The present invention is directed to a method for treating allergic rhinitis without causing an adverse effect of bitter taste. The method comprises administering to a patient an aqueous pharmaceutical formulation comprising 0.1-0.15% (w/v) of epinastine or an acid addition salt thereof, 0.05-0.5% (w/v) of hydroxypropylmethylcellulose to maintain the viscosity between 1.5-10 centipoise, 1-2% (w/v) of propylene glycol, and a buffer to maintain the pH between 5-8, said aqueous epinastine formulation has a tonicity between 200-400 mOsm/kG; the formulation does not contain a sweetening agent. The present invention provides a method for effectively treating allergic rhinitis by delivering a small volume of the epinastine formulation to the nose of a patient using a small volume metered-dose nasal spray pump. The present method does not cause an adverse effect of bitter taste without including sweetening agents in the formulation.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention provides a method for treating allergic rhinitis in a subject without causing an adverse effect of bitter taste. The method comprises the steps of: identifying a subject suffering from allergic rhinitis; administering to the nose of the subject one to two sprays at .ltoreq.115 .mu.L per nostril per spray once or twice daily of an aqueous epinastine formulation; wherein said aqueous epinastine formulation comprises (a) 0.1-0.15% (w/v) of epinastine or an acid addition salt thereof, (b) 0.05-0.5% (w/v) of hydroxypropylmethylcellulose to maintain the viscosity between 1.5-10 centipoise, (c) 1-2% (w/v) of propylene glycol, and (d) a buffer to maintain the pH between 5-8, said aqueous epinastine formulation has a tonicity between 200-400 mOsm/kG, said formulation does not contain a sweetening agent; whereby the subject perceives a minimal or no bitter taste of said epinastine and the symptoms of allergic rhinitis are reduced.

DETAILED DESCRIPTION OF THE INVENTION

The inventor has unexpectedly discovered an aqueous epinastine formulation that contains a combination of a particular concentration of each ingredient; the formulation can be delivered topically to the nose of an allergic rhinitis patient to treat the patient effectively while the patient only perceives a minimal or no bitter taste. The aqueous epinastine formulation is viscous and has a viscosity of 1.5-10 centipoises. When intranasally delivered in a small volume of .ltoreq.120 .mu.L, preferably .ltoreq.115 .mu.L, preferably .ltoreq.105 .mu.L, preferably .ltoreq.90 .mu.L, more preferably .ltoreq.85 .mu.L per nostril per spray, the epinastine formulation of the present invention is effective in treating allergic rhinitis, and does not cause a strong bitter aftertaste, even without including taste-masking agents such as sweeteners or flavoring agents in the formulation. Applicants also unexpectedly discovered that when patients are administered with a small volume of 0.1 to 0.15% w/v of epinastine in combination with other ingredients, patients had better sensory attribute scores when sweetening agents are excluded from the formulation.

Although the nose has a large space relative to the spray volume emitted by a small volume metered-dose nasal spray pump, the inventor has discovered that reducing the nasal spray volume from 137 .mu.L (ASTELIN.RTM. nasal spray volume) to .ltoreq.115 .mu.L, preferably to .ltoreq.85 .mu.L, plays an important role in minimizing the bitter aftertaste of epinastine. The inventor has discovered that delivering a small volume of the viscous epinastine formulation of the present invention reduces the bitter aftertaste significantly without compromising the therapeutic efficacy of epinastine. The viscous epinastine formulation is delivered to the nose of a patient using a metered-dose nasal spray pump. The viscous epinastine formulation has minimal post-nasal drip and does not cause an unacceptable quick-acting bitterness or a long-acting bitterness after dosing.

This invention is directed to an aqueous pharmaceutical formulation comprising an antihistamine chemical compound such as epinastine and salts thereof. This invention provides a formulation containing one or more viscosity-enhancing agents that increase the viscosity of the formulation and minimize the bitter taste of epinastine. The formulation does not contain a substantial amount of unacceptable agents for pharmaceutical use, particularly, nasal use. The invention provides a stable aqueous formulation of epinastine; the formulation is suitable for therapeutic uses and remains stable under normal use storage conditions for an extended period of time.

The aqueous pharmaceutical formulations of the present invention exclude the use of inappropriate adjuvants that can cause toxicological outcomes and tissue damage when used in humans or mammals for a long term. The aqueous pharmaceutical formulations of the present invention contain epinastine in solution at sufficient concentrations, and provide an anti-allergic response in mammals. The aqueous pharmaceutical formulations are non-irritating and tolerable to human epithelial cells, and are suitable for multiple instillations.

The present invention is directed to an aqueous pharmaceutical formulation comprising epinastine or a salt thereof, and a viscosity-enhancing agent. Epinastine can be used either as free base or as a pharmaceutically acceptable salt thereof. Preferably, epinastine is used in the form of its acid addition salts such as hydrochloride salt.

"A viscosity-enhancing agent," as used herein, refers to a compound when added to a solution increases the viscosity of the solution. A viscosity-enhancing agent at a suitable concentration can modify or alter the flow properties of the system from a Newtonian fashion (e.g. water) to a pseudo plastic or plastic flow. An increased viscosity alters the residence time, drainage characteristics, and/or bioavailability of the pharmaceutical formulation. A viscosity-enhancing agent typically increases the viscosity of the pharmaceutical formulation 1.5-10 fold (e.g. 1.5-10 centipoises) with respect to water (approximately 1 centipoise).

The viscosity-enhancing agent used in the formulation provides an enhanced viscosity of the formulation without causing precipitation of the active ingredient epinastine or other ingredients, or causing an undesirable flocculation of the final preparation. Furthermore, the viscosity-enhancing agent is compatible with other agents in the formulation. The increased viscosity of the formulation provides a sustained action, minimizes post-nasal drip, and reduces the possibility of the formulation to `drip back` from the nasal cavity to the back of the throat. By minimizing the postnasal drip and therefore minimizing the amount of preparation that is deposited in the back of the throat wherein the bitter taste of epinastine is less perceived by the subject.

A viscosity-enhancing agent useful for the present invention is often a polymer such as hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, and polyvivnyl pyrrolidone. A preferred viscosity-enhancing agent is hydroxypropylmethylcellulose. The viscosity-enhancing agent often improves the physical stability of the formulation. The inventor has discovered that not all typical pharmaceutically acceptable viscosity modifiers are suitable for use in this invention because they are physically incompatible with epinastine in solution and result in flocculation and phase separation, and/or they do not function well at pH 4-8. For example, polyvinyl acrylic acid, polystyrene sulfonic acid, sodium carboxymethylcellulose, xanthan gum, microcrystalline cellulose and sodium carboxymethylcellulose are not suitable for this invention.

Typically, the aqueous pharmaceutical formulation of the present invention comprises 0.001-3% (w/v) epinastine or an acid addition salt thereof, 0.001-0.5% (w/v) viscosity-enhancing agent, a buffer to maintain a pH between 4-8, and a tonicity agent to maintain a tonicity between 200-400 mOsm/kG. The viscosity of the formulation is about 1.5-10 centipoises (cps), preferably 1.5-10 cps, more preferably 2-9 cps, and more preferably 2-6 cps.

The concentration of epinastine in the aqueous formulation is in general 0.001-3%, preferably 0.005-1% or 0.005-0.6%, and more preferably 0.05-0.2%, and most preferably 0.1-0.15% (w/v). For example, a preferred concentration of epinastine is about 0.1% or about 0.15%. The inventor has discovered that epinastine at 0.10-0.15% (w/v) concentration, coupled with 0.05-0.5% (w/v) of hydroxypropylmethylcellulose and 1-2% (w/v) of propylene glycol, and without inclusion of any sweetening agents, when administered to a patient in a small volume of <115 .mu.L, is effective in treating allergic rhinitis without causing an adverse effect of bitter taste. When the epinastine concentration is lower than 0.1% (w/v), e.g., 0.05%, the aqueous formulation is not effective in alleviating the symptoms of allergic rhinitis by the present method. When the epinastine concentration is higher than 0.15% (w/v), e.g., 0.2%, excluding sweetening agents does not provide advantages as to taste perception.

As used in this application, "about" refers to .+-.15% of the value recited.

The concentration of a viscosity-enhancing agent in the aqueous formulation is in general 0.001-0.5%, preferably 0.05-0.5%, and more preferably 0.1-0.3% (w/v).

The pH of the present formulation is 4-8, preferably 5-8, more preferably 6.0-7.5. Buffers suitable to maintain the pH between 4-8 include phosphate, citrate buffer, acetate buffer, maleate buffer, tartarate buffer, or combination thereof. Phosphate buffer or citrate buffer is preferred. For long-term stability, the formulation is preferred to have a pH of 5-8. Buffers suitable to maintain the pH of 5-8 include citrate buffer, phosphate buffer, citrate/phosphate buffer, maleate buffer, tartarate buffer, or combination thereof. A suitable concentration of the buffer is 1-100 mM, preferably 5-50 mM, more preferably 5-25 mM, and most preferably 10-20 mM.

The tonicity agent is present in an amount to achieve a tonicity between 200-400, preferably 220-380, and more preferably 250-340 mOsm/kG. The tonicity agent can be non-ionic or ionic. A non-ionic tonicity agent is preferred because its compatibility with polymeric adjuvant that functions as a viscosity-enhancing agent. Non-ionic tonicity agents include diols, such as glycerol, mannitol, erythritol; and sugars such as sucrose and dextrose. Other non-ionic tonicity agents such as glycerol, polyethylene glycol, propylene glycol, which also function as cosolvents and taste-masking agent, can also be used. The non-ionic tonicity agent is in general in an amount of 1-20%, preferably 1-10%, more preferably 1-5%. Preferred non-ionic agents are mannitol, sucrose, dextrose, propylene glycol, in an amount of 1-5%. For example, propylene glycol at 1-2% or 1-1.8% (w/v) is a preferred non-ionic tonicity agent for the present invention.

The tonicity agent can also be ionic agents such as sodium chloride, potassium chloride, or a balanced salt solution. The ionic tonicity agents are typically present in an amount of 0.5-0.9%, preferably 0.6-0.9%.

The pharmaceutical formulation of the present invention optionally comprises a chelating agent. A chelating agent is a substance which can form several coordinate bonds to a metal ion. Chelating agents offers a wide range of sequestrants to control metal ions in aqueous systems. By forming stable water-soluble complexes with multivalent metal ions, chelating agents prevent undesired interaction by blocking normal reactivity of metal ions. Ethylenediamine tetraacetate (EDTA), diethylenetriaminepentaacetic acid (DTPA), and N,N-bis(carboxymethyl)glycine (NTA) are examples of chelating agents for the present inventions. EDTA (ethylenediamine tetraacetate) is a preferred chelating agent. The chelating agents are typically present in an amount of 0.01-1%, and preferably 0.02-0.5% w/v.

Health regulations in various countries require that multi-dose ophthalmic and nasal preparations include a preservative. The pharmaceutical formulation of the present invention optionally comprises a preservative. Many well known preservatives that have been used in some other nasal and ophthalmic preparations cannot be used in the present invention, since those preservatives are not considered safe for repeatedly ocular use, or they interact with the viscosity-enhancing agent employed herein to form a complex that reduces the bactericidal activity of the preservative. Suitable preservatives for the present invention include benzalkonium chloride, benzyl alcohol, methyl parabens, propyl parabens, and benzethonium chlorides. In one embodiment, benzalkonium chloride is included as a safe preservative; preferably, benzalkonium chloride is used with EDTA. Typically, preservatives are employed at a level of 0.001-1%, preferably, 0.005-0.25%, and most preferably 0.05-0.2% (w/v).

Taste-masking agents are substances that can mask the undesired taste of a drug. Taste-masking agents include sweeting agents, flavoring agents, or other agents that can mask the taste of a formulation. Sweetening agents, which provide a sweet taste, in general are more effective in masking the bitter taste of a drug than other taste masking agents. Sweetening agents include saccharin sodium, erythritol, aspartame, sucrose, glycerin, sorbitol, glycyrrhinic acid, or glycyrrihinate ammonium salts, and sucralose. Another commonly used sweetening agent is SWEETAM.TM., which contains monoammonium glycyrrihinate salts pre-blended with suitable adjuvants such as sucrose and dextrose.

However, the inventor has discovered that the aqueous epinastine formulation of the present invention does not cause bitter aftertaste even without including a taste-masking agent such as sweeteners or flavoring agents. Unexpectedly, the inventor further discovered that it is advantageous to exclude sweetening agents from the present formulation as patients perceive better taste when administered with the present formulation containing 0.10-0.15% (w/v) epinastine without a sweetening agent than with a similar formulation with an added sweetening agent.

The inventor has discovered that in a clinical study, the scores reported by patients on smell, satisfaction on smell, taste, satisfaction of taste, bitterness, aftertaste, satisfaction on aftertaste, dryness of nose, and dryness of throat, had a numerical trend that epinastine-unmasked (without a sweetening agent) had better sensory attribute ratings than epinastine-masked (with a sweetening agent). Furthermore, the average score and the individual score of satisfaction on smell of epinastine-unmasked was statistically significantly higher (p<0.05) than that of epinastine-masked at 5 minute post dose when the epinastine formulation of the present invention was administered at a target volume of approximately 70 .mu.L. This is unexpected as a person skilled in the art would expect that using a sweetening agent would improve the after taste perceived by patients.

In addition to the clinical advantages, there are other advantages when excluding a sweetening agent in the formulation. One may encounter fewer problems with regulatory approval processes with one less unnecessary ingredient. The raw material cost and the manufacturing cost are also reduced without a sweetening agent.

The viscosity-enhancing agent, the tonicity agent, the buffer, the taste-masking agent, and any other ingredient introduced in the formulation must have a good solubility in water, have compatibility with other components, and have mild effects on the final viscosity of the formulation. This viscosity of the formulation is important such that the formulation can be delivered as a topical nasal spray using a metered-dose nasal spray device and is filter-sterilizable. The formulation is preferably a clear solution without any precipitate.

In one embodiment, the pharmaceutical formulation comprises epinastine or its salts in an amount of 0.10-0.15% (w/v), a non-ionic tonicity agent such as propylene glycol at 1-2% (w/v), a buffer (such as sodium phosphates) at 10-25 mM, a viscosity-enhancing agent in a range of 0.05-0.5% (w/v), an optional chelating agent in a range of 0.02-0.5% (w/v), and an optional preservative in a range of 0.005-0.2% (w/v). Such an aqueous composition has a tonicity of 250-350 mOsm/kG and is formulated at pH 5-8.

The pharmaceutical formulations of the present invention are preferred to be chemically stable at room temperature for at least 12 months, preferably 24 months, and more preferably 36 months. Chemical stability, as used herein, means that epinastine maintains at least 80%, preferably 85%, 90%, or 95% of its initial chemical assay value.

The pharmaceutical formulations of the present invention can be prepared by aseptic technique. The purity levels of all materials used in the preparation exceed 90%. The solutions of the invention are prepared by thoroughly mixing the epinastine or salts thereof, buffer(s), tonicity agent(s), viscosity-enhancing agent(s), optionally, chelating agent(s), complexing agent(s), solubilizing agent(s), preservative(s) and antioxidant agent(s). Examples of complexing agents are cyclodextrins, gamma-cyclodextrin, and crosspovidone. Examples of solubilizing agents are polysorbates, cremophor, and glycerin. Examples of antioxidants are tocopherol, butylated hydroxytoulene, butylated hydroxyanisole. Complexing agents, solubilizing agents, antioxidants can be added to the formulation; however, they are not essential for the formulation of the present invention.

The pharmaceutical formulation can be sterilized by filtering the formulation through a sterilizing grade filter, preferably of a 0.1 micron nominal pore size. The pharmaceutical formulation can also be sterilized by terminally sterilization using one or more sterilization techniques including but not limited to a thermal process, or a radiation sterilization process, or using pulsed light to produce a sterile formulation.

The pharmaceutical formulation of the present invention is administered locally to the nose in the form of nasal preparations. The pharmaceutical formulation can be administered to the nasal cavity of a patient topically by any suitable means, but is preferably administered in the form of drops or spray; with spray being more preferred. For topical nasal administration, one or two sprays per nostrile of the formulation are delivered to the surface of the nose one to three times, preferably two times per day, according to the routine discretion of a skilled clinician.

The pharmaceutical formulation is preferably packaged in opaque plastic containers equipped with a nasal spray pump for topical nasal delivery. While a variety of metered-dose nasal spray pumps are available for delivery of an aqueous formulation, a metered-dose nasal spray pump that can deliver a small volume spray is preferred in order to minimize the bitter taste of epinastine. This bitter taste of epinastine is due to post-nasal drip of a solution drainage following nasal administration. The use of a viscous formulation of the present invention coupled with a small volume delivery minimizes the bitter taste perception due to epinastine. When multiple small volumes are administered to provide an overall total volume equal to a single larger volume, the bitterness is reduced or eliminated while the therapeutic efficacy is maintained. For example, when one 140 .mu.L spray is delivered in two 70 .mu.L sprays, the bitter taste is reduced or totally eliminated without affecting the treatment efficacy. The preferred range of dose volume of a nasal spray pump for delivering the present formulation is 50-100 milligrams (about 50-100 .mu.L aqueous solution) per actuation, more preferably 50-90 milligrams (about 50-90 .mu.L aqueous solution) per actuation, and most preferably 60-80 milligrams (about 60-80 .mu.L aqueous solution) per actuation.

The pharmaceutical formulations of the present invention can be used to prevent or treat diseases or disorders related to allergic and inflammatory diseases of the nose. For example, the pharmaceutical formulation is useful for treating seasonal and perennial allergic rhinitis, vasomotor rhinitis, sinusitis, asthma, COPD, or emphysema.

The present invention further provides a method for treating allergic rhinitis in a subject, without the adverse effect of bitter taste. The method comprises the steps of: (a) identifying a subject suffering from allergic rhinitis; and (b) administering to the nose of the subject one to two sprays at .ltoreq.115 .mu.L (50-115 .mu.L) per nostril per spray once or twice daily of an aqueous epinastine formulation comprising (a) 0.1-0.15% (w/v) of epinastine or an acid addition salt thereof, (b) 0.05-0.5% (w/v) of hydroxypropylmethylcellulose to maintain the viscosity between 1.5-10 centipoise, (c)1-2% (w/v) of propylene glycol, and (d) a buffer to maintain the pH between 5-8, said aqueous epinastine formulation does not contain a sweetening agent and has a tonicity between 200-400 mOsm/kG, whereby the subject perceives a minimal or no bitter taste of said epinastine and the symptoms of allergic rhinitis are reduced. "A minimal bitter taste," as used herein, refers to an acceptable taste perceived by the subject. In this method, the preferred concentration of hydroxypropylmethylcellulose is 0.1-0.3% (w/v). The preferred concentration of propylene glycol is 1-2, or 1-1.8% (w/v).

In a preferred method, the epinastine is administered to the subject using a metered-dose nasal spray pump. The target volume of the nasal spray pump, for example, is 70 .mu.L (.+-.15%) or 100 .mu.L (.+-.15%). The aqueous epinastine formulation is preferably administered at 60-85 .mu.L per nostril per spray, or 85-115 .mu.L per nostril per spray. The aqueous epinastine formulation can be administered one to three times a day, preferably one to two times a day, and more preferably twice a day.
 

Claim 1 of 12 Claims

1. A method for treating allergic rhinitis without causing an adverse effect of bitter taste in a subject, comprising the steps of: identifying a subject suffering from allergic rhinitis; administering to the nose of the subject one to two sprays at 50-115 .mu.L per nostril per spray once or twice daily of an aqueous epinastine formulation; wherein said aqueous epinastine formulation consists essentially of (a) about 0.1% (w/v) of epinastine or an acid addition salt thereof, (b) 0.05-0.5% (w/v) of hydroxypropylmethylcellulose to maintain the viscosity between 1.5-10 centipoise, (c)1-2% (w/v) of propylene glycol, and (d) a buffer to maintain the pH between 5-8, said aqueous epinastine formulation has a tonicity between 200-400 mOsm/kG, said formulation does not contain a sweetening agent; whereby the subject perceives a minimal or no bitter taste and the symptoms of allergic rhinitis are reduced.
 

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