammatory agent(s);
(c) one or more ionic polymer(s), wherein the composition has a pH in the range of 4 to 4.8.
In yet another aspect, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(a) one or more antibiotic(s);
(b) one or more steroidal anti-inflammatory agent(s);
(c) one or more ionic polymer(s), wherein the composition optionally comprises preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s) and/or chelating agent(s).
In yet another aspect, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(a) one or more antibiotic(s);
(b) one or more steroidal anti-inflammatory agent(s);
(c) one or more ionic polymer(s), wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg; a pH in the range of 4 to 4.8; and the composition optionally comprises preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s) and/or chelating agent(s).
In yet another aspect, the present invention provides a stable topically administrable otic pharmaceutical suspension composition comprising one or more antibiotic(s) and one or more steroidal anti-inflammatory agent(s), the said pharmaceutical otic suspension further comprises one or more ionic polymer(s) wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg; a pH in the range of 4 to 4.8; and the composition optionally comprises preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s) and/or chelating agent(s).
In yet another aspect, the present invention provides a method of treating, preventing or reducing the risk of an otic infection in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising one or more antibiotic(s) and one or more steroidal anti-inflammatory agent(s).
In yet another aspect, the present invention provides a method of treating, preventing or reducing the risk of an otic infection in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising one or more antibiotic(s), one or more steroidal anti-inflammatory agent(s), one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another aspect, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic pharmaceutical composition comprising one or more antibiotic(s) and one or more steroidal anti-inflammatory agent(s).
In yet another aspect, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic pharmaceutical composition comprising one or more antibiotic(s), one or more steroidal anti-inflammatory agent(s), one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet preferred aspect, the present invention provides a method of treating acute otitis media and acute otitis externa in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical composition comprising one or more antibiotic(s), one or more steroidal anti-inflammatory agent(s).
In yet another preferred aspect, the present invention provides a method of treating acute otitis media and acute otitis externa in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical composition comprising one or more antibiotic(s), one or more steroidal anti-inflammatory agent(s), one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred aspect, the present invention provides a sterile, storage-stable topically administrable otic pharmaceutical composition comprising Ciprofloxacin and Dexamethasone.
In yet another preferred aspect, the present invention provides a sterile, storage-stable topically administrable otic pharmaceutical composition comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred aspect, the present invention provides a sterile, storage-stable topically administrable otic pharmaceutical composition comprising Ciprofloxacin, Dexamethasone, sodium carboxy methyl cellulose and pharmaceutically acceptable excipients thereof.
In yet another preferred aspect, the present invention provides a method of treating, preventing or reducing the risk of an otic infection in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising Ciprofloxacin and Dexamethasone.
In yet another preferred aspect, the present invention provides a method of treating, preventing or reducing the risk of an otic infection in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred aspect, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic pharmaceutical composition comprising Ciprofloxacin and Dexamethasone.
In yet another preferred aspect, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic pharmaceutical composition comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another aspect, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(c) sodium carboxymethylcellulose in an amount not more than 0.5% (wt.), wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg; a pH in the range of 4 to 4.8; and the composition optionally comprises preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s), chelating agent(s) and/or pH-adjusting agent.
In yet another preferred aspect, the present invention provides a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin and Dexamethasone.
In yet another preferred aspect, the present invention provides a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred aspect, the present invention provides a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin, Dexamethasone, sodium carboxy methyl cellulose and pharmaceutically acceptable excipients thereof.
In yet another preferred aspect, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred aspect, the present invention provides a method of treating acute otitis media and acute otitis externa in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
The present invention relates to the sterile, storage-stable topically administrable otic pharmaceutical compositions comprising one or more antibiotic(s) and one or more steroidal anti-inflammatory agent(s).
As used herein, the term “antibiotics” refers to drugs which are produced by micro-organism in nature and isolated from this natural source or synthesized by chemical process which can kill harmful microorganism and cure bacterial infections in human and animals.
As used herein, the term “steroidal anti-inflammatory agents” refers to the drugs that block the synthesis of new histamine release by mast cells, inactivate available histamine, inhibit mast cell degranulation, decrease capillary permeability, and inhibit phospholipase A synthesis, which is used in the production of arachidonic acid and thereby prevent inflammation.
The topical pharmaceutical compositions of the present invention comprises but not limited to suspensions, solutions, emulsions, ointments, liniments, lotions, creams and gels.
In one embodiment, the present invention provides a pharmaceutical composition comprising fixed dose combination comprising one or more antibiotic(s) and one or more steroidal anti-inflammatory agent(s).
In yet another embodiment, the present invention provides a pharmaceutical composition comprising fixed dose combination comprising one or more antibiotic(s), one or more steroidal anti-inflammatory agent(s) and one or more Ionic polymer(s).
In yet another embodiment, the present invention provides a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising:
(a) one or more antibiotic(s),
(b) one or more steroidal anti-inflammatory agent(s),
(c) one or more Ionic polymer(s).
In yet another embodiment, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(a) one or more antibiotic(s);
(b) one or more steroidal anti-inflammatory agent(s);
(c) one or more ionic polymer(s), wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg.
In yet another embodiment, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(a) one or more antibiotic(s);
(b) one or more steroidal anti-inflammatory agent(s);
(c) one or more ionic polymer(s), wherein the composition has a pH in the range of 4 to 4.8.
In yet another embodiment, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(a) one or more antibiotic(s);
(b) one or more steroidal anti-inflammatory agent(s);
(c) one or more ionic polymer(s), wherein the composition optionally comprises preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s) and/or chelating agent(s).
In yet another embodiment, the present invention provides a method of treating, preventing or reducing the risk of an otic infection in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising one or more antibiotic(s) and one or more steroidal anti-inflammatory agent(s).
In yet another embodiment, the present invention provides a method of treating, preventing or reducing the risk of an otic infection in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising one or more antibiotic(s), one or more steroidal anti-inflammatory agent(s), one or more Ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another embodiment, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic pharmaceutical composition comprising one or more antibiotic(s) and one or more steroidal anti-inflammatory agent(s).
In yet another embodiment, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic pharmaceutical composition comprising one or more antibiotic(s), one or more steroidal anti-inflammatory agent(s), one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred embodiment, the present invention provides a method of treating acute otitis media and acute otitis externa in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising one or more antibiotic(s), one or more steroidal anti-inflammatory agent(s).
In yet another preferred embodiment, the present invention provides a method of treating acute otitis media and acute otitis externa in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical composition comprising one or more antibiotic(s), one or more steroidal anti-inflammatory agent(s), one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
Examples of antibiotics according to the present invention include, but are not limited to, Ciprofloxacin, Moxifloxacin, Ofloxacin, Enoxacin Gatifloxacin, Norfloxacin, Perfloxacin, Amifloxacin, Pirfloxacin or their pharmaceutically acceptable derivatives thereof.
Examples of steroidal anti-inflammatory agents according to the present invention include, but are not limited to Dexamethasone, Hydrocortisone or their pharmaceutically acceptable derivatives thereof.
Dexamethasone can be present in any otically acceptable form having poor water solubility such that the resulting composition is a suspension composition. Suitable forms of Dexamethasone include Dexamethasone alcohol and Dexamethasone acetate.
In yet another preferred embodiment, the present invention provides a sterile, storage-stable topically administrable otic pharmaceutical composition comprising Ciprofloxacin and Dexamethasone.
In yet another preferred embodiment, the present invention provides a sterile, storage-stable topically administrable otic pharmaceutical composition comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another embodiment, the present invention provides a method of treating, preventing or reducing the risk of an otic infection in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising Ciprofloxacin and Dexamethasone.
In yet another embodiment, the present invention provides a method of treating, preventing or reducing the risk of an otic infection in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred embodiment, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic pharmaceutical composition comprising Ciprofloxacin and Dexamethasone.
In yet another preferred embodiment, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic pharmaceutical composition comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred embodiment, the present invention provides a method of treating acute otitis media and acute otitis externa in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical composition comprising Ciprofloxacin and Dexamethasone.
In yet another preferred embodiment, the present invention provides a method of treating acute otitis media and acute otitis externa in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical composition comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred embodiment, the present invention provides a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin and Dexamethasone.
In yet another preferred embodiment, the present invention provides a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred embodiment, the present invention provides a method of treating, preventing or reducing the risk of an otic infection in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin and Dexamethasone.
In yet another preferred embodiment, the present invention provides a method of treating, preventing or reducing the risk of an otic infection in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred embodiment, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin and Dexamethasone.
In yet another preferred embodiment, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
In yet another preferred embodiment, the present invention provides a method of treating acute otitis media and acute otitis externa in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin and Dexamethasone.
In yet another preferred embodiment, the present invention provides a method of treating acute otitis media and acute otitis externa in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin, Dexamethasone, one or more ionic polymer(s) and pharmaceutically acceptable excipients thereof.
The average particle size (mean volume basis) of the Dexamethasone ingredient should be less than about 20 micrometers to avoid irritation or discomfort. Dexamethasone particles can be sized using known techniques, such as ball-milling, microfluidization, high shear homogenization, high pressure homogenization and sonication.
Ciprofloxacin can be present in any otically acceptable form such that the Ciprofloxacin is in solution in the final composition.
In yet another embodiment, the antibiotics (e.g. Ciprofloxacin or its pharmaceutically acceptable salts or hydrates or combinations thereof) are present in a composition or formulation described herein in an amount of about 0.01% (wt.) to about 10% (wt.), preferably about 0.1% (wt.) to about 1% (wt.). A preferred form of Ciprofloxacin is Ciprofloxacin hydrochloride.
In yet another embodiment, the anti-inflammatory steroids (e.g. Dexamethasone or its pharmaceutically acceptable derivatives thereof) are present in a composition or formulation described herein in an amount of about 0.01% (wt.) to about 10% (wt.), preferably about 0.05% (wt.) to about 1% (wt.).
The preferred amounts of Ciprofloxacin and Dexamethasone in the composition of the present invention are 0.3 and 0.1% (wt.), respectively.
In yet another embodiment, the topical pharmaceutical compositions of present invention have a pH from 3.0 to 7.0, preferably from 4.0 to 5.5.
In yet another embodiment, the topical pharmaceutical compositions of present invention has an osmolarity from 200 to 400 milliosmoles/liter (mOsm/L), preferably from 250 to 375 mOsm/L.
A pharmaceutical composition according to the present invention may include one or more pharmaceutically acceptable buffering agents, preservatives, tonicity-adjusting agents, antioxidants, pH-adjusting agents, chelating agents, viscosity modifiers such as ionic polymers, surfactants, solubilizing agents and the like present in an amount ranging from 0.01% w/v to about 99.9% w/v.
Examples of buffering agents include, but are not limited to, phosphate buffer such as dibasic sodium phosphate heptahydrate, monobasic sodium phosphate monohydrate; and/or borate buffer such as sodium borate, boric acid; and/or citrate buffer, acetate buffer such as sodium acetate or its hydrate(s), acetic acid or combination thereof; carbonate buffer; borate-polyol complexes, and the like.
Examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, p-oxybenzoates such as methyl p-oxybenzoate or ethyl p-oxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid or its salt, thimerosal, chlorobutanol, other quaternary amines and the like, chlorhexidine gluconate and the like.
Examples of tonicity-adjusting agents include, but are not limited to, ionic tonicity agents and non-ionic tonicity agents.
Examples of ionic tonicity agents include, but are not limited to, sodium chloride, potassium chloride, magnesium chloride or calcium chloride and the like.
Examples of non-ionic tonicity agents include, but are not limited to, mannitol, glycerine dextrose and the like.
Examples of antioxidants include, but are not limited to, ascorbic acid, malic acid, citric acid, sodium citrate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium ascorbate, sodium metabisulfite and the like and mixtures thereof.
Examples of the alkaline agents that may be used as pH adjusting agents, include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, monoethanolamine, sodium bicarbonate (NaHCO3) and other organic and inorganic bases.
Examples of the acidic agents that may be used as pH adjusting agents include, but are not limited to, hydrochloric acid, citric acid, tartaric acid, lactic acid and other organic and inorganic acids and the like and mixtures thereof.
Examples of chelating agents include, but are not limited to, EDTA, disodium edetate, sodium citrate, condensed sodium phosphate and the like.
Examples of viscosity modifiers chosen from ionic polymers include, but are not limited to; carboxyvinyl polymer or polyacrylic acid which are commercially available under the tradename Carbopol and sodium carboxymethylcellulose which is commercially available under the tradename Cekol. Examples of sodium carboxymethylcellulose for use herein include various grades of Cekol such as, for example Cekol 700P and Cekol 150.
Examples of surfactants include, but are not limited to, cetylpyridinium chloride, tyloxapol, and various polysorbates such as Tween® which includes Tween 80 (Polysorbate 80), polyethoxylated substances and poloxamers.
Examples of solubilizing agents include, but are not limited to, cyclodextrins (CDs) such as Hydroxypropyl beta-CD, hydroxypropyl gamma-CD (Cavasol®), sulfobutyl ether4 beta-CD (Captisol®), and hydroxypropyl beta-CD (Kleptose®).
In yet another preferred embodiment, the present invention provides a sterile, storage-stable topically administrable otic pharmaceutical compositions comprising:
(c) Sodium carboxymethylcellulose.
In yet another preferred embodiment, the present invention provides a sterile, storage-stable topically administrable otic suspension comprising Ciprofloxacin, Dexamethasone, sodium carboxy methyl cellulose and pharmaceutically acceptable excipients thereof.
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(c) Sodium carboxymethylcellulose, wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg.
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(c) Sodium carboxymethylcellulose, wherein the composition has a pH in the range of 4 to 4.8.
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(c) Sodium carboxymethylcellulose, wherein the composition optionally comprises preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s) and/or chelating agent(s).
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical composition comprising:
(c) Sodium carboxymethylcellulose, one or more preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s), chelating agent(s) and/or pH-adjusting agent(s); wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg and a pH in the range of 4 to 4.8.
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical suspension comprising:
(c) Sodium carboxymethylcellulose, one or more preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s), chelating agent(s) and/or pH-adjusting agent(s); wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg and a pH in the range of 4 to 4.8.
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical compositions comprising:
(c) sodium carboxymethylcellulose in an amount not more than 0.5% (wt.), one or more preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s), chelating agent(s) and/or pH-adjusting agent(s); wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg and a pH in the range of 4 to 4.8.
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical suspension comprising:
(c) sodium carboxymethylcellulose in an amount not more than 0.5% (wt.), one or more preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s), chelating agent(s) and/or pH-adjusting agent(s); wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg and a pH in the range of 4 to 4.8.
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical composition comprising:
(c) sodium carboxymethylcellulose in an amount not more than 0.5% (wt.), one or more preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s), chelating agent(s) and/or pH-adjusting agent(s); wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg and a pH in the range of 4 to 4.8.
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical suspension comprising:
(c) sodium carboxymethylcellulose in an amount not more than 0.5% (wt.), one or more preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s), chelating agent(s) and/or pH-adjusting agent(s); wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg and a pH in the range of 4 to 4.8.
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical composition comprising:
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical suspension comprising:
In yet another embodiment, the topically administrable otic pharmaceutical compositions of present invention is sterilized using methods such as heat sterilization methods including dry heat sterilization and autoclaving (steam sterilization), gaseous sterilization methods including filtration sterilization methods, ethylene oxide sterilization and radiation sterilization.
In yet another embodiment, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic pharmaceutical composition comprising the steps of:
In yet another preferred embodiment, the present invention provides a process of preparing a sterile, storage-stable topically administrable otic pharmaceutical composition comprising the steps of:
In yet another embodiment, the present invention provides a method of treating, preventing or reducing the risk of an otic infection in a patient in need thereof comprising administering a sterile, storage-stable topically administrable otic pharmaceutical suspension comprising:
It is to be understood for the purpose of invention that the sterile topical pharmaceutical compositions of invention can be stored in different types of containers and packaging which are well known in the art. Such types of containers and packaging keeps the sterile topical pharmaceutical compositions stable for adequate period of time.
In yet another embodiment, the topical pharmaceutical compositions of present invention are thermally stable at room temperature, at 25° C. with relative humidity 40% for at least 6 months.
In yet another preferred embodiment, the present invention provides a stable topically administrable otic pharmaceutical suspension comprising:
(c) sodium carboxymethylcellulose in an amount not more than 0.5% (wt.), preservative(s), buffering agent(s), tonicity-adjusting agent(s), surfactant(s), chelating agent(s) and/or pH-adjusting agent; wherein the composition has an osmolality in the range from 270 to 330 mOsml/kg and a pH in the range of 4 to 4.8; wherein the composition comprises not more than 2.6% of 20-carboxy-17-desoxy related compound when stored under the condition of 25° C.±2° C./40% RH±5% RH for 6 months.
In yet another embodiment, the topical pharmaceutical compositions of present invention are found to be sterile when sterility test performed as per United States Pharmacopoeia (USP) Chapter <71>.
In yet another embodiment, the topical pharmaceutical compositions of present invention when subjected for Resuspension time in “real time” settling studies exhibits resuspendability comparable to marketed formulations like CiproDex®.
The invention will be further illustrated by the following examples, which are intended to be illustrative but not limiting.
The formulation as shown in table 1 was prepared as follows:
1. Sodium carboxy methyl cellulose was dissolved in sufficient quantity of water for injection and sterilized by using Autoclave.
2. Accurately weighed quantity of Dexamethasone and half quantity of Tyloxapol was added in sufficient quantity of water to form slurry and sterilized by using Autoclave.
3. Accurately weighed quantities of Ciprofloxacin hydrochloride, Edetate disodium, and Sodium chloride, Sodium acetate trihydrate, Boric acid, Tyloxapol, Acetic acid, Benzalkonium chloride were successively added in sufficient quantity of water and stirred till clear a solution was obtained, desired pH was adjusted using Hydrochloric acid/Sodium hydroxide and the volume was made up to the 65% of the desired batch size. This solution was then filtered and sterilized using sterilization in place (SIP) technique.
4. The solution as obtained in step-1 and the slurry as obtained in step-2 were added the solution as obtained in step-3 and stirred and finally volume made up to the desire batch size.
5. The composition as obtained in step-4 was homogenized to obtained final sterile suspension and filed into suitable container.
The formulations as shown in table 2, 3 & 4 were prepared as follows:
1. Sodium carboxy methyl cellulose was dissolved in sufficient quantity of water for injection and sterilized by using Autoclave at 121° C.
2. Accurately weighed quantity of Dexamethasone and half quantity of Tyloxapol was added in sufficient quantity of water and mixed well to form slurry and sterilized by using Autoclave at 121 PC.
3. Accurately weighed quantities of Ciprofloxacin hydrochloride, Edetate disodium, and Sodium chloride, Sodium acetate trihydrate, Boric acid, Acetic acid, Benzalkonium chloride, half quantity of Tyloxapol were successively added in sufficient quantity of water and stirred till a clear solution was obtained; desired pH was adjusted using Hydrochloric acid/Sodium hydroxide and the volume was made up to the 65% of the desired batch size. This solution was then filtered and sterilized using sterilization in place (SIP) technique at 121° C.
4. The solution as obtained in step-1 and the slurry as obtained in step 2 were added to the solution as obtained in step-3 and stirred and finally volume made up to the desire batch size.
5. The composition as obtained in step-4 was homogenized to obtained final sterile suspension and filed into suitable container.
The otic suspension of Example 4 was found stable for the period of 6 month when stored under conditions of 25° C.±2° C./40% RH±5% RH. Table no. 5 contains result of the stability studies performed on otic suspension of Example 4.
Real time settling studies were performed by allowing samples of Example 4 in measuring cylinder to undergo natural settling (under gravity) for seven days. The resuspendability of the settled material is tested by measuring the number of inversions required to fully re-suspend the sediment.
Table no. 6 contains the result of resuspendability carried out on otic suspension of Example 4.
| Number | Date | Country | Kind |
|---|---|---|---|
| 4897/CHE/2013 | Oct 2013 | IN | national |
