WO2022035388A1 - Pharmaceutical compositions comprising azelastine and relevant excipients - Google Patents
Pharmaceutical compositions comprising azelastine and relevant excipients Download PDFInfo
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- WO2022035388A1 WO2022035388A1 PCT/TR2020/050708 TR2020050708W WO2022035388A1 WO 2022035388 A1 WO2022035388 A1 WO 2022035388A1 TR 2020050708 W TR2020050708 W TR 2020050708W WO 2022035388 A1 WO2022035388 A1 WO 2022035388A1
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- nasal
- azelastine
- composition
- allergic rhinitis
- sorbitol
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- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- the present invention relates to the preperation of pharmaceutical compositions comprising azelastine HCI in the treatment of seasonal and perenial allergic rhinitis, having a specific ratio for sweetener to achieve iso-osmotic value.
- Azelastine is a selective antihistamine, Hl receptor antagonist, generally administered as an intranasal spray with hydrochloride form.
- Azelastine HCI has a chemical name as ( ⁇ )-l-(2H)-phthalazinone, 4-[(4-chlorophenyl) methyl]-2-(hexahydro-l-methyl-lH-azepin-4-yl)-monohydrochloride and its chemical structure is shown in the Figure I.
- Azelastine hydrochloride has molecular weight of 418.37 g/mol, white colored, almost odorless, crystalline powder with a bitter taste.
- Azelastine HCI is indicated for the relief of the symptoms of allergic rhinitis including seasonal allergic rhinitis and perennial allergic rhinitis.
- Allergic rhinitis commonly known as “hay fever” is an allergic disease which affects many people worldwide. Allergic rhinitis is inflammation of the inside of the nose caused by an allergen, such as pollen, dust, mould or flakes of skin from certain animals. There are two kinds of allergic rhinitis: seasonal allergic rhinitis and perennial allergic rhinitis.
- Seasonal allergic rhinitis Symptoms of seasonal allergic rhinitis can ocur on specific seasons; especially in spring, summer, and early fall. Reason of this allergic sensitivity is spores or pollens from trees, grass, and weeds.
- Perennial allergic rhinitis People with perennial allergic rhinitis experience symptoms in all year. It is generally caused by dust mites, pet hair or dander, mold. In perennial rhinitis, chronic nasal obstruction is often prominent and may extend to eustachian tube obstruction. Sensitive person inhales an allergen, shows following symptoms: Stuffy nose due to blockage or congestion, runny nose or post nasal drainage, itching (usually in the nose, mouth, eyes, or throat), red and watery eyes, puffy/swollen eyelids, sneezing, cough.
- Symptoms also may be effected by following irritants in negatively such as: cigarette smoke, strong odors (Such as perfume, or hair spray and fumes), cleaning solutions, pool chlorine, car exhaust and other air pollutants (i.e., ozone), air fresheners.
- irritants in negatively such as: cigarette smoke, strong odors (Such as perfume, or hair spray and fumes), cleaning solutions, pool chlorine, car exhaust and other air pollutants (i.e., ozone), air fresheners.
- excipients can be used for nasal spray dosage forms. But some of the excipients has negative effect to compliance of patients. Using preservatives in a nasal spray may affect patient adherence due to its risks and possible side effects. It argued that a certain amount is well tolerated by patients, whereas others state that they might increase the risk of adverse events for patients. Especially, ciliotoxicity (impaired ciliary activity) of the nasal mucosa irritation is known according to some in-vitro studies.
- nasal administration is an effective way of systemic delivery.
- Nasal administration compositions can be formulated under the following conditions: high water solubility, sufficient chemical stability, pleasant smell or taste, favourable nasal absorption parameters, minimum nasal irritation, low dose and non toxic metabolites.
- aqueous nasal preparations are usually iso-osmotic.
- This preparations may comprise excipients; to adjust the viscosity or to adjust stabilise the pH value or to increase the solubility of active ingredient or to stabilise the preparation.
- Administration device for nasal route should be designed without contamination.
- Phyicochemical properties of active ingredient Water soluble form of active ingredient is preferred. Oxidation and hydrolysis issues should be take into consideration for each active ingrediant. Desired dose for product must be selected in possible small volume.
- Vehicle property is effective to pH, buffer capacity, osmolarity, stability, compatibility for nasal solutions. Most common excipient is water as the solvent, because other solvents show negative properties on nasal composition.
- pH and buffer capacity The pH of nasal formulation is very effective on irritaiting of the nasal mucosa, to prevent pathogenic bacteria growth, to maintain preservative functionality.
- Physicological nasal liquid is 6-8 for the pH. Physicological normal is very important for mucociiary clearance and minimal nasal initiation.
- Osmotic value Nasal sprays without iso-osmotic properties have a negative effect on ciliary epithelium. Osmotic pressure and tonicity can effect on nasal spray products.
- Viscosity enhancers and surfactants can use to stabilise for suspensions. Using high concentration of these excipients effects mucociliary clearance negatively.
- Appearance/smell/taste Nasal sprays will not contact with taste buds, but they can give a sensation of taste. Nasal preparations usually do not have any flavouring agents. Users of nasal spray can prefer better sensation of taste.
- Osmosis is a process by which molecules of a solvent tend to pass through a semipermeable membrane from a less concentrated solution into a more concentrated one.
- Osmolarity is the number of miliosmoles in a kg of solution.
- the normal osmolarity value (Iso-osmotic) for plasma and other body fluids ranges from 270 to 300 mOsm/L. The body functions best when the osmolarity of all body fluid spaces is close to 300 mOsm/L.
- Tonicity is a measure of the effective osmotic pressure gradient; the water potential of two solutions separated by a semipermeable cell membrane.
- a solution's tonicity is related to its osmolarity, which is the total concentration of all solutes in the solution.
- isotonic, hypertonic and hypotonic can be generally used to compare concentration of a solute in two solutions.
- Isotonic solutions are two solutions that have the same concentration of a solute.
- Hypertonic solution is one of two solutions that has a higher concentration of a solute.
- Hypotonic solution is one of two solutions that has a lower concentration of a solute.
- isosmotic isotonic, normotonic
- hypo-osmotic hypo-osmotic
- hyper-osmotic hyper-osmotic
- the Infusion Nurses Society classifies a solution as isotonic if its tonicity falls within (or near) the normal range for (parenteral route) blood serum-between 280 and 300 mOsm/liter.
- a hypotonic solution has an osmolarity less than 280 mOsm/liter, and a hypertonic solution has an osmolarity greater than 300 mOsm/liter.
- US5164194 relates to a medicament for nasal use or for use in the eye which contains as active ingredient azelastine or a physiologically acceptable salt. Summary of the invention
- the present invention relates to the preparation of pharmaceutical compositions comprising azelastin HCI, and one or more pharmaceutically acceptable excipients except preservatives, to achieve iso-osmotic value.
- the present invention relates to the preperation of pharmaceutical compositions comprising azelastine HCI in the treatment of seasonal and perennial allergic rhinitis, having a specific ratio for sweetener to achieve iso-osmotic value.
- the present invention relates to the preparation of pharmaceutical compositions comprising azelastin or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable carriers or excipients.
- compositions particularly pharmaceutical compositions, comprising azelastine and/or one or more of its pharmacologically acceptable salts or esters thereof, particularly azelastine hydrochloride, and one or more pharmaceutically acceptable carriers or excipients.
- the present invention relates to the preparation of pharmaceutical compositions comprising azelastin HCI, and one or more pharmaceutically acceptable carriers or excipients, to achieve iso-osmotic value.
- a pharmaceutical composition comprising azelastine, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, wherein said taste-masking agent is sorbitol, present at a concentration of from 6.7% to 7.2% (w/v), and wherein said composition is formulated for intranasal administration having osmolarity between 270 to 300 mOsm/L.
- the present invention provides pharmaceutical compositions comprising azelastine hydrochloride formulated for use as nasal sprays.
- Nasal spray formulations are categorized into two types, solutions and suspensions.
- properties such as pH, buffer capacity, osmololity and viscosity are very critical.
- the FDA guideline about nasal sprays emphesizes measurement for osmolarity values and the other values such as pH, osmolality, and viscosity during drug development.
- excipients that is used in nasal sprays are viscosity agent, chelating agent, tonicity agent, sweetening agent and solvent except active ingredient.
- Many nasal spray products in the market containing azelastin, sucrose and sorbitol are used together with other substances as excipients.
- Dosage form of nasal spray is known a cost-effective pharmaceutical form with easy to use and self-administrable.
- BKC benzalkonium chloride
- sorbitol is used instead of sucrose and sorbitol as excipients in nasal sprays containing active ingredient of azelastin hydrochloride.
- sorbitol in nasal spray composition, we can obtain iso-osmotic products in terms of osmolarity using only sorbitol in our formulation instead of using sucrose and sorbitol.
- sorbitol is used as taste masking agent.
- the ratio of sorbitol used to the total weight is between 6.7% -7.2%.
- the composition comprises sorbitol at the concentration of 6.7, 6.8, 6.9, 7.0, 7.1 or 7.2% (w/v). The most preferred amount in this range is 6.9%.
- Azelastin HCI has so intense bitter taste. At first sight, taste is not a problem for nasal compositions. But, some of the subjects in clinical trials claimed that unpleasant and undesired taste in studies.
- Nasal preparations characterized iso-osmotic may comprise excipients; to adjust the viscosity or to adjust stabilise the pH value or to increase the solubility of active ingredient or to stabilise the preparation.
- Tonicity is the 'effective osmolality' and is equal to the sum of the concentrations of the solutes which have the capacity to exert an osmotic force across the membrane.
- Hypotonicity is a property that can be addressed by the compounding pharmacist; hypertonicity can be addressed, if it is possible to decrease the concentration of some components of the formulation.
- optimum osmolarity value iso-osmotic or isotonic or normotonic of nasal composition are between 270 to 300 mOsm/L, preferably 280-290 mOsm/L, most preferably 285-290 mOsm/L.
- Table 1 The relationship between sorbitol (%) and osmolarity (Osmol/kg) in pharmaceutical compositions containing azelastin
- the formulations preferably contain viscosity agent, taste masking, chelating agent, pH agent and solvent.
- the present invention provides a pharmaceutical composition for use in a method of treating allergic rhinitis in a patient in need thereof, including seasonal allergic rhinitis and/or perenial allergic rhinitis.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising tadalafil or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
- compositions particularly pharmaceutical compositions, comprising azelastine and/or one or more of its pharmacologically acceptable salts or esters thereof, particularly azelastine hydrochloride.
- Neutral taste is achieved with the single use of sorbitol. If sorbitol and sucrose are used together in composition, it gives a very sweet taste.
- the present invention has developed preservative free approache. It provides pharmaceutical composition has no preservatives, protecting toxic reactions in the nose, eyes, ears, and lungs and also possibilty of exacerbating the symptoms of allergic rhinitis.
- the present invention provides pharmaceutical composition comprising azelastin HCI and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation
- a nasal spray product with optimum characteristics about osmolality was obtained by using minimum excipient in the formulation.
- iso-osmotic osmolarity was achieved with our formulation.
- Nasal spray dosage form is cost-effective, easy to use and self-administrable, so it has high patient compliance.
- treatment means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.
- compositions of the present invention can be administered via intranasal administration to a patient.
- the compositions are administered directly to the nasal mucosa (i.e., intranasally, e.g., in the form of a nasal spray or drops).
- allergic rhinitis will be understood to include “allergic” irritation and/or inflammation, including seasonal rhinitis (e.g. caused by outdoor agents such as pollen; hay fever) and/or perennial rhinitis (e.g. caused by house dust mites, indoor mold etc), as well as the symptoms thereof.
- seasonal rhinitis e.g. caused by outdoor agents such as pollen; hay fever
- perennial rhinitis e.g. caused by house dust mites, indoor mold etc
- composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s).
- Pharmaceutically acceptable excipients comprise, but are not limited to, preservatives, viscosity modifiers, emulsifiers, buffering agents, and the mixtures thereof, to facilitate the physical formulation of various dosage forms for intranasal administration like nasal sprays.
- Preservatives can be selected from the group, but not limited to, benzalkonium chloride, acetone sodium bisulfite, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, butylated hydroxyanisole, butylene glycol, calcium acetate, cetylpyridinium chloride, chlorhexidine, glycerin, potassium metabisulfite, potassium nitrate, potassium sorbate, propionic acid, propylene glycol, propylparaben sodium, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium metabisulfite, sodium propionate, sodium sulfite, sorbic acid, zinc oxide, and N-acetylcysteine, and a mixture thereof.
- the viscosity agent can be selected from the group, but not limited to, HPMC, concentrated glycerin, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethylcellulose and a mixture thereof.
- HPMC concentrated glycerin
- polyvinylpyrrolidone polyvinylpyrrolidone
- ethyl cellulose sodium carboxymethylcellulose and a mixture thereof.
- the preferred viscosity agent is HPMC.
- pH agents can be selected from the group, but not limited to, sodium citrate, citric acid, sodium phosphate (dibasic, heptahydrate form), and boric acid or equivalent conventional buffers, or combinations thereof.
- the preferred pH agents is sodium citrate.
- Solvents/cosolvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, purified water and other materials known to one of ordinary skill in the art and mixtures thereof.
- the preferred solvent is purified water.
- composition comprising Azelastin Forte Nasal Spray
Abstract
The present invention relates to a pharmaceutical compositions comprising azelastine HCI in the treatment of seasonal and perennial allergic rhinitis, having a specific ratio for sweetener to achieve iso-osmotic value. Spesifically, pharmaceutical composition comprises azelastine, sorbitol as a taste-masking agent and the composition is formulated for intranasal administration.
Description
PHARMACEUTICAL COMPOSITIONS COMPRISING AZELASTINE AND RELEVANT EXCIPIENTS
Field of invention
The present invention relates to the preperation of pharmaceutical compositions comprising azelastine HCI in the treatment of seasonal and perenial allergic rhinitis, having a specific ratio for sweetener to achieve iso-osmotic value.
Background of the invention
Azelastine is a selective antihistamine, Hl receptor antagonist, generally administered as an intranasal spray with hydrochloride form.
Azelastine HCI has a chemical name as (±)-l-(2H)-phthalazinone, 4-[(4-chlorophenyl) methyl]-2-(hexahydro-l-methyl-lH-azepin-4-yl)-monohydrochloride and its chemical structure is shown in the Figure I. Azelastine hydrochloride has molecular weight of 418.37 g/mol, white colored, almost odorless, crystalline powder with a bitter taste.
Figure 1
Azelastine HCI is indicated for the relief of the symptoms of allergic rhinitis including seasonal allergic rhinitis and perennial allergic rhinitis.
Allergic rhinitis, commonly known as “hay fever” is an allergic disease which affects many people worldwide. Allergic rhinitis is inflammation of the inside of the nose caused by an allergen, such as pollen, dust, mould or flakes of skin from certain animals. There are two kinds of allergic rhinitis: seasonal allergic rhinitis and perennial allergic rhinitis.
Seasonal allergic rhinitis: Symptoms of seasonal allergic rhinitis can ocur on specific seasons; especially in spring, summer, and early fall. Reason of this allergic sensitivity is spores or pollens from trees, grass, and weeds.
Perennial allergic rhinitis: People with perennial allergic rhinitis experience symptoms in all year. It is generally caused by dust mites, pet hair or dander, mold. In perennial rhinitis, chronic nasal obstruction is often prominent and may extend to eustachian tube obstruction.
Sensitive person inhales an allergen, shows following symptoms: Stuffy nose due to blockage or congestion, runny nose or post nasal drainage, itching (usually in the nose, mouth, eyes, or throat), red and watery eyes, puffy/swollen eyelids, sneezing, cough. Symptoms also may be effected by following irritants in negatively such as: cigarette smoke, strong odors (Such as perfume, or hair spray and fumes), cleaning solutions, pool chlorine, car exhaust and other air pollutants (i.e., ozone), air fresheners.
Many excipients can be used for nasal spray dosage forms. But some of the excipients has negative effect to compliance of patients. Using preservatives in a nasal spray may affect patient adherence due to its risks and possible side effects. It argued that a certain amount is well tolerated by patients, whereas others state that they might increase the risk of adverse events for patients. Especially, ciliotoxicity (impaired ciliary activity) of the nasal mucosa irritation is known according to some in-vitro studies.
Alternative to oral and intarvascular route, nasal administration is an effective way of systemic delivery. Nasal administration compositions can be formulated under the following conditions: high water solubility, sufficient chemical stability, pleasant smell or taste, favourable nasal absorption parameters, minimum nasal irritation, low dose and non toxic metabolites.
In generally, aqueous nasal preparations are usually iso-osmotic. This preparations may comprise excipients; to adjust the viscosity or to adjust stabilise the pH value or to increase the solubility of active ingredient or to stabilise the preparation. Administration device for nasal route should be designed without contamination.
Specifications of phyicochemical properties of active ingredient, vehicle, pH and buffer capacity, osmotic value, viscosity, preservation and appearance/smell/taste should take into consideration product development process for liquid preparations such as nasal spray.
Phyicochemical properties of active ingredient: Water soluble form of active ingredient is preferred. Oxidation and hydrolysis issues should be take into consideration for each active ingrediant. Desired dose for product must be selected in possible small volume.
Vehicle: Vehicle property is effective to pH, buffer capacity, osmolarity, stability, compatibility for nasal solutions. Most common excipient is water as the solvent, because other solvents show negative properties on nasal composition. pH and buffer capacity: The pH of nasal formulation is very effective on irritaiting of the nasal mucosa, to prevent pathogenic bacteria growth, to maintain preservative functionality. Physicological nasal liquid is 6-8 for the pH. Physicological normal is very important for mucociiary clearance and minimal nasal initiation.
Osmotic value: Nasal sprays without iso-osmotic properties have a negative effect on ciliary epithelium. Osmotic pressure and tonicity can effect on nasal spray products.
Viscosity: Viscosity enhancers and surfactants can use to stabilise for suspensions. Using high concentration of these excipients effects mucociliary clearance negatively.
Appearance/smell/taste: Nasal sprays will not contact with taste buds, but they can give a sensation of taste. Nasal preparations usually do not have any flavouring agents. Users of nasal spray can prefer better sensation of taste.
Osmosis is a process by which molecules of a solvent tend to pass through a semipermeable membrane from a less concentrated solution into a more concentrated one. Osmolarity is the number of miliosmoles in a kg of solution. The normal osmolarity value (Iso-osmotic) for plasma and other body fluids ranges from 270 to 300 mOsm/L. The body functions best when the osmolarity of all body fluid spaces is close to 300 mOsm/L.
Tonicity is a measure of the effective osmotic pressure gradient; the water potential of two solutions separated by a semipermeable cell membrane. A solution's tonicity is related to its osmolarity, which is the total concentration of all solutes in the solution.
Terms isotonic, hypertonic and hypotonic can be generally used to compare concentration of a solute in two solutions.
Isotonic solutions: Isotonic solutions are two solutions that have the same concentration of a solute.
Hypertonic solution: Hypertonic solution is one of two solutions that has a higher concentration of a solute.
Hypotonic solution: Hypotonic solution is one of two solutions that has a lower concentration of a solute.
There are three terms for osmolarity: isosmotic (isotonic, normotonic), hypo-osmotic (hypotonic) and hyper-osmotic (hypertonic). iso-osmotic (isotonic, normotonic): Fluids range between 270 to 300 mOsm/L. When all fluids have this particle concentration, the fluids are isosmotic or isotonic to each other. hypo-osmotic (hypotonic): Fluids with osmolarities less than 270 mOsm/L, compared with isosmotic fluids. hyper-osmotic (hypertonic): Fluids with osmolarities greater than 300 mOsm/L, compared with isosmotic fluids.
The Infusion Nurses Society (INS) classifies a solution as isotonic if its tonicity falls within (or near) the normal range for (parenteral route) blood serum-between 280 and 300 mOsm/liter. A hypotonic solution has an osmolarity less than 280 mOsm/liter, and a hypertonic solution has an osmolarity greater than 300 mOsm/liter.
US5164194 relates to a medicament for nasal use or for use in the eye which contains as active ingredient azelastine or a physiologically acceptable salt.
Summary of the invention
The present invention relates to the preparation of pharmaceutical compositions comprising azelastin HCI, and one or more pharmaceutically acceptable excipients except preservatives, to achieve iso-osmotic value.
The present invention relates to the preperation of pharmaceutical compositions comprising azelastine HCI in the treatment of seasonal and perennial allergic rhinitis, having a specific ratio for sweetener to achieve iso-osmotic value.
Detailed description of the invention
The present invention relates to the preparation of pharmaceutical compositions comprising azelastin or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable carriers or excipients.
The present invention provides compositions, particularly pharmaceutical compositions, comprising azelastine and/or one or more of its pharmacologically acceptable salts or esters thereof, particularly azelastine hydrochloride, and one or more pharmaceutically acceptable carriers or excipients.
The present invention relates to the preparation of pharmaceutical compositions comprising azelastin HCI, and one or more pharmaceutically acceptable carriers or excipients, to achieve iso-osmotic value.
In this invention, a pharmaceutical composition comprising azelastine, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, wherein said taste-masking agent is sorbitol, present at a concentration of from 6.7% to 7.2% (w/v), and wherein said composition is formulated for intranasal administration having osmolarity between 270 to 300 mOsm/L.
The present invention provides pharmaceutical compositions comprising azelastine hydrochloride formulated for use as nasal sprays.
Nasal spray formulations are categorized into two types, solutions and suspensions. When formulating nasal spray products, properties such as pH, buffer capacity, osmololity and viscosity are very critical. The FDA guideline about nasal sprays emphesizes measurement for osmolarity values and the other values such as pH, osmolality, and viscosity during drug development.
Generally, excipients that is used in nasal sprays are viscosity agent, chelating agent, tonicity agent, sweetening agent and solvent except active ingredient.
Many nasal spray products in the market containing azelastin, sucrose and sorbitol are used together with other substances as excipients.
Dosage form of nasal spray is known a cost-effective pharmaceutical form with easy to use and self-administrable.
In this invention, there is no preservatives that used for nasal compositions. Most decongestant sprays comprises the preservative benzalkonium chloride (BKC), which causes toxic reactions in the nose, eyes, ears, and lungs, and may exacerbate the symptoms of allergic rhinitis. These side effects can be increased mucosal swelling and nasal hyperreactivity, type IV hypersensitivity, decrease of mucociliary clearance, and nasal mucosa dysplasia.
In this invention, only sorbitol is used instead of sucrose and sorbitol as excipients in nasal sprays containing active ingredient of azelastin hydrochloride. With the mono use of sorbitol in nasal spray composition, we can obtain iso-osmotic products in terms of osmolarity using only sorbitol in our formulation instead of using sucrose and sorbitol.
In this invention, sorbitol is used as taste masking agent.
In this invention, the ratio of sorbitol used to the total weight is between 6.7% -7.2%. The composition comprises sorbitol at the concentration of 6.7, 6.8, 6.9, 7.0, 7.1 or 7.2% (w/v). The most preferred amount in this range is 6.9%.
According to U.S. Patent No. 5,164,194, Azelastin HCI has so intense bitter taste. At first sight, taste is not a problem for nasal compositions. But, some of the subjects in clinical trials claimed that unpleasant and undesired taste in studies.
Nasal preparations characterized iso-osmotic may comprise excipients; to adjust the viscosity or to adjust stabilise the pH value or to increase the solubility of active ingredient or to stabilise the preparation.
Tonicity is the 'effective osmolality' and is equal to the sum of the concentrations of the solutes which have the capacity to exert an osmotic force across the membrane. Hypotonicity is a property that can be addressed by the compounding pharmacist; hypertonicity can be addressed, if it is possible to decrease the concentration of some components of the formulation.
For comfort during administration, many dosage forms must be "isotonic" with body fluids. This is especially valid of parenterals, ophthalmics and nasal solutions. Pain and irritation at the site of administration may occur if the formulation is either hypertonic or hypotonic.
In this invention, optimum osmolarity value (iso-osmotic or isotonic or normotonic) of nasal composition are between 270 to 300 mOsm/L, preferably 280-290 mOsm/L, most preferably 285-290 mOsm/L.
Table 1: The relationship between sorbitol (%) and osmolarity (Osmol/kg) in pharmaceutical compositions containing azelastin
In this invention, the formulations preferably contain viscosity agent, taste masking, chelating agent, pH agent and solvent.
The present invention provides a pharmaceutical composition for use in a method of treating allergic rhinitis in a patient in need thereof, including seasonal allergic rhinitis and/or perenial allergic rhinitis.
In one embodiment, the present invention relates to a pharmaceutical composition comprising tadalafil or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
The present invention provides compositions, particularly pharmaceutical compositions, comprising azelastine and/or one or more of its pharmacologically acceptable salts or esters thereof, particularly azelastine hydrochloride.
Advantages
It is obtained iso-osmotic osmolarity that is the best range for nasal sprays without using sucralose.
Neutral taste is achieved with the single use of sorbitol. If sorbitol and sucrose are used together in composition, it gives a very sweet taste.
The present invention has developed preservative free approache. It provides pharmaceutical composition has no preservatives, protecting toxic reactions in the nose, eyes, ears, and lungs and also possibilty of exacerbating the symptoms of allergic rhinitis.
The present invention provides pharmaceutical composition comprising azelastin HCI and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation
In this invention, a nasal spray product with optimum characteristics about osmolality was obtained by using minimum excipient in the formulation.
In present invention, iso-osmotic osmolarity was achieved with our formulation.
Nasal spray dosage form is cost-effective, easy to use and self-administrable, so it has high patient compliance.
The term "treatment" or "treating" means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.
The compositions of the present invention can be administered via intranasal administration to a patient. The compositions are administered directly to the nasal mucosa (i.e., intranasally, e.g., in the form of a nasal spray or drops).
In this invention, the term "allergic rhinitis" will be understood to include “allergic” irritation and/or inflammation, including seasonal rhinitis ( e.g. caused by outdoor agents such as pollen; hay fever) and/or perennial rhinitis ( e.g. caused by house dust mites, indoor mold etc), as well as the symptoms thereof.
Pharmaceutical composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, preservatives, viscosity modifiers, emulsifiers, buffering agents, and the mixtures thereof, to facilitate the physical formulation of various dosage forms for intranasal administration like nasal sprays.
Preservatives can be selected from the group, but not limited to, benzalkonium chloride, acetone sodium bisulfite, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, butylated hydroxyanisole, butylene glycol, calcium acetate, cetylpyridinium chloride, chlorhexidine, glycerin, potassium metabisulfite, potassium nitrate, potassium sorbate, propionic acid, propylene glycol, propylparaben sodium, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium metabisulfite, sodium propionate, sodium sulfite, sorbic acid, zinc oxide, and N-acetylcysteine, and a mixture thereof.
The viscosity agent can be selected from the group, but not limited to, HPMC, concentrated glycerin, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethylcellulose and a mixture thereof. The preferred viscosity agent is HPMC. pH agents can be selected from the group, but not limited to, sodium citrate, citric acid, sodium phosphate (dibasic, heptahydrate form), and boric acid or equivalent conventional buffers, or combinations thereof. The preferred pH agents is sodium citrate.
Solvents/cosolvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, purified water and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred solvent is purified water.
Example: Azelastin Forte Nasal Spray
Procedure for composition comprising Azelastin Forte Nasal Spray;
1. Stage 1 Dissolving and Mixing
In the required quantity of purified water, mix HPMC, Disodium Edetate, sorbitol, azelastine hydrochloride and Sodium citrate. Mix them after each addition.
2. Stage 2 Volume make-up
Make up the final volume using purified water.
3. Stage 3 Filtration
Solution is filtered then transferred to storage tank.
Claims
1. A pharmaceutical composition comprising azelastine, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, wherein said taste-masking agent is sorbitol, present at a concentration of from 6.7% to 7.2% (w/v), and wherein said composition is formulated for intranasal administration having osmolarity between 270 to 300 mOsm/L.
2. The pharmaceutical composition of claim 1, wherein said composition has no preservatives.
3. The pharmaceutical composition of claim 1, wherein said composition comprises azelastine hydrochloride.
3. The pharmaceutical composition of claim 1, wherein said composition comprises tastemasking agent is sorbitol, preferred concentration is 6.9% (w/v).
4. The pharmaceutical composition of claim 1, wherein osmolarity of composition is 280-290 mOsm/L, most preferably 285-290 mOsm/L.
5. A nasal spray composition according to any of preceding claims, for use in the treatment of allergic rhinitis, including seasonal and perennial allergic rhinitis.
9
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2020/050708 WO2022035388A1 (en) | 2020-08-14 | 2020-08-14 | Pharmaceutical compositions comprising azelastine and relevant excipients |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2020/050708 WO2022035388A1 (en) | 2020-08-14 | 2020-08-14 | Pharmaceutical compositions comprising azelastine and relevant excipients |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022035388A1 true WO2022035388A1 (en) | 2022-02-17 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2020/050708 WO2022035388A1 (en) | 2020-08-14 | 2020-08-14 | Pharmaceutical compositions comprising azelastine and relevant excipients |
Country Status (1)
| Country | Link |
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| WO (1) | WO2022035388A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060110331A1 (en) * | 2004-11-24 | 2006-05-25 | Medpointe Healthcare Inc. | Compositions comprising azelastine and methods of use thereof |
| AU2012201428A1 (en) * | 2004-11-24 | 2012-04-05 | Meda Pharmaceuticals Inc. | Compositions comprising azelastine and methods of use thereof |
| EP2647380A2 (en) * | 2010-11-29 | 2013-10-09 | Hanlim Pharmaceutical Co., Ltd. | Pharmaceutical composition including mometasone furoate and azelastine hydrochloride for nasal administration |
-
2020
- 2020-08-14 WO PCT/TR2020/050708 patent/WO2022035388A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060110331A1 (en) * | 2004-11-24 | 2006-05-25 | Medpointe Healthcare Inc. | Compositions comprising azelastine and methods of use thereof |
| AU2012201428A1 (en) * | 2004-11-24 | 2012-04-05 | Meda Pharmaceuticals Inc. | Compositions comprising azelastine and methods of use thereof |
| EP2647380A2 (en) * | 2010-11-29 | 2013-10-09 | Hanlim Pharmaceutical Co., Ltd. | Pharmaceutical composition including mometasone furoate and azelastine hydrochloride for nasal administration |
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