WO2014092346A1 - Bitter taste masked pharmaceutical formulation comprising corticosteroid, antihistamine and stevia - Google Patents
Bitter taste masked pharmaceutical formulation comprising corticosteroid, antihistamine and stevia Download PDFInfo
- Publication number
- WO2014092346A1 WO2014092346A1 PCT/KR2013/010417 KR2013010417W WO2014092346A1 WO 2014092346 A1 WO2014092346 A1 WO 2014092346A1 KR 2013010417 W KR2013010417 W KR 2013010417W WO 2014092346 A1 WO2014092346 A1 WO 2014092346A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- stevia
- pharmaceutical formulation
- formulation
- corticosteroid
- bitter taste
- Prior art date
Links
Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
Definitions
- the present invention relates to a bitter taste masked pharmaceutical formulation comprising corticosteroid or a pharmaceutically acceptable salt thereof; antihistamine selected from the group consisting of olopatadine, azelastine and a pharmaceutically acceptable salt thereof; and stevia.
- an allergen interacts with and cross-links surface IgE antibodies on the surface mast cells and basophil cells. Once the mast cell- antibody-antigen complex is formed, cell-degranulation takes place which causes secretion of histamines from the mast cells or basophil cells, and thereby causing allergic reactions.
- Hpantihistamines are clinically used in the treatment of histamine-mediated allergic conditions, e.g. , allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis, urticaria, angioedema, pruritus (atopic dermatitis), and the like.
- Such antihistamines can be administered topically, through the skin, nose or eyes, or systemically.
- antihistamines often used to treat or relieve the symptoms of seasonal allergic symptoms include azelastine, olopatadine, chlorpheniramine, loratadine and an isomer thereof, fexofenadine, astemizole, terfenadine, diphenhydramine, cetirizine and an isomer thereof, pseudoephedrine and the like.
- azelastine Astepro ® , MEDA Pharm.
- olopatadine Panase ® , Alcon
- the like examples that are currently available in the market as nasal inhalers include azelastine (Astepro ® , MEDA Pharm.), olopatadine (Patanase ® , Alcon), and the like.
- Corticosteroids are a class of chemicals that is closely related with Cortisol, which is naturally produced in the adrenal cortex.
- Examples of corticosteroids include betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, deltasone, triamcinolone, mometasone, fluticasone and the like.
- Corticosteroids act to block the production of substances that cause allergic reactions and inflammatory responses such as prostaglandins; however, they also cause undesirable side effects such as an increased sensitivity to infections because they interrupt leukocytes, which act as a part of the immune system by destroying foreign bodies.
- Corticosteroids may be used in combination with other drugs, and prescribed for short-term or long-term use. In the case where corticosteroids are absorbed systemically for a long period of time, it may cause undesirable side effects such as increased appetite and weight gain; fat deposits in chest, face and the like; a build-up of water or salt in the body which may be developed into edema or dropsy; hypertension; diabetes; osteoporosis; cataracts; etc. Thus, corticosteroids may be used in the form of nasal spray and drop for the treatment of nasal diseases and, similarly, in the form of inhaler for the treatment of trachea- bronchial diseases to prevent corticosteroids from being absorbed systemically in the body. Examples of corticosteroids in the form of nasal spray available in the market include mometasone, fluticasone, budesonide, etc.
- a synergistic effect can be expected when a combination of antihistamine and corticosteroids are applied via nasal cavity.
- Mometasone is a long-acting corticosteroid used to treat allergic rhinitis which alleviates symptoms of rhinitis in patients; whereas azelastine is a rapid-acting which alleviates the symptoms immediately.
- the combination formulation of these two drugs is an effective medication for the treatment of allergic rhinitis having both long-acting and rapid-acting characteristics.
- Stevia rebaudiana is an herbaceous perennial in the Chrysanthemum family that is native to Paraguay in South America; its sweet ingredients, whose main ingredient is steviol glycoside, are mostly found in the leaves. Steviol glycoside is about 200 to 300 times sweeter than sucrose and known to contain almost no calories.
- the present inventors have discovered a combination nasal spray for nasal administration having improved taste and patient compliance by using a certain amount of stevia as a sweetener, and thus accomplished the present invention.
- a bitter taste masked pharmaceutical formulation comprising corticosteroid, an antihistamine and stevia.
- a bitter taste masked pharmaceutical formulation comprising:
- an antihistamine selected from the group consisting of olopatadine, azelastine and a pharmaceutically acceptable salt thereof;
- the inventive pharmaceutical formulation comprises stevia as a sweetener, which can effectively block the bitter taste of azelastine and olopatadine, and also provide good nasal sensation when administered via intranasal route, and thus can be effectively used as a pharmaceutical formulation for nasal delivery in the treatment of allergic rhinitis.
- the present invention provides a bitter taste masked pharmaceutical formulation comprising: (i) corticosteroid or a pharmaceutically acceptable salt thereof; (ii) an antihistamine selected from the group consisting of olopatadine, azelastine and a pharmaceutically acceptable salt thereof; and (iii) stevia.
- the corticosteroid or a pharmaceutically acceptable salt thereof may be mometasone, fluticasone, budesonide, or a pharmaceutically acceptable salt or free base thereof, preferably mometasone or a pharmaceutically acceptable salt thereof.
- the corticosteroid may be comprised in an amount of 0.01 to 1 weight%, based on the total weight of the formulation.
- the antihistamine may be selected from the group consisting of olopatadine, azelastine and a pharmaceutically acceptable salt thereof, and particular examples include olopatadine hydrochloride or azelastine hydrochloride.
- the antihistamine may be comprised in an amount of 0.1 to 20 weight%, preferably 0.1 to 10 weight%, based on the total weight of the formulation.
- any type of stevia known in the art may be used in the present invention, e.g., steviol glycoside, enzymatically modified stevia or a mixture thereof.
- the steviol glycoside is a sweetener, which is prepared by extracting the sweet ingredient of stevia from the plant and subjecting the stevia extract to a distillation process; for example, subjecting Stevia rebaudiana to extraction and purification by using ethanol or purified water as a solvent.
- the enzymatically modified stevia is stevia with improved sweetness whose main ingredient of sweet taste is a-glucosylstevioside, that is obtainable by subjecting Stevia rebaudiana to an enzymatic treatment; preferably, extracting stevia by using ethanol or purified water as a solvent, and subjecting the stevia extract to an enzymatic treatment using an enzyme such as a-glucosyltransferase to obtain a- glucosylstevioside and a-glucosyl rebaudioside A, followed by purifying the products thus obtained.
- an enzyme such as a-glucosyltransferase
- the stevia may be comprised in an amount of 0.1 to 5 weight%, preferably 0.5 to 2.0 weight%, e.g., 1.0 weight%. If the amount of the steviol glycoside and the enzymatically modified stevia is less than 0.1 weight%, it may not give bitter taste masking effects; and when the amount of the enzymatically modified stevia exceeds 5 weight%, it may cause severe irritation in the mucosa membranes of the nasal cavity.
- the pharmaceutical formulation of the present invention may further comprise thaumatin as a sweetener.
- the pharmaceutical formulation in accordance with the present invention may be a liquid formulation, preferably a nasal spray-type liquid formulation.
- the pharmaceutical formulation in accordance with the present invention may comprise pharmaceutically acceptable additives, e.g., carriers or excipients, particularly one or more of pharmaceutically acceptable carriers or excipients useful for preparing a nasal spray formulation.
- pharmaceutically acceptable additives e.g., carriers or excipients, particularly one or more of pharmaceutically acceptable carriers or excipients useful for preparing a nasal spray formulation.
- the pharmaceutical formulation in accordance with the present invention may further comprise, besides the sweetener that masks bitter taste of an antihistamine such as azelastine and olopatadine, a viscosity increasing agent to reduce or prevent the formulation to reach the pharynx via postnasal drip when the formulation is administered to the nasal cavity.
- a viscosity increasing agent may be selected from the group consisting of cellulose derivatives such as microcrystalline cellulose and carboxymethyl cellulose, gums, povidone and a mixture thereof, but not limited thereto.
- the nasal spray-type liquid formulation may comprise a pharmaceutically acceptable carrier or excipient which may be useful for preparing the formulation as a nasal spray- type liquid formulation, e.g., one or more components selected from the group consisting of a solvent, a preservative, a viscosity increasing agent, a pH modifier, an additional sweetening agent, a solubilizing agent and a mixture thereof.
- a pharmaceutically acceptable carrier or excipient which may be useful for preparing the formulation as a nasal spray- type liquid formulation, e.g., one or more components selected from the group consisting of a solvent, a preservative, a viscosity increasing agent, a pH modifier, an additional sweetening agent, a solubilizing agent and a mixture thereof.
- the solvent may be a purified water.
- the preservative may be selected from the group consisting of benzalkonium chloride, potassium sorbate, sodium benzonate and a mixture thereof, but not limited thereto.
- the pH modifier may be selected from the group consisting of citric acid, succinic acid, malic acid, sodium citrate, and a mixture thereof, but not limited thereto.
- the additional sweetening agent may be selected from the group consisting of thaumatin, saccharin, xylitol, aspartame, potassium acesulfame and a mixture thereof, but not limited thereto.
- the solubilizing agent may be polysorbate, glycerin and a mixture thereof, but not limited thereto.
- the pharmaceutical formulation of the present invention comprises stevia as a sweetening agent in an amount of 0.1 to 5 weight%, based on the total weight of the formulation, which can effectively block bitter taste of azelastine and olopatadine, and also provide good nasal sensation when administered via intranasal route, and thus can be effectively used as a pharmaceutical formulation for nasal delivery in the treatment of allergic rhinitis.
- Example 1 Azelastine Hydrochloride Nasal Spray Suspension
- a nasal spray suspension was prepared in accordance with the ingredients described in Table 1.
- a viscosity increasing agent Avicel RC-591 (FMC, USA), and glycerin
- Sterile purified water was placed in a separate container, added with mometasone furoate (Cipla) and polysorbate 80 (Croda), and dispered (Mixture 3). First, Mixture 1 and Mixture 2 prepared above were admixed and stirred, and then Mixture 3 was added thereto, followed by stirring. Sterile purified water was added to the final mixture up to the final volume to obtain the nasal spray suspension.
- Example 2 Azelastine Hydrochloride Nasal Spray Suspension Comprising Mometasone
- a nasal spray suspension was prepared in accordance with the ingredients described in Table 1 by repeating the procedures of Example 1, except for using enzymatically modified stevia (Choheung Corp.) instead of steviol glycoside. [Table 1]
- Example 3 Olopatadine Hydrochloride Nasal Spray Suspension Comprising Mometasone
- a nasal spray suspension was prepared in accordance with the ingredients described in Table 2 by repeating the procedures of Example 1, except for using olopatadine hydrochloride instead of azelastine hydrochloride.
- Example 4 Olopatadine Hydrochloride Nasal Spray Suspension Comprising Mometasone
- a nasal spray suspension was prepared in accordance with the ingredients described in Table 2 by repeating the procedures of Example 2, except for using olopatadine hydrochloride instead of azelastine hydrochloride.
- Example 5 Azelastine Hydrochloride Nasal Spray Suspension Comprising Mometasone A nasal spray suspension was prepared by repeating the procedures of
- Example 1 except for not adding thaumatin.
- a nasal spray suspension was prepared with the ingredients described in Table 3 by repeating the procedures of Example 1 , except for not adding steviol glycoside. Comparative Examples 2 to 4: Azelastine Hydrochloride Nasal
- Nasal spray suspensions were prepared with the ingredients described in Table 3 by repeating the procedures of Example 1 , except for using each of the artificial sweeteners saccharin, xylitol and aspartame, respectively, instead of steviol glycoside.
- a nasal spray suspension was prepared with the ingredients described in Table 3 by repeating the procedures of Example 1 , except for using olopatadine hydrochloride instead of azelastine hydrochloride, and using aspartame instead of stevio glycoside.
- Nasal spray suspensions were prepared by repeating the procedures of Examples 1 and 2 each, except for using 0.05 weight% of steviol glycoside and enzymatically modified stevia in Examples 1 and 2, respectively.
- Example 1 Evaluation of Bitter Taste (Nasal Sensation Test)
- Nasal spray suspensions prepared in Examples 1, 2 and 5, and Comparative Examples 1 to 4, and 6 to 9 were filtered through 100 mesh screen, and packaged in a high density polyethylene container having a Valois pump which was designed to administer 0.1 mL of the suspension composition into the nasal cavity to prepare a pharmaceutical formulation for nasal delivery.
- the pharmaceutical formulations for nasal delivery were administered to 16 test participants, and the degree of bitterness and the duration of bitterness in the mouth were evaluated in combination by measuring them in accordance with the following criteria and averaging the results:
- the degree of bitterness and the duration of bitterness of the inventive pharmaceutical formulation for nasal delivery comprising steviol glycoside or enzymatically modified stevia decreased by about 1/4 and 1/3, respectively, as compared with those of the conventional products not containing sweetener or using conventional artificial sweeteners, and thus showing improved bitter taste masking effects.
- the inventive pharmaceutical formulation for nasal delivery prepared in Example 5 comprising stevia, as its only sweetener, showed similar bitter taste masking effects as that of Example 1.
- the pharmaceutical formulations for nasal delivery prepared in Comparative Examples 6 and 7 comprising stevia in an amount of 0.05 weight%, based on the total weight of the formulation showed the degree of bitterness (4.0) and the duration of bitterness (3.7) similar to those of Comparative Example 1.
- the pharmaceutical formulations for nasal delivery prepared in Comparative Examples 8 and 9 comprising stevia in an amount of 10 weight%, based on the total weight of the formulation were administered to the test participants, all the participants complained of irritation in the nasal mucous membrane, and thus it was concluded that the pharmaceutical formulations prepared in Comparative Examples 8 and 9 were not appropriate for use.
- Test Example 1 The test methods of Test Example 1 were used to compare bitter taste masking effects of the pharmaceutical formulations for nasal delivery prepared in Examples 3 and 4, and Comparative Example 5. The results are shown in Table 5 below.
- the degree of bitterness and the duration of bitterness measured for the inventive pharmaceutical formulation for nasal delivery comprising steviol glycoside or enzymatically modified stevia, as its sweetener, were reduced by 1/3 as compared with the pharmaceutical formulation containing the conventional artificial sweetener, indicating that they have improved bitter taste masking effects.
- the use of steviol glycoside or enzymatically modified stevia, as its sweetener allows improved bitter taste masking effects as compared with the use of conventional artificial sweeteners, thereby enhancing patient compliance; therefore, it can be effectively used in the treatment of allergic rhinitis.
Abstract
The present invention relates to a bitter taste masked pharmaceutical formulation comprising: (i) corticosteroid or a pharmaceutically acceptable salt thereof; (ii) an antihistamine selected from the group consisting of olopatadine, azelastine and a pharmaceutically acceptable salt thereof; and (iii) stevia. The pharmaceutical formulation according to the present invention effectively blocks bitter taste of the active ingredients, thereby having improved taste and patient compliance, and thus can be efficiently used in the treatment of allergic rhinitis.
Description
DESCRIPTION
BITTER TASTE MASKED PHARMACEUTICAL FORMULATION COMPRISING CORTICOSTEROID, ANTIHISTAMINE AND
STEVIA
FIELD OF THE INVENTION The present invention relates to a bitter taste masked pharmaceutical formulation comprising corticosteroid or a pharmaceutically acceptable salt thereof; antihistamine selected from the group consisting of olopatadine, azelastine and a pharmaceutically acceptable salt thereof; and stevia. BACKGROUND OF THE INVENTION
In allergic rhinitis, an allergen interacts with and cross-links surface IgE antibodies on the surface mast cells and basophil cells. Once the mast cell- antibody-antigen complex is formed, cell-degranulation takes place which causes secretion of histamines from the mast cells or basophil cells, and thereby causing allergic reactions.
Histamine, acting on Hrreceptors, triggers pruritus, vasodilation, hypotension, flushing, headache, tachycardia, bronchoconstriction, increase in vascular permeability and potentiation of pain. Accordingly, Hpantihistamines are clinically used in the treatment of histamine-mediated allergic conditions, e.g. , allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis, urticaria, angioedema, pruritus (atopic dermatitis), and the like. Such antihistamines can be administered topically, through the skin, nose or eyes, or systemically.
Examples of antihistamines often used to treat or relieve the symptoms of seasonal allergic symptoms include azelastine, olopatadine, chlorpheniramine, loratadine and an isomer thereof, fexofenadine, astemizole, terfenadine, diphenhydramine, cetirizine and an isomer thereof, pseudoephedrine and the like. Among them, particular examples that are currently available in the market as nasal inhalers include azelastine (Astepro®, MEDA Pharm.), olopatadine (Patanase®, Alcon), and the like.
Corticosteroids are a class of chemicals that is closely related with Cortisol, which is naturally produced in the adrenal cortex. Examples of corticosteroids include betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, deltasone, triamcinolone, mometasone, fluticasone and the like.
Corticosteroids act to block the production of substances that cause allergic reactions and inflammatory responses such as prostaglandins; however, they also cause undesirable side effects such as an increased sensitivity to infections because they interrupt leukocytes, which act as a part of the immune system by destroying foreign bodies.
Corticosteroids may be used in combination with other drugs, and prescribed for short-term or long-term use. In the case where corticosteroids are absorbed systemically for a long period of time, it may cause undesirable side effects such as increased appetite and weight gain; fat deposits in chest, face and the like; a build-up of water or salt in the body which may be developed into edema or dropsy; hypertension; diabetes; osteoporosis; cataracts; etc. Thus, corticosteroids may be used in the form of nasal spray and drop for the treatment of nasal diseases and, similarly, in the form of inhaler for the treatment of trachea- bronchial diseases to prevent corticosteroids from being absorbed systemically in the body. Examples of corticosteroids in the form of nasal spray available in the market include mometasone, fluticasone, budesonide, etc.
In the treatment of seasonal allergic rhinitis, a synergistic effect can be expected when a combination of antihistamine and corticosteroids are applied via nasal cavity. Mometasone is a long-acting corticosteroid used to treat allergic rhinitis which alleviates symptoms of rhinitis in patients; whereas azelastine is a rapid-acting which alleviates the symptoms immediately. Thus, the combination formulation of these two drugs is an effective medication for the treatment of allergic rhinitis having both long-acting and rapid-acting characteristics.
In the development of a combined formulation, however, it is difficult to prepare a formulation using azelastine and a pharmaceutically acceptable salt thereof because of its bitter taste which makes patients hard to take it. When a patient takes the formulation via inhalation by using a nasal spray, the formulation passes through the pharynx, and thereby causing unpleasant taste and irritation.
Meda AB, the pharmaceutical company who developed the Azelastine nasal spray, have disclosed a taste masked pharmaceutical composition using sucralose to improve the bitter taste of azelastine (Korean Laid-Open Patent No. 2007- 0104884). Nevertheless, Astepro 0.15% (Azelastine HC1), the nasal spray developed by using the above composition still caused displeasing bitter taste of azelastine.
Meanwhile, Stevia rebaudiana is an herbaceous perennial in the Chrysanthemum family that is native to Paraguay in South America; its sweet ingredients, whose main ingredient is steviol glycoside, are mostly found in the leaves. Steviol glycoside is about 200 to 300 times sweeter than sucrose and known to contain almost no calories.
Accordingly, the present inventors have discovered a combination nasal spray for nasal administration having improved taste and patient compliance by using a certain amount of stevia as a sweetener, and thus accomplished the present invention.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a bitter taste masked pharmaceutical formulation comprising corticosteroid, an antihistamine and stevia.
In accordance with one object of the present invention, there is provided a bitter taste masked pharmaceutical formulation comprising:
(i) corticosteroid or a pharmaceutically acceptable salt thereof;
(ii) an antihistamine selected from the group consisting of olopatadine, azelastine and a pharmaceutically acceptable salt thereof; and
(iii) stevia (Stevia rebaudiana).
The inventive pharmaceutical formulation comprises stevia as a sweetener, which can effectively block the bitter taste of azelastine and olopatadine, and also provide good nasal sensation when administered via intranasal route, and thus can be effectively used as a pharmaceutical formulation for nasal delivery in the treatment of allergic rhinitis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a bitter taste masked pharmaceutical formulation comprising: (i) corticosteroid or a pharmaceutically acceptable salt thereof; (ii) an antihistamine selected from the group consisting of olopatadine, azelastine and a pharmaceutically acceptable salt thereof; and (iii) stevia.
In the present invention, the corticosteroid or a pharmaceutically acceptable salt thereof may be mometasone, fluticasone, budesonide, or a pharmaceutically acceptable salt or free base thereof, preferably mometasone or a pharmaceutically acceptable salt thereof.
The corticosteroid may be comprised in an amount of 0.01 to 1 weight%, based on the total weight of the formulation.
In the present invention, the antihistamine may be selected from the group consisting of olopatadine, azelastine and a pharmaceutically acceptable salt thereof, and particular examples include olopatadine hydrochloride or azelastine hydrochloride.
The antihistamine may be comprised in an amount of 0.1 to 20 weight%, preferably 0.1 to 10 weight%, based on the total weight of the formulation.
Additionally, any type of stevia known in the art may be used in the present invention, e.g., steviol glycoside, enzymatically modified stevia or a mixture thereof. The steviol glycoside is a sweetener, which is prepared by extracting the sweet ingredient of stevia from the plant and subjecting the stevia extract to a distillation process; for example, subjecting Stevia rebaudiana to extraction and purification by using ethanol or purified water as a solvent. Also, the enzymatically modified stevia is stevia with improved sweetness whose main ingredient of sweet taste is a-glucosylstevioside, that is obtainable by subjecting Stevia rebaudiana to an enzymatic treatment; preferably, extracting stevia by using ethanol or purified water as a solvent, and subjecting the stevia extract to an enzymatic treatment using an enzyme such as a-glucosyltransferase to obtain a- glucosylstevioside and a-glucosyl rebaudioside A, followed by purifying the products thus obtained.
The stevia may be comprised in an amount of 0.1 to 5 weight%, preferably 0.5 to 2.0 weight%, e.g., 1.0 weight%. If the amount of the steviol glycoside and the enzymatically modified stevia is less than 0.1 weight%, it may not give bitter taste masking effects; and when the amount of the enzymatically modified stevia
exceeds 5 weight%, it may cause severe irritation in the mucosa membranes of the nasal cavity.
Moreover, the pharmaceutical formulation of the present invention may further comprise thaumatin as a sweetener.
The pharmaceutical formulation in accordance with the present invention may be a liquid formulation, preferably a nasal spray-type liquid formulation.
The pharmaceutical formulation in accordance with the present invention may comprise pharmaceutically acceptable additives, e.g., carriers or excipients, particularly one or more of pharmaceutically acceptable carriers or excipients useful for preparing a nasal spray formulation.
Further, the pharmaceutical formulation in accordance with the present invention may further comprise, besides the sweetener that masks bitter taste of an antihistamine such as azelastine and olopatadine, a viscosity increasing agent to reduce or prevent the formulation to reach the pharynx via postnasal drip when the formulation is administered to the nasal cavity. Examples of the viscosity increasing agent may be selected from the group consisting of cellulose derivatives such as microcrystalline cellulose and carboxymethyl cellulose, gums, povidone and a mixture thereof, but not limited thereto.
In accordance with one embodiment of the present invention, the nasal spray-type liquid formulation may comprise a pharmaceutically acceptable carrier or excipient which may be useful for preparing the formulation as a nasal spray- type liquid formulation, e.g., one or more components selected from the group consisting of a solvent, a preservative, a viscosity increasing agent, a pH modifier, an additional sweetening agent, a solubilizing agent and a mixture thereof.
The solvent may be a purified water.
The preservative may be selected from the group consisting of benzalkonium chloride, potassium sorbate, sodium benzonate and a mixture thereof, but not limited thereto.
The pH modifier may be selected from the group consisting of citric acid, succinic acid, malic acid, sodium citrate, and a mixture thereof, but not limited thereto.
The additional sweetening agent may be selected from the group consisting of thaumatin, saccharin, xylitol, aspartame, potassium acesulfame and a mixture thereof, but not limited thereto.
The solubilizing agent may be polysorbate, glycerin and a mixture thereof,
but not limited thereto.
The pharmaceutical formulation of the present invention comprises stevia as a sweetening agent in an amount of 0.1 to 5 weight%, based on the total weight of the formulation, which can effectively block bitter taste of azelastine and olopatadine, and also provide good nasal sensation when administered via intranasal route, and thus can be effectively used as a pharmaceutical formulation for nasal delivery in the treatment of allergic rhinitis.
EXAMPLES
Hereinafter, the present invention is described more specifically by the following Examples. However, these are provided only for illustration purposes, and are not intended to limit the scope of the present invention. Example 1: Azelastine Hydrochloride Nasal Spray Suspension
Comprising Mometasone
A nasal spray suspension was prepared in accordance with the ingredients described in Table 1.
A viscosity increasing agent, Avicel RC-591 (FMC, USA), and glycerin
(Seojin Chemical) were added to sterile purified water and dispersed (Mixture 1). Sterile purified water was poured in a separate container, added with azelastine hydrochloride (Aarti), benzalkonium chloride (Dolder AG), citric acid hydrate (DSM), sodium citrate hydrate (Jungbunzlauer GMBH), disodium edetate hydrate (Ridel-de Haen), D-sorbitol (Roquette), taumatin (Natex) and steviol glycoside (Choheung Corp.), and stirred to dissolve the ingredients (Mixture 2). Sterile purified water was placed in a separate container, added with mometasone furoate (Cipla) and polysorbate 80 (Croda), and dispered (Mixture 3). First, Mixture 1 and Mixture 2 prepared above were admixed and stirred, and then Mixture 3 was added thereto, followed by stirring. Sterile purified water was added to the final mixture up to the final volume to obtain the nasal spray suspension.
Example 2: Azelastine Hydrochloride Nasal Spray Suspension Comprising Mometasone
A nasal spray suspension was prepared in accordance with the ingredients described in Table 1 by repeating the procedures of Example 1, except for using enzymatically modified stevia (Choheung Corp.) instead of steviol glycoside. [Table 1]
Example 3: Olopatadine Hydrochloride Nasal Spray Suspension Comprising Mometasone A nasal spray suspension was prepared in accordance with the ingredients described in Table 2 by repeating the procedures of Example 1, except for using olopatadine hydrochloride instead of azelastine hydrochloride.
Example 4: Olopatadine Hydrochloride Nasal Spray Suspension Comprising Mometasone
A nasal spray suspension was prepared in accordance with the ingredients described in Table 2 by repeating the procedures of Example 2, except for using olopatadine hydrochloride instead of azelastine hydrochloride.
[Table 2]
Ingredient (w/v%) Example 3 Example 4
Mometasone furoate 0.05 0.05
Olopatadine hydrochloride 6.65 6.65
Avicel RC-591 2.0 2.0
Glycerin 2.1 2.1
Disodium edetate hydrate 0.1 0.1
Citric acid hydrate 0.2 0.2
Sodium citrate hydrate 0.28 0.28
Polysorbate 80 0.01 0.01
Benzalkonium chloride 0.02 0.02
D-sorbitol 6.6 6.6
Thaumatin 0.25 0.25
Steviol glycoside 1.0 -
Enzymatically modified stevia - 1.0
Distilled water Residual quantity Residual quantity
Example 5: Azelastine Hydrochloride Nasal Spray Suspension Comprising Mometasone A nasal spray suspension was prepared by repeating the procedures of
Example 1, except for not adding thaumatin.
Comparative Example 1: Azelastine Hydrochloride Nasal Spray Suspension Comprising Mometasone
A nasal spray suspension was prepared with the ingredients described in Table 3 by repeating the procedures of Example 1 , except for not adding steviol glycoside. Comparative Examples 2 to 4: Azelastine Hydrochloride Nasal
Spray Suspensions Comprising Mometasone
Nasal spray suspensions were prepared with the ingredients described in Table 3 by repeating the procedures of Example 1 , except for using each of the artificial sweeteners saccharin, xylitol and aspartame, respectively, instead of steviol glycoside.
Comparative Example 5: Azelastine Hydrochloride Nasal Spray Suspension Comprising Mometasone
A nasal spray suspension was prepared with the ingredients described in Table 3 by repeating the procedures of Example 1 , except for using olopatadine hydrochloride instead of azelastine hydrochloride, and using aspartame instead of
stevio glycoside.
[Table 3]
Spray Suspensions Comprising Mometasone
Nasal spray suspensions were prepared by repeating the procedures of Examples 1 and 2 each, except for using 0.05 weight% of steviol glycoside and enzymatically modified stevia in Examples 1 and 2, respectively.
Comparative Examples 8 and 9: Azelastine Hydrochloride Nasal Spray Suspensions Comprising Mometasone Nasal spray suspensions were prepared by repeating the procedures of
Examples 1 and 2 each, except for using 10 weight% of steviol glycoside and enzymatically modified stevia in Examples 1 and 2, respectively.
Test Example 1: Evaluation of Bitter Taste (Nasal Sensation Test)
Nasal spray suspensions prepared in Examples 1, 2 and 5, and Comparative Examples 1 to 4, and 6 to 9 were filtered through 100 mesh screen, and packaged in a high density polyethylene container having a Valois pump which was designed to administer 0.1 mL of the suspension composition into the nasal cavity to prepare a pharmaceutical formulation for nasal delivery.
In order to conduct the sensory evaluation test for comparing bitter taste masking effects of different kinds of sweeteners, the pharmaceutical formulations for nasal delivery were administered to 16 test participants, and the degree of bitterness and the duration of bitterness in the mouth were evaluated in combination by measuring them in accordance with the following criteria and averaging the results:
- Degree of bitterness -
1 : almost no bitterness
2: somewhat bitter
3: bitter
4: strongly bitter
5: too bitter to be used
- Duration of bitterness -
1 : substantially no duration
2: lasted less than 10 seconds
3: lasted less than 60 seconds
4: lasted less than 5 minutes
5: lasted more than 1 hour.
The results are shown in Table 4 below. [Table 4]
Duration of bitterness
Degree of bitterness
in the mouth
Example 1 1.1 1.2
Example 2 1.1 1.3
Example 5 1.2 1.2
Comparative Example 1 4.1 3.6
Comparative Example 2 4.3 3.3
Comparative Example 3 4.5 3.8
Comparative Example 4 - 4.0 3.8
Comparative Example 6 4.0 3.7
Comparative Example 7 4.0 3.7
As shown in Table 4 above, the degree of bitterness and the duration of bitterness of the inventive pharmaceutical formulation for nasal delivery comprising steviol glycoside or enzymatically modified stevia decreased by about 1/4 and 1/3, respectively, as compared with those of the conventional products not containing sweetener or using conventional artificial sweeteners, and thus showing improved bitter taste masking effects. Also, the inventive pharmaceutical formulation for nasal delivery prepared in Example 5 comprising stevia, as its only sweetener, showed similar bitter taste masking effects as that of Example 1.
Meanwhile, the pharmaceutical formulations for nasal delivery prepared in Comparative Examples 6 and 7 comprising stevia in an amount of 0.05 weight%, based on the total weight of the formulation, showed the degree of bitterness (4.0) and the duration of bitterness (3.7) similar to those of Comparative Example 1. When the pharmaceutical formulations for nasal delivery prepared in Comparative Examples 8 and 9 comprising stevia in an amount of 10 weight%, based on the total weight of the formulation, were administered to the test participants, all the participants complained of irritation in the nasal mucous membrane, and thus it was concluded that the pharmaceutical formulations prepared in Comparative Examples 8 and 9 were not appropriate for use.
Test Example 2: Evaluation of Bitter Taste (Nasal Sensation Test)
The test methods of Test Example 1 were used to compare bitter taste masking effects of the pharmaceutical formulations for nasal delivery prepared in Examples 3 and 4, and Comparative Example 5. The results are shown in Table 5 below.
[Table 5]
Degree of bitterness Duration of bitterness
Example 3 1.1 1.2
Example 4 1.2 1.4
Comparative Example
As shown in Table 5 above, the degree of bitterness and the duration of bitterness measured for the inventive pharmaceutical formulation for nasal delivery comprising steviol glycoside or enzymatically modified stevia, as its sweetener, were reduced by 1/3 as compared with the pharmaceutical formulation containing the conventional artificial sweetener, indicating that they have improved bitter taste masking effects.
Thus, in the preparation of nasal spray-type formulation comprising mometasone, and azelastine or olopatadine, the use of steviol glycoside or enzymatically modified stevia, as its sweetener, allows improved bitter taste masking effects as compared with the use of conventional artificial sweeteners, thereby enhancing patient compliance; therefore, it can be effectively used in the treatment of allergic rhinitis.
Claims
1. A bitter taste masked pharmaceutical formulation comprising:
(i) corticosteroid or a pharmaceutically acceptable salt thereof;
(ii) an antihistamine selected from the group consisting of olopatadine, azelastine and a pharmaceutically acceptable salt thereof; and
(iii) stevia.
2. The pharmaceutical formulation of claim 1, wherein the corticosteroid is mometasone, fluticasone, budesonide, or a pharmaceutically acceptable salt or free base thereof.
3. The pharmaceutical formulation of claim 1, wherein the corticosteroid is mometasone.
4. The pharmaceutical formulation of claim 1, wherein the corticosteroid is comprised in an amount of 0.01 to 1 weight%, based on the total weight of the formulation.
5. The pharmaceutical formulation of claim 1, wherein the antihistamine is comprised in an amount of 0.1 to 20 weight%, based on the total weight of the formulation.
6. The pharmaceutical formulation of claim 1, wherein the stevia is steviol glycoside, enzymatically modified stevia or a mixture thereof.
7. The pharmaceutical formulation of claim 6, wherein the enzymatically modified stevia is prepared by subjecting a stevia extract to an enzymatic treatment using an a-glucosyltransferase to obtain a-glucosylstevioside and a- glucosyl rebaudioside A, followed by purification.
8. The pharmaceutical formulation of claim 1, wherein the stevia is comprised in an amount of 0.1 to 5 weight%, based on the total weight of the formulation.
9. The pharmaceutical formulation of claim 1, wherein the formulation is a liquid formulation.
10. The pharmaceutical formulation of claim 9, wherein the liquid formulation is a nasal spray-type liquid formulation.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020120144524A KR20140081925A (en) | 2012-12-12 | 2012-12-12 | Taste masked pharmaceutical formulation comprising corticosteroid, antihistamine and stevia |
KR10-2012-0144524 | 2012-12-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014092346A1 true WO2014092346A1 (en) | 2014-06-19 |
Family
ID=50934585
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2013/010417 WO2014092346A1 (en) | 2012-12-12 | 2013-11-15 | Bitter taste masked pharmaceutical formulation comprising corticosteroid, antihistamine and stevia |
Country Status (2)
Country | Link |
---|---|
KR (1) | KR20140081925A (en) |
WO (1) | WO2014092346A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015036902A1 (en) | 2013-09-13 | 2015-03-19 | Glenmark Pharmaceuticals Ltd | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
WO2015049665A1 (en) * | 2013-10-04 | 2015-04-09 | Glenmark Pharmaceuticals Limited | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
US9370483B2 (en) | 2013-09-13 | 2016-06-21 | Glenmark Specialty S.A. | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
US9919050B2 (en) | 2004-11-24 | 2018-03-20 | Meda Pharmaceuticals Inc. | Compositions comprising azelastine |
US9937189B2 (en) | 2013-09-13 | 2018-04-10 | Glenmark Specialty S.A. | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
US10016443B2 (en) | 2013-10-04 | 2018-07-10 | Glenmark Specialty S.A. | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
US10064817B2 (en) | 2004-11-24 | 2018-09-04 | Meda Pharmaceuticals Inc. | Compositions comprising azelastine and methods of use thereof |
US10548907B2 (en) | 2013-10-04 | 2020-02-04 | Glenmark Specialty S.A. | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
US10653661B2 (en) | 2013-10-04 | 2020-05-19 | Glenmark Specialty S.A. | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
US10758550B2 (en) | 2013-10-04 | 2020-09-01 | Glenmark Specialty S.A. | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
US11679210B2 (en) | 2014-10-03 | 2023-06-20 | Glenmark Specialty S.A. | Dispensing device and pharmaceutical composition for the treatment of rhinitis |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050118273A1 (en) * | 2001-11-15 | 2005-06-02 | Yasushi Sasaki | Microcapsules and oral composition containing the same |
US20060025391A1 (en) * | 2002-06-14 | 2006-02-02 | Amar Lulla | Combination of azelastine and steroids |
US20060216353A1 (en) * | 2005-03-23 | 2006-09-28 | Elan Pharma International Limited | Nanoparticulate corticosteroid and antihistamine formulations |
US20070020330A1 (en) * | 2004-11-24 | 2007-01-25 | Medpointe Healthcare Inc. | Compositions comprising azelastine and methods of use thereof |
US20110189311A1 (en) * | 2009-09-02 | 2011-08-04 | Toyo Sugar Refining Co., Ltd. | Highly Absorbable Drug Composition and Method of Producing the Same |
-
2012
- 2012-12-12 KR KR1020120144524A patent/KR20140081925A/en not_active Application Discontinuation
-
2013
- 2013-11-15 WO PCT/KR2013/010417 patent/WO2014092346A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050118273A1 (en) * | 2001-11-15 | 2005-06-02 | Yasushi Sasaki | Microcapsules and oral composition containing the same |
US20060025391A1 (en) * | 2002-06-14 | 2006-02-02 | Amar Lulla | Combination of azelastine and steroids |
US20070020330A1 (en) * | 2004-11-24 | 2007-01-25 | Medpointe Healthcare Inc. | Compositions comprising azelastine and methods of use thereof |
US20060216353A1 (en) * | 2005-03-23 | 2006-09-28 | Elan Pharma International Limited | Nanoparticulate corticosteroid and antihistamine formulations |
US20110189311A1 (en) * | 2009-09-02 | 2011-08-04 | Toyo Sugar Refining Co., Ltd. | Highly Absorbable Drug Composition and Method of Producing the Same |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9919050B2 (en) | 2004-11-24 | 2018-03-20 | Meda Pharmaceuticals Inc. | Compositions comprising azelastine |
US10064817B2 (en) | 2004-11-24 | 2018-09-04 | Meda Pharmaceuticals Inc. | Compositions comprising azelastine and methods of use thereof |
US10376526B2 (en) | 2013-09-13 | 2019-08-13 | Glenmark Specialty S.A. | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
EP3718533A1 (en) | 2013-09-13 | 2020-10-07 | Glenmark Specialty S.A. | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
US9750754B2 (en) | 2013-09-13 | 2017-09-05 | Glenmark Specialty S.A. | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
US9078923B2 (en) | 2013-09-13 | 2015-07-14 | Glenmark Pharmaceuticals Limited | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
US9937189B2 (en) | 2013-09-13 | 2018-04-10 | Glenmark Specialty S.A. | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
EP3043773B1 (en) | 2013-09-13 | 2021-06-30 | Glenmark Specialty S.A. | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine for nasal administration |
US9370483B2 (en) | 2013-09-13 | 2016-06-21 | Glenmark Specialty S.A. | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
RU2687551C2 (en) * | 2013-09-13 | 2019-05-15 | Гленмарк Спешиалити С.А. | Stable pharmaceutical composition with fixed dose, containing mometasone and olopatadine |
WO2015036902A1 (en) | 2013-09-13 | 2015-03-19 | Glenmark Pharmaceuticals Ltd | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
US10517880B2 (en) | 2013-09-13 | 2019-12-31 | Glenmark Specialty S.A. | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
US10765686B2 (en) | 2013-09-13 | 2020-09-08 | Glenmark Specialty S.A. | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
US10561672B2 (en) | 2013-09-13 | 2020-02-18 | Glenmark Specialty S.A. | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine |
US10646500B2 (en) | 2013-10-04 | 2020-05-12 | Glenmark Specialty S.A. | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
US10653661B2 (en) | 2013-10-04 | 2020-05-19 | Glenmark Specialty S.A. | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
US10758550B2 (en) | 2013-10-04 | 2020-09-01 | Glenmark Specialty S.A. | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
US10548907B2 (en) | 2013-10-04 | 2020-02-04 | Glenmark Specialty S.A. | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
WO2015049665A1 (en) * | 2013-10-04 | 2015-04-09 | Glenmark Pharmaceuticals Limited | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
US10016443B2 (en) | 2013-10-04 | 2018-07-10 | Glenmark Specialty S.A. | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
US11400101B2 (en) | 2013-10-04 | 2022-08-02 | Glenmark Specialty S.A. | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
EP4272839A3 (en) * | 2013-10-04 | 2024-01-03 | Glenmark Specialty S.A. | Treatment of allergic rhinitis using a combination of mometasone and olopatadine |
US11679210B2 (en) | 2014-10-03 | 2023-06-20 | Glenmark Specialty S.A. | Dispensing device and pharmaceutical composition for the treatment of rhinitis |
Also Published As
Publication number | Publication date |
---|---|
KR20140081925A (en) | 2014-07-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2014092346A1 (en) | Bitter taste masked pharmaceutical formulation comprising corticosteroid, antihistamine and stevia | |
JP5683719B2 (en) | Bepotastine composition | |
US8859531B2 (en) | Pharmaceutical composition including mometasone furoate and azelastine hydrochloride for nasal administration | |
EP3043773B1 (en) | Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine for nasal administration | |
JP5759553B2 (en) | Bepotastine composition | |
JP5785360B2 (en) | Pharmaceutical formulation containing azelastine and corticosteroids for treating inflammatory or allergic conditions | |
IL148691A (en) | Pharmaceutical compositions containing ciclesonide | |
KR101304341B1 (en) | PHARMACEUTICAL COMPOSITION COMPRISING CORTICOSTEROID, ANTIHISTAMINIC AGENT AND β-CYCLODEXTRIN WITH IMPROVED STABILITY | |
JP6905994B2 (en) | Betamethasone oral spray formulation and its use in the treatment of ataxia | |
KR102083621B1 (en) | Oral liquid formulation having improved stability comprising ambroxol and levodropropizine | |
CN114173761B (en) | Pharmaceutical composition comprising udenafil | |
RU2406498C2 (en) | Pharmaceutical composition exhibiting anti-inflammatory, particularly antiasthmatic action, applications of pharmaceutical composition (versions) and drug (versions) | |
US20220387452A1 (en) | Treatment of allergic rhinitis using a combination of mometasone and olopatadine | |
KR102362848B1 (en) | Stable pharmaceutical composition comprising Ursodeoxycholic acid and method for preparing the same | |
CN111787954A (en) | Treatment of allergic rhinitis in pediatric subjects using a combination of mometasone and olopatadine | |
WO2014087347A1 (en) | Fixed dose pharmaceutical composition comprising mometasone and azelastine |
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: 13862493 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: 13862493 Country of ref document: EP Kind code of ref document: A1 |