WO2014158118A1 - Suspension composition containing ipratropium and oxymetazoline - Google Patents
Suspension composition containing ipratropium and oxymetazoline Download PDFInfo
- Publication number
- WO2014158118A1 WO2014158118A1 PCT/TR2014/000100 TR2014000100W WO2014158118A1 WO 2014158118 A1 WO2014158118 A1 WO 2014158118A1 TR 2014000100 W TR2014000100 W TR 2014000100W WO 2014158118 A1 WO2014158118 A1 WO 2014158118A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oxymetazoline
- ipratropium
- composition according
- group
- sodium
- Prior art date
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Classifications
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- 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
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
Definitions
- formulated is intended to relate to the selection of excipients, carriers, vehicles, solvents, co-solvents, preservatives, colouring agents, flavouring agents and so forth in the preparation of a medicament using said composition.
Abstract
The present invention relates to a nasal suspension comprising ipratropium bromide and oxymetazoline hydrochloride.
Description
SUSPENSION COMPOSITION CONTAINING IPRATROPIUM and OXYMETAZOLINE
Field of invention
The invention relates to a suspension composition containing ipratropium and oxymetazoline, humectant, preservative, pH-adjusting agent, emulsifier and a suspending agent for the symptomatic treatment of common cold symptoms through mucosal delivery, preferably suitable for local administration into the nose.
Background of the Invention
Ipratropium, a derivative of N-isopropyl noratropine, has an anticholinergic effect on upper respiratory tract. The basic patent of Ipratropium is US 3505337. For the symptomatic treatment of rhinorrhea associated with perennial rhinitis, a nasal spray (Atrovent®) containing Ipratropium bromide (Formule I) is available on the market.
Oxymetazoline (Formula II) is a vasoconstrictor imidazole-Sympathomimetics, which is preferably used locally in the nose for the decongestion of the mucosa. The basic patent of Oxymetazoline is DE 1117588. Nasal preparations with decongestant activity containing Oxymetazoline hydrochloride (lliadin Merck® Metered-dose Nasal Spray, Drops, Pediatric Spray) are available on the market.
Formiil I Formiil II
A nasal spray containing Ipratropium in combination with Xylometazoline, a Oxymetazoline similar molecule available on the market (Otrivin Comp®).
Co-administration of Ipratropium and Xylometazoline has been investigated by Pitkaranta et al. (Pitkaranta et aL, Am J Rhinol., Mar-Apr; 12(2): 125-9, 1998). However, a preparation comprising a combination of Oxymetazoline or a salt thereof with Ipratropium or a salt thereof used for the symptomatic treatment of common cold and/or of rhinitis and in cases related to
l
these symptoms such as nasal congestion, sneezing and hypersecretion (rhinorrhea) is not present currently on the market.
Detailed description of the invention
This invention relates to dosage forms used for the treatment of common cold symptoms via mucosal delivery, which are formulated to comprise Oxymetazoline or a salt thereof and Ipratropium or a salt thereof together with at least one humectant, preservative, pH-adjusting agent, emulsifier and a suspending agent as excipients in a stable viscous suspension.
The term "Ipratropium or a salt thereof" is intended to relate to Ipratropium, a pharmaceutically acceptable salt thereof, a mixture of Ipratropium and one or more pharmaceutically acceptable salts thereof, or a mixture of pharmaceutically acceptable salts of Ipratropium. Pharmaceutically acceptable salt of Ipratropium is selected among the group of Ipratropium bromide, Ipratropium chloride, Ipratropium iodide, Ipratropium fluoride, or Ipratropium hydroxide.
Likewise, the term "Oxymetazoline or a salt thereof" is intended to relate to Oxymetazoline, a pharmaceutically acceptable salt thereof, a mixture of Oxymetazoline and one or more salts thereof, or a mixture pharmaceutically acceptable salts of Oxymetazoline. Pharmaceutically acceptable salt of Oxymetazoline is selected among the group of Oxymetazoline hydrochloride, Oxymetazoline hydrobromide, Oxymetazoline hydroiodide, Oxymetazoline hydrofluoride, Oxymetazoline sulphate, Oxymetazoline nitrate, Oxymetazoline formate, Oxymetazoline acetate, Oxymetazoline citrate, Oxymetazoline tartrate, or Oxymetazoline fumarate.
The term "pharmaceutically acceptable salts" is denoted to mean substances that are essentially non-toxic following administration to a mucosa and meet a specified chemical or microbial quality.
The term "humectant" relates to an agent that brings about a moisturising effect to the target where it is applied. Typically humectants according to the invention are sorbitol, propylene glycol, glycerol, glycerine, polyethylene glycols, triacetin, hydroxypropylmethylcellulose methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, poloxamer. In a particular suitable embodiment of the invention, the humectant is glycerol.
The term " preservative" relates to any kind of agent in a composition or in a dosage form that can prevent or reduce the physical and/or chemical degradation of the active substances. Typically preservatives according to the invention are benzalkonium chloride, benzyl alcohol, potassium sorbate, sorbic acid, chlorobuthanol, phenoxyethanol, phenylethyl alcohol, chlorocresol, boric acid, phenyl mercuric borate, phenyl mercuric acetate, phenyl mercuric nitrate, methyl paraben, ethyl paraben, propyl paraben, butyl paraben and their salts. In a
particular suitable embodiment of the invention, the preservative is benzalkonium chloride and/or phenylethyl alcohol.
The term "pH-adjusting agent" relates to any suitable inorganic base, inorganic acid, organic base or organic acid, including acids and bases with one or multiple pKa values. The pH of the suspension is adjusted between 4.0 and 7.5 by using a suitable pH-adjusting agent like phosfate buffer, citrate buffer. Suitable buffering agents that can be used are sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, sodium hydroxide, hydroxchloric acid or a mixture thereof. In a particular suitable embodiment of the invention, the pH-adjusting agent is citric acid and/or sodium citrate.
The term "emulsifier" relates to the surface active substances that can decrease the surface tension between the immiscible phases that are usually used in combination. Typically emulsifiers according to the invention are nonionic polyoxyethylene sorbitan fatty acid esters (Polysorbates). In a particular suitable embodiment of the invention, the emulsifier is Polysorbate 80.
The term " suspending agent " relates to any kind of agent that can keep the viscosity of a solution or a composition in form of suspension or a dosage unit at a desired range. The amount of the suspending agent used changes depending on the features of the selected thickener. Typically suspending agents according to the invention are microcrystalline cellulose, carmellose sodium, croscarmellose sodium. In a particular suitable embodiment of the invention, the suspending agent is a mixture of microcrystalline cellulose and carmellose sodium (Avicel®RC/CL).
The term "formulated" is intended to relate to the selection of excipients, carriers, vehicles, solvents, co-solvents, preservatives, colouring agents, flavouring agents and so forth in the preparation of a medicament using said composition.
The term "dosage" relates to the quantity of active drugs administered to a mucosa by means of one delivery operation. In the embodiment, wherein the active drugs are formulated for administration to a nasal mucosa, the term "dosage" relates to the quantity of active drugs administered to one nostril by means of one delivery operation.
The term "dosage unit" relates to a composition administered by means of one or more delivery operation. In the embodiment, wherein the composition is a liquid, "a dosage unit" is the volume of the composition administered by means of one or more delivery operation.
The term "delivery operation" is an operation, which delivers a dosage to a mucosa.
The term "mucosal delivery" relates to delivery of a composition to a mucous membrane, such as the buccal or labial mucosa or the mucosa of the respiratory tract, such as the nasal mucosa.
In the context of this invention, the use of a emulsifier and a suspending agent together with other excipients (e.g. preservative, pH-adjusting agent, etc.) in order to stabilise a suspension comprising Ipratropium and Opxymetazoline are included in the preferred embodiments of the invention.
Preferred embodiments of the invention comprise Ipratropium bromide and Oxymetazoline hydrochloride.
A suspension composition formulated for mucosal delivery comprises;
a) Ipratropium or a salt thereof;
b) Oxymetazoline or a salt thereof; and
c) At least one of the humectant, preservative, pH-adjusting agent, emulsifier and suspending agent
Suspension comprises as active ingredient, 0.05 mg/ml to 5 mg/ml Ipratropium bromide and 0.05 mg/ml to 5 mg/ml Oxymetazoline hydrochloride. pH of the solution is between 4.0 to 7.5. A suspension composition comprising a combination of Ipratropium or a salt thereof and Oxymetazoline or a salt thereof is used for the treatment of the symptoms related with common cold and/or of rhinitis. It is applied in cases related to these symptoms such as nasal congestion, sneezing and hypersecretion (rhinorrhea).
The example given below, illustrates the invention without being limited to the compounds and their amounts mentioned.
Example:
Claims
1. A suspension composition formulated for mucosal delivery comprising;
a) Ipratropium or a pharmaceutically acceptable salt thereof,
b) Oxymetazoline hydrochloride or a pharmaceutically acceptable salt thereof, and c) In additions to above mentioned active ingredients, should comprise at least one of humectant, preservative, pH-adjusting agent, emulsifier and suspending agent.
2. The composition according to claim 1 , wherein Ipratropium or a pharmaceutically acceptable salt thereof is selected from the group consisting of Ipratropium bromide, Ipratropium chloride, Ipratropium iodide, Ipratropium fluoride, and Ipratropium hydroxide.
3. Ipratropium salt selected according to preceding claim is Ipratropium bromide.
4. The composition according to claim 1 , wherein Oxymetazoline or a pharmaceutically acceptable salt thereof is selected from the group consisting of Oxymetazoline hydrochloride, Oxymetazoline hydrobromide, Oxymetazoline hydroiodide, Oxymetazoline hydrofluoride, Oxymetazoline sulphate, Oxymetazoline nitrate, Oxymetazoline formate, Oxymetazoline acetate, Oxymetazoline citrate, Oxymetazoline tartrate, and Oxymetazoline fumarate
5. Oxymetazoline salt selected according to preceding claim is Oxymetazoline hydrochloride.
6. The composition according to any one of the preceding claims formulated in the form of an aqueous solution comprises as active substance 0.05 mg/ml to 5 mg/ml Ipratropium bromide and 0.05 mg/ml to 5 mg/ml Oxymetazoline hydrochloride.
7. The composition according to claim 1 , wherin the humectant is selected from the group consisting of glycerol, sorbitol, propylene glycol, polyethylene glycols, triacetin, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and poloxamer.
8. The humectant selected according to preceding claim is glycerol.
9. The composition according to claim 1 , wherin the preservative is selected from the group consisting of benzalkonium chloride, benzyl alcohol, potassium sorbate, sorbic acid, chlorobuthanol, phenoxyethanol, phenylethyl alcohol, chlorocresol, boric acid, phenyl mercuric borate, phenyl mercuric acetate, phenyl mercuric nitrate, methyl paraben, ethyl paraben, propyl paraben, butyl paraben and their salts.
10. The preservative selected according to preceding claim is benzalkonium chloride an/or phenylethyl alcohol.
11. The composition according to claim 1 , wherin the pH-adjusting agent is selected from the group consisting of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, sodium hydroxide, hydroxchloric acid or a mixture thereof.
12. The pH-adjusting agent selected according to preceding claim is citric acid and/or sodium citrate.
13. The composition according to claim 1 , wherin the emulsifier is selected from the group consisting of polyoxyethylene sorbitan fatty acid esters (Polysorbates) or a mixture thereof.
14. The emulsifier selected according to preceding claim is Polysorbate 80.
15. The composition according to claim 1 , wherin the suspending agent is selected from the group consisting of microcrystalline cellulose, carmellose sodium, croscarmellose sodium or a mixture thereof.
16. The suspending agent selected according to preceding claim is a mixture of microcrystalline cellulose and carmellose sodium.
17. The composition according to any one of the preceding claims comprises,
a) Ipratropium bromide,
b) Oxymetazoline hydrochloride,
c) Glycerol as humectant, benzalkonium chloride and/or phenylethyl alcohol as preservative, citric acir and/or sodium citrate as pH-adjusting agent, polysorbate 80 as emulsifier and a mixture of microcrystalline cellulose and carmellose sodium as suspending agent.
18. The composition according to any one of the preceding claims, has a pH in the range from 4.0 to 7.5.
19. The composition according to any one of the preceding claims, is applied to nasal mucosa.
20. The composition according to any one of the preceding claims, is used for the treatment of conditions selected from the group consisting of symptoms associated with the common cold and symptoms associated with rhinitis in human.
21. The use according to preceding claim, wherein the conditions are nasal congestion, sneezing and hypersecretion (rhinorrea).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201303841 | 2013-03-29 | ||
| TR2013/03841 | 2013-03-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2014158118A1 true WO2014158118A1 (en) | 2014-10-02 |
Family
ID=51168326
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2014/000100 WO2014158118A1 (en) | 2013-03-29 | 2014-03-27 | Suspension composition containing ipratropium and oxymetazoline |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2014158118A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015054359A1 (en) * | 2013-10-08 | 2015-04-16 | Ebadi Mark A | Methods and compositions for symptomatic reflief of the common cold |
| EP3569221A1 (en) * | 2018-05-17 | 2019-11-20 | Notoxins IP B.V. | Aqueous formulations comprising ipratropium for topical treatment of hyperhidrosis |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1117588B (en) | 1960-09-30 | 1961-11-23 | Merck Ag E | Process for the preparation of a new imidazoline derivative |
| US3505337A (en) | 1967-12-22 | 1970-04-07 | Boehringer Sohn Ingelheim | N - hydrocarbyl-substituted noratropinium,haloalkylates and o-acyl derivatives thereof |
| WO1999038492A1 (en) * | 1998-01-30 | 1999-08-05 | Novartis Consumer Health S.A. | Nasal solutions |
| US20040053902A1 (en) * | 2002-09-13 | 2004-03-18 | Smith C. Steven | Novel composition and method for treatment of upper respiratory conditions |
| US20040248924A1 (en) * | 2001-09-18 | 2004-12-09 | Moesgaard Hanne Anette | Compositions for treatment of common cold |
-
2014
- 2014-03-27 WO PCT/TR2014/000100 patent/WO2014158118A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1117588B (en) | 1960-09-30 | 1961-11-23 | Merck Ag E | Process for the preparation of a new imidazoline derivative |
| US3505337A (en) | 1967-12-22 | 1970-04-07 | Boehringer Sohn Ingelheim | N - hydrocarbyl-substituted noratropinium,haloalkylates and o-acyl derivatives thereof |
| WO1999038492A1 (en) * | 1998-01-30 | 1999-08-05 | Novartis Consumer Health S.A. | Nasal solutions |
| US20040248924A1 (en) * | 2001-09-18 | 2004-12-09 | Moesgaard Hanne Anette | Compositions for treatment of common cold |
| US20040053902A1 (en) * | 2002-09-13 | 2004-03-18 | Smith C. Steven | Novel composition and method for treatment of upper respiratory conditions |
Non-Patent Citations (1)
| Title |
|---|
| PITKARANTA ET AL., AM J RHINOL., vol. 12, no. 2, March 1998 (1998-03-01), pages 125 - 9 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015054359A1 (en) * | 2013-10-08 | 2015-04-16 | Ebadi Mark A | Methods and compositions for symptomatic reflief of the common cold |
| EP3569221A1 (en) * | 2018-05-17 | 2019-11-20 | Notoxins IP B.V. | Aqueous formulations comprising ipratropium for topical treatment of hyperhidrosis |
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