WO2015054359A1

WO2015054359A1 - Methods and compositions for symptomatic reflief of the common cold

Info

Publication number: WO2015054359A1
Application number: PCT/US2014/059648
Authority: WO
Inventors: Mark A. EBADI
Original assignee: Ebadi Mark A
Priority date: 2013-10-08
Filing date: 2014-10-08
Publication date: 2015-04-16

Abstract

The present invention relates to methods and compositions for the treatment of symptoms of the common cold that include combinations of adrenergic receptor agonists and anticholinergic agents. In a preferred aspect, the invention features a composition including (a) an anticholinergic (e.g., ipratropium) and (b) a non-selective adrenergic receptor agonist (e.g., epinephrine). In some embodiments, the composition further includes (c) an alpha adrenergic receptor agonist (e.g., oxymetazoline). In some embodiments, the anticholinergic agent is selected from the group consisting of ipratropium, benztropine, oxitropium, tiotropium, glycopyrrolate, oxybutynin, tolterodine, chlorphenamine, diphenhydramine, dimenhydrinate, orphenadrine, trihexyphenidyl, and dicyclomine, or a pharmaceutically acceptable salt thereof.

Description

METHODS AND COMPOSITIONS FOR SYMPTOMATIC RELIEF OF THE COMMON COLD

Cross Reference to Related Applications

This application claims the benefit of U.S. Provisional Application Number 61 /888,409, filed October 8, 2013, which is hereby incorporated by reference in its entirety.

Background of the Invention

The common cold is a viral infection of the upper respiratory tract which primarily affects the nose. The common cold is the most common human disease, and the average person suffers from multiple infections each year. Symptoms include coughing, sore throat, runny nose (rhinorrea), nasal congestion, rhinitis, sneezing, and fever. Various topical and systemic nasal decongestants, analgesics, antipyretics, and cough suppressants are used to provide symptomatic relief.

New combination treatments that simultaneously treat multiple symptoms of the common cold are desirable.

Summary of the Invention

The present disclosure is directed to methods and compositions for the treatment of symptoms of the common cold that include combinations of adrenergic receptor agonists (e.g., epinephrine and/or oxymetazoline) and anticholinergic agents (e.g., ipratropium).

Accordingly, in a first aspect, the invention features a composition including (a) an anticholinergic (e.g., ipratropium) and (b) a non-selective adrenergic receptor agonist (e.g., epinephrine). In some embodiments, the composition further includes (c) an alpha adrenergic receptor agonist (e.g., oxymetazoline).

In some embodiments, the anticholinergic agent is selected from the group consisting of ipratropium, benztropine, oxitropium , tiotropium , glycopyrrolate, oxybutynin, tolterodine, chlorphenamine, diphenhydramine, dimenhydrinate, orphenadrine, trihexyphenidyl, and dicyclomine, or a pharmaceutically acceptable salt thereof.

In other embodiments, the non-selective adrenergic receptor agonist is selected from the group consisting of epinephrine, norepinephrine, and isoprenaline, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the alpha adrenergic receptor agonist is selected from the group consisting of oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, methoxamine, cirazoline, xylometazoline, midodrine, and metaraminol, or a pharmaceutically acceptable salt thereof.

In particular embodiments, the anticholinergic agent is ipratropium (e.g., ipratropium bromide) or a pharmaceutically acceptable salt thereof. In other embodiments, the non-selective adrenergic receptor agonist is epinephrine. In yet other embodiments, the alpha adrenergic receptor agonist is oxymetazoline (e.g., oxymetazoline hydrochloride).

In another aspect, the invention features a composition including (a) ipratropium (e.g., present in an amount from 0.2 mg to 0.4 mg per ml_) or a pharmaceutically acceptable salt thereof (e.g., ipratropium bromide) ; (b) oxymetazoline (e.g., present in an amount from 0.2 mg to 0.3 mg per m l_) or a pharmaceutically acceptable salt thereof (e.g., oxymetazoline hydrochloride) ; and (c) at least 99% water (e.g., at least 99.9% water), wherein the solution has a pH greater than 5.5.

In certain embodiments, the composition may further include epinephrine (e.g., present in an amount from 0.02 to 0.04 mg per ml_).

In certain embodiments, any of the foregoing compositions may further include a binder selected from edetic acid, pentetic acid, nitrilotriacetic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, tartaric acid, malic acid, cortic acid, and citric acid or a pharmaceutically acceptable salt thereof.

In other embodiments, any of the foregoing compositions may further include a humectant selected from sorbitol, propylene glycol, glycerin, polyethylene glycols, triacetin,

hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and poloxamer.

In a further aspect, the invention features a method of treating a condition selected from rhinorrea, rhinitis, sore throat, or nasal congestion. This method includes administering (e.g., nasally administering) to a subject in need thereof a therapeutically effective amount of any of the foregoing compositions.

By "agent" is meant a compound (e.g., ipratropium , oxymetazoline, epinephrine), or a mixture of compounds, having a pharmacological activity.

By "agonist" is meant a compound that binds to a receptor (e.g., an adrenergic receptor) and stimulates a response.

The expression "effective amount" as used herein, refers to a sufficient amount of a composition of the invention to exhibit the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the particular therapeutic agent and the like. The compositions of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the condition being treated and the severity of the condition; the activity of the specific compounds employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compounds employed; the duration of the treatment; drugs used in combination or coincidental with the specific composition employed ; and like factors well known in the medical arts.

The term "humectants" refers to an agent that is used to provide a moisturizing effect.

Humectants are often hygroscopic substances. Common humectants are sorbitol, propylene glycol, glycerin, polyethylene glycols, triacetin, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and poloxamer.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1 -1 9 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid.

Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts, such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, without limitation, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include, without limitation, sodium, lithium , potassium, calcium, magnesium , and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium , quaternary ammonium , and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

By "subject" is meant any animal (e.g., a primate, e.g., a human). Any animal can be treated using the methods, compositions, and kits of the invention. A subject may be from any age group, i.e., neonatal (0 to 1 months of age), infant (1 month to 2 years of age), child (2-12 years of age), adolescent (12-16 years of age), adult (16-65 years of age), or geriatric (65 years of age and older).

As used herein, the term "treatment" refers to administering a composition of the invention or a combination therapy of the invention for therapeutic purposes. To "prevent or inhibit disease" refers to prophylactic treatment of a subject who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease or condition. To "treat a condition" or use for "therapeutic treatment" refers to administering treatment to a subject already suffering from a condition to improve or stabilize the subject's condition. Detailed Description of the Invention

The present disclosure is directed to the discovery that co-administration of anticholinergic agents (e.g., ipratropium) and adrenergic agonists (e.g., epinephrine and/or oxymetazoline) provides significant symptomatic relief for subjects suffering from the common cold. Accordingly, the present invention provides compositions and methods useful in the treatment of rhinorrea, rhinitis, sore throat, and nasal congestion. Compositions of the invention can include a combination of two agents (e.g., ipratropium and oxymetazoline or ipratropium and epinephrine) or a combination of three or more agents (e.g., ipratropium, epinephrine, and oxymetazoline).

Symptoms of the common cold

The common cold is a viral infectious disease of the upper respiratory tract that primarily affects the nose, the symptoms of which generally last from a few days to weeks. Over 200 different viruses have been implicated as the cause of the common cold with the rhinoviruses being the most common. Conditions that are associated with the common cold include rhinorrea, rhinitis, sore throat, and nasal congestion. These conditions may be caused by viral infection, allergic rhinitis, non-allergic rhinitis, and/or perennial rhinitis; additionally, these conditions may be spontaneously acquired without any further indication of the presence of viral infection. Rhinitis denotes a condition involving inflammation of the nasal mucosa in response to various stimuli, and may be considered either allergic or non-allergic and of a seasonal or perennial nature. The symptoms that often most bother subjects suffering from the common cold are nasal congestion and rhinorrhea.

Anticholinergic agents

"Anticholinergic agents" as used herein refers to a compound (e.g., ipratropium) that blocks the neurotransmitter acetylcholine (e.g., inhibits the binding of acetylcholine by at least 5%, 10%, 20%, 40%, 60%, 80%, 90,%, 95% or greater). Examples of common anticholinergics are benztropine, ipratropium , oxitropium, tiotropium, glycopyrrolate, oxybutynin, tolterodine, chlorphenamine, diphenhydramine, dimenhydrinate, orphenadrine, trihexyphenidyl, dicyclomine, bupropion, hexamethonium, tubocurarine, dextromethorphan, mecamylamine, and doxacurium.

Adrenergic receptor agonists

The term "adrenergic receptor agonist" as used herein refers to compounds that stimulate a response from the adrenergic receptors (e.g., increase signaling of the adrenergic receptor by at least 5%, 10%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, or more). Reporter assays known in the art can be used to determine a compound's ability to increase adrenergic receptor signaling. Five categories of adrenergic receptors are known, alpha- 1 , alpha-2, beta-1 , beta-2, and beta-3. Adrenergic receptor agonists vary in their specificity for the receptors. "Non-selective adrenergic receptor agonists" interact with all five of the adrenergic receptor types. Common non-selective adrenergic receptor agonists are epinephrine, norepinephrine, and isoprenaline. "Alpha adrenergic receptor agonists" interact with the alpha- 1 and/or alpha-2 adrenergic receptors. Alpha adrenergic receptor agonists can be selective for alpha-adrenergic receptors over beta-adrenergic receptors or can be selective for one of the alpha subtypes (e.g., alpha- 1 or alpha-2) all other adrenergic receptor types. Common alpha adrenergic agonists are methoxamine, methylnorepinephrine, midodrine, oxymetazoline, metaraminol,

phenylephrine, clonidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, methyldopa, fadolmidine, naphazoline, tetrahydrozoline, cirazoline, xylometazoline, midodrine, metaraminol, and dexmedetomidine.

Formulation of pharmaceutical compositions

The compositions and methods of the invention can include formulation(s) of compound(s) that, upon administration to a subject, result in a concentration of the compound(s) that treats a condition related to the common cold. The compound(s) may be contained in any appropriate amount in any suitable carrier substance, and are generally present in an amount of 0.001 -0.04% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for the oral, nasal, or inhalant administration route. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, sprays, or aerosols. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).

Pharmaceutical compositions according to the invention or used in the methods of the invention may be formulated to release the active compound immediately upon administration or at any predetermined time or time period after administration. The latter types of compositions are generally known as controlled release formulations, which include (i) formulations that create substantially constant concentrations of the agent(s) of the invention within the body over an extended period of time; (ii) formulations that after a predetermined lag time create substantially constant concentrations of the agent(s) of the invention within the body over an extended period of time; (iii) formulations that sustain the agent(s) action during a predetermined time period by maintaining a relatively constant, effective level of the agent(s) in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the agent(s) (sawtooth kinetic pattern) ; (iv) formulations that localize action of agent(s), e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ; (v) formulations that achieve convenience of dosing, e.g., administering the composition once per day; and (vi) formulations that target the action of the agent(s) by using carriers or chemical derivatives to deliver the combination to a particular target cell type. Administration of compound(s) in the form of a controlled release formulation is especially preferred for compounds having a narrow absorption window in the gastro-intestinal tract or a relatively short biological half-life.

Any of a number of strategies can be pursued in order to obtain controlled release in which the rate of release outweighs the rate of metabolism of the compound in question. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Thus, the compound(s) are formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the compound(s) in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, molecular complexes, microspheres, nanoparticles, patches, and liposomes.

Compositions of the inventions can include binding agents or "binders." Any binding agent known in the art can be used in the methods and compositions of the invention. Examples of common binders include edetic acid, pentetic acid, nitrilotriacetic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, tartaric acid, malic acid, cortic acid, and citric acid, and pharmaceutically acceptable salts thereof.

Compositions of the invention can include humectants to control the moisture level of the formulation. Any humectants known in the art can be used in the methods and compositions of the invention. Examples of common humectants include sorbitol, propylene glycol, glycerin, polyethylene glycols, triacetin, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and poloxamer.

Delivery of compound(s)

While preferred, it is not required that administration of compounds be limited to a single formulation or delivery method for all compounds of a combination. The combination can be administered using separate formulations and/or delivery methods for each compound of the combination using, for example, any of the above-described formulations and methods. In one example, a first agent is delivered orally, and a second agent is delivered nasally.

Dosages

The dosage of a compound or a combination of compounds depends on several factors, including: the administration method, the type of condition to be treated, the severity of the condition, whether administration first occurs at an early or late stage of the condition, and the age, weight, and health of the patient to be treated.

For combinations that include a synergistic pair of agents identified herein, the recommended dosage for the agents can be less than or equal to the recommended dose as given in the Physician's Desk Reference, 60^th Edition (2006).

As described above, the compound(s) in question may be administered orally in the form of tablets, capsules, elixirs or syrups. In cases where the compound in itself is not sufficiently soluble to be dissolved, a solubilizer such as ethanol can be applied.

An agent is usually given by the same route of administration that is known to be effective for delivering it as a monotherapy. When used in combination therapy according to the methods of this invention, an agent is dosed in amounts and frequencies equivalent to or less than those that result in its effective monotherapeutic use. Examples

The following examples are intended to illustrate rather than limit the invention.

Example 1. Formulation of a combination of oxymetazoline hydrochloride, ipratropium bromide, and epinephrine

5 m l_ of 0.05% oxymetazoline hydrochloride in saline, 5 m l_ of 0.06% ipratropium bromide in saline, and 0.3 ml_ of 0.1 % epinephrine in water were combined. This formulation is termed "50/50e".

Example 2. Clinical efficacy of oxymetazoline hydrochloride/ipratropium bromide/epinephrine combination (50/50e)

In clinical practice, the exemplary combination of the invention, oxymetazoline, ipratropium, and epinephrine, has shown suprising efficacy in patients as indicated by the following case studies:

A 55 year old woman with a history of asthma presented with two days of nasal congestion, sneezing, and rhinorrhea with no objective evidence of infection. 50/50e was dispensed two sprays in each nostril, three times a day for symptom control. The patient noted resolution of congestion within 5 minutes and resolution of rhinorrhea within 30 minutes of starting the medication.

A 49 year old woman, with a history of allergic rhinitis, presented with 10 days of nasal congestion and runny nose. Exam was consistent with a viral infection/cold. 50/50e was mixed and dispensed two sprays in each nostril, three times a day and patient reported almost immediate symptomatic relief.

A 10 year old boy, with a history of recurrent sinusitis, and recurrent use of antibiotics, was referred by his primary care physician for workup. Examination resulted in the diagnosis of

rhinovirus/cold as opposed to bacterial sinusitis. 50/50e was dispensed two sprays in each nostril, three times a day and patient reported resolution of congestion with 5 minutes and resolution of rhinorrhea with 30 minutes of starting the medication.

A 46 year old man, with a history of environmental allergies, presented with nasal congestion and profuse rhinorrhea. 50/50e was dispensed two sprays in each nostril, three times a day and patient reported resolution of congestion with 5 minutes and resolution of rhinorrhea with 30 minutes of starting the medication.

A 37 year old woman, with a history of asthma, presented with a viral induced asthma exacerbation. Oral steroids were prescribed for asthma and 50/50e was prescribed for the rhinovirus that caused the exacerbation. Patient reported 100% resolution of congestion with 5 minutes and resolution of rhinorrhea with 30 minutes of starting the medication. Other Embodiments

All publications, patent applications, and patents mentioned in this specification are herein incorporated by reference.

Various modifications and variations of the described compositions, methods, and kits of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it will be understood that the invention as claimed should not be unduly limited to such specific embodiments.

What is claimed is:

Claims

1 . A composition comprising:

a) an anticholinergic agent; and

b) a non-selective adrenergic receptor agonist.

2. The composition of claim 1 further comprising:

c) an alpha adrenergic receptor agonist.

3. The composition of claims 1 or 2, wherein said anticholinergic agent is selected from the group consisting of ipratropium , benztropine, oxitropium, tiotropium, glycopyrrolate, oxybutynin, tolterodine, chlorphenamine, diphenhydramine, dimenhydrinate, orphenadrine, trihexyphenidyl, and dicyclomine, or a pharmaceutically acceptable salt thereof.

4. The composition of any one of claims 1 -3, wherein said non-selective adrenergic receptor agonist is selected from the group consisting of epinephrine, norepinephrine, and isoprenaline or a pharmaceutically acceptable salt thereof.

5. The composition of any one of claims 2-4, wherein said alpha adrenergic receptor agonist is selected from the group consisting of oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, methoxamine, cirazoline, xylometazoline, midodrine, and metaraminol or a pharmaceutically acceptable salt thereof.

6. The composition of any one of claims 1 -5, wherein said anticholinergic agent is ipratropium or a pharmaceutically acceptable salt thereof.

7. The composition of claim 6, wherein said anticholinergic agent is ipratropium bromide.

8. The composition of any one of claims 1 -7, wherein said non-selective adrenergic receptor agonist is epinephrine.

9. The composition of any one of claims 2-8, wherein said alpha adrenergic receptor agonist is oxymetazoline or a pharmaceutically acceptable salt thereof.

10. The composition of claim 9, wherein said alpha adrenergic receptor agonist is oxymetazoline hydrochloride.

1 1 . A composition in the form of an aqueous solution comprising:

a) ipratropium or a pharmaceutically acceptable salt thereof

b) oxymetazoline or a pharmaceutically acceptable salt thereof

c) at least 99% water wherein the solution has a pH greater than 5.5.

12. The composition of claim 1 1 , wherein ipratropium or a salt thereof is present in an amount from 0.2 mg to 0.4 mg per imL

13. The composition of claims 1 1 or 12, wherein oxymetazoline or a salt thereof is present in an amount from 0.2 mg to 0.3 mg per m l_.

14. The composition of any one of claims 1 1 -13, wherein said composition comprises ipratropium bromide.

15. The composition of any one of claims 1 1 -14, where said composition comprises

oxymetazoline hydrochloride.

16. The composition of any one of claims 1 1 -15, wherein said composition comprises at least 99.9% water.

17. The composition of any one of claims 1 1 -16, wherein said composition further comprises epinephrine.

18. The composition of claim 17, wherein said epinephrine is present in an amount from 0.02 mg to 0.04 mg per ml_.

19. The composition of any one of claims 1 -18, further comprising a binder selected from edetic acid, pentetic acid, nitrilotriacetic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, tartaric acid, malic acid, cortic acid, and citric acid and pharmaceutically acceptable salts thereof.

20. The composition of any one of claims 1 -19, further comprising a humectant selected from sorbitol, propylene glycol, glycerin, polyethylene glycols, triacetin, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and poloxamer.

21 . A method for the treatment of a condition selected from rhinorrea, rhinitis, sore throat and nasal congestion comprising administering to a subject in need thereof a therapeutically effective amount of a composition of any one of claims 1 -20.

The method of claim 21 , wherein administering comprises nasal administration.

23. The method of claim 21 or 22, wherein said subject is a human.