The present application claims priority from us provisional patent application serial No. 61/431,308 entitled "use of beta-adrenergic inverse agonists for smoking cessation" (UseofBeta-adrenergicinverageeagnostists for smoking cessation) filed 2011, p.a. bond et al, 2011, p.1.10, the contents of which are incorporated herein by reference in their entirety.
Drawings
The following invention will become better understood with regard to the following description, appended claims and accompanying drawings where:
FIG. 1 is a photomicrograph of a lung tissue section from a control mouse showing normal epithelium; hematoxylin-eosin was used for staining.
FIG. 2 is a photomicrograph of a lung tissue section from an asthmatic mouse showing changes in the epithelium; hematoxylin-eosin was used for staining.
FIG. 3 is a photomicrograph of a lung tissue section from an asthmatic mouse chronically treated with the β -adrenergic inverse agonist ICI118,551; hematoxylin-eosin was used for staining.
FIG. 4 is a photomicrograph of a lung tissue section from a control mouse stained with periodic acid-Schiff (PAS) stain; most epithelial cells were not stained.
FIG. 5 is a photomicrograph of a lung tissue section from an asthmatic mouse stained with PAS stain; the epithelium has mostly been transformed into mucus secreting goblet cells.
Fig. 6 is a photomicrograph of a lung tissue section stained with PAS stain from an asthmatic mouse chronically treated with the β -adrenergic inverse agonist ICI118,551; epithelial cells appear substantially normal.
Detailed Description
As used herein, the term "agonist" is defined, in a generally accepted bi-modal model of receptor theory, as a substance that has affinity for the active site of a receptor and thus tends to stabilize the active state of the receptor, or that produces receptor activation and enhances the signaling of those receptors, including but not limited to drugs, hormones, or neurotransmitters. Regardless of the mechanism of action, agonists produce activation of receptors and enhance signaling of those receptors.
As used herein, in the receptor theory of two-state models, the term "antagonist" is defined as a substance that does not tend to stabilize either active or inactive form of the receptor, or that prevents or interferes with the effects of agonists and/or inverse agonists, including but not limited to drugs, hormones, and neurotransmitters. Regardless of the mechanism of action, antagonists prevent or block the effects of agonists and/or inverse agonists.
As used herein, in the receptor-theoretic two-state model, the term "inverse agonist" is defined as an agent that has affinity for, and therefore tends to stabilize, the inactive state of a receptor, or that produces inactivation of a receptor and/or prevents or hinders activation by an agonist, thereby reducing signaling from those receptors, including but not limited to drugs, hormones, or neurotransmitters.
As used herein, the term "concurrently administered" refers to the administration of two or more active agents close enough in time to achieve a therapeutic effect that is preferably greater than the combined therapeutic effects achieved by the administration of either agent alone. Such simultaneous administration may be effected simultaneously, for example, by administering the active agents together in one or more doses in a common pharmaceutically acceptable carrier.
As used herein, the term "subject" refers to a human or animal species. In general, the methods and compositions of the present invention are useful not only for the treatment of humans, but also for the treatment of socially or economically important animal species, such as cows, horses, sheep, pigs, goats, dogs and cats. Unless indicated, the methods and compositions of the present invention are not limited to treatment of humans. However, since only human smoking is known, methods and compositions designed to quit smoking are considered herein to be directed to treatment of humans.
The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent or composition effective to treat, ameliorate or prevent a target disease or disorder, or to exhibit a detectable therapeutic or prophylactic effectAmount of fruit. The effect may be measured, for example, by chemical markers, antigen levels, or physiological indicators such as airway resistance, forced expiratory volume in 1 second (FEV)1) Causing FEV1Decrease by 20% (PC)20) Is detected by a change in the concentration of the irritant methacholine or other indicators such as, but not limited to: (1) pre-bronchodilator FEV1(forced expiratory volume in 1 second); (2) post-bronchodilator FEV1(forced expiratory volume within 1 second after inhalation of salbutamol rescue medication); (3) FVC (forced vital capacity); (4) FEF 25-75% (flow during 25-75% of vital capacity); (5) PEFR (peak expiratory flow rate); (6) TLC (total lung volume); (7) VC (vital capacity); (8) FRC (volume in lungs after normal expiration); (9) exhaled nitrous oxide; (10) eosinophil levels in the lung and/or blood; or (11) IgE levels. Therapeutic effects also include reduction of physical symptoms, such as reduced bronchoconstriction or reduced airway resistance, and may include subjective improvement in physical health noted by the subject or its caregiver. Other tests may include the following: daily or other time period emergency drug use; exacerbation of asthma over a defined period of time, e.g. one year (exacerbation is unscheduled medical visit, delivery to ER, hospitalization); changes in inhaled/oral steroid dose levels; juniper asthma control questionnaire symptom score (ACQ); asthma symptom scores (individually or in combination; nighttime arousal from wheezing/coughing, daytime wheezing, daytime coughing, shortness of breath, chest tightness, coughing of mucus or sputum). The exact therapeutically effective amount of a subject will depend upon the size, weight, and health of the subject, the nature and extent of the conditions affecting the subject, the therapeutic agent or combination of therapeutic agents selected for administration, and variables such as liver and kidney function that affect the pharmacokinetics of the administered therapeutic agent. Therefore, it is not useful to specify an accurate effective amount in advance. However, an effective amount for a given situation can be determined by routine experimentation and is within the judgment of the clinician. In the case of using inverse agonists to treat or prevent mucus hypersecretion in a subject attempting to quit smoking, the term "therapeutically effective amount" may be based on subjective discomfort and nicotine withdrawal symptoms, the viscosity associated with nicotine withdrawal symptoms, experienced by the subjectA reduction in fluid secretion volume, an improvement in the mood and psychological aspects exhibited by the subject, or the subject's ability to refrain from returning to smoking. Other parameters suitable for use in determining a therapeutically effective amount of an inverse agonist or other therapeutic agent in a situation where a subject is attempting to quit smoking are known in the art.
One embodiment of the invention is a method of preventing or controlling mucus hypersecretion in the respiratory tract, said method comprising administering a therapeutically effective amount of a beta-adrenergic inverse agonist to a subject suffering from, or at risk of, mucus hypersecretion. Subjects with chronic cough and/or mucus hypersecretion or at risk of mucus hypersecretion, are typically subjects attempting to quit smoking or about to quit smoking.
Likewise, another embodiment of the invention is a method of treating or preventing a disease or condition characterized by hypersecretion of mucus, comprising administering to a subject having or at risk of having such a disease or condition a therapeutically effective amount of a β -adrenergic inverse agonist. As described in detail above, the subject may be a subject attempting to quit smoking or planning to quit smoking.
In classical receptor theory, two classes of G protein-coupled receptors (GPCRs) are considered: agonists and antagonists. It is believed that the receptor exists in a single inactive state that induces cell signaling only after agonist binding to produce an activated receptor state. In this model, antagonist binding does not produce cell signaling, but only prevents receptor binding and activation by agonist. Subsequently, Costa and Herz demonstrated that the receptor can operate in a constitutively or spontaneously active state, which produces cell signaling in the absence of agonist occupancy. They also provide evidence that certain compounds inactivate these spontaneously active receptors (t&Herz, an antagonist with negative intrinsic activity at opioid receptors coupled to GTP-binding proteins (AntigonistswithNegative IntrinsiccatyOpioid receptors coupled to binding proteins),Proc.Natl.Acad.Sci.USA86:7321-7325(1989)). Also provided areEvidence suggests that GPCRs exist in a constitutively or spontaneously active state that are to some extent inactivated by inverse agonists (R.A. deligt et al, inverse agonism at G protein-coupled receptors (Patho-) physiological correlations and implications of drug discovery (Patho) physiologic Relevance and regulatory for drug discovery),Br.J.Pharmacol.130:1-12 (2000); milligan et al, inverse agonism: is pharmacological curiosity or potential therapeutic strategy? (InverseAgonism: pharmaceutical CuriositotyPotenuous therapeutic Stratagene,TrendsPharmacol.Sci.16:10-13(2000))。
the strategy of this embodiment of the invention is based on the recognition of the presence of inverse agonists and understanding the effect on receptor function that long-term treatment with inverse agonists has. What are inverse agonists? How does it work? Receptors, such as β -adrenergic receptors, which respond to epinephrine, are generally in a balance between an active state and an inactive state. When receptors bind to agonists, such as epinephrine for the beta-adrenergic receptor, they cease to cycle themselves back to the inactive state, thus shifting the balance between the active and inactive states according to the laws of mass action. This is due to the removal of receptors bound to agonists from the equilibrium. Typically, antagonists bind to the receptor, but prevent binding of the agonist. However, molecules known as "inverse agonists" bind to receptors in the inactive state, causing the equilibrium between the active and inactive states to shift towards the inactive state. This is not merely a problem of blocking agonist binding.
In addition, there are populations in vivo that spontaneously have active receptors. These receptors provide a baseline constitutive level of activity; the activity is never completely "off.
As noted above, it has been well demonstrated that chronic administration of beta-adrenergic agonists causes agonist-dependent desensitization. After short-term administration of the β -agonists, the adrenergic receptors are internalized, preventing them from being restimulated for further lung relaxation. By chronic administration of beta agonists, there is in fact a down-regulation of the total number of beta adrenergic receptors. As described above, the result may be a loss of responsiveness observed in asthmatic patients after the use of long-acting beta-agonists, which is referred to as tolerance or rapid drug resistance response.
The treatment methods of the invention are based on the discovery that chronic administration of an inverse agonist has the effect of up-regulating the population number of active beta-adrenergic receptors. The observed activity may be due to constitutive baseline activity of the receptor or a combined effect of increased receptor levels in response to endogenous agonists. This leads to seemingly contradictory results, namely at first glance it appears that the administration of a drug that reduces a physiological function, for example by causing airway hyperresponsiveness in asthma, can enhance said physiological function by up-regulating the number of spontaneously active β -adrenergic receptors associated with said physiological function if administered over a long period of time. In addition or as an alternative, inverse agonists may also increase the coupling of the receptor to its cognate internal G protein, leading to higher outcome outputs such as cellular cAMP production and lower proportion of activated receptor. This is a specific application of the principle of "contradictory pharmacology".
In Klein et al, U.S. Pat. No. 5,116,867, which is incorporated herein by reference, it is proposed to use D-propranolol or a racemic mixture consisting of 85% or more of the D-form for the treatment of asthma. The potency of propranolol form D in terms of inhibition of the beta-adrenergic receptor is 1/100 for form L. Instead, the patent specifies the use of the active form or racemic mixture containing 50% or more of the active beta-adrenergic antagonist.
In U.S. patent No. 6,284,800 to Broder et al, which is incorporated herein by reference, it is proposed to use propranolol, metoprolol, carvedilol or bisoprolol in the D-form for the treatment of asthma. Experiments performed comparing D-form and L-form of propranolol confirm that short-term administration of D-propranolol is beneficial for inhibiting antigen-induced bronchoconstriction and reducing airway hyperresponsiveness. In contrast, short term administration of the L-form increases specific lung resistance, as would be expected for an active β -adrenergic agonist. Propranolol in the D-form is inactive at the beta-adrenergic receptor. Thus, U.S. patent No. 6,284,800 is not directed to the inverse agonistic phenomenon.
PCT patent publication No. WO02/29534 by Bond proposes a synthetic resin having β1And/or β2In conducted experiments, asthmatic mice were chronically treated with compounds characterized as β -antagonists, including alprenolol, carvedilol, and ICI-118,551. then, the trachea from the mice was resected and the contraction of the trachea in response to methacholine, a surrogate for asthmatic attacks, was monitored.
Physiologically more relevant experiments performed by the inventors of the present application in a mouse model of obstructive pulmonary disease demonstrated that alprenolol, which was initially considered long-term beneficial, did not reduce the high responsiveness of the airways compared to untreated sensitized and challenged mice, although alprenolol is an β -adrenergic antagonist, it has partial agonist activity1β of adrenergic antagonist activity1/β2A non-selective adrenergic antagonist. In the experiments reported in this application, chronic administration of carvedilol reduced airway hyperresponsiveness, which would benefit patients with asthma, but it also shifted the sensitivity to responsiveness to methacholine towards lower concentrations, which would be harmful to asthmatic patients.
However, in the experiments reported in PCT patent publication No. WO02/29534, the trachea was cut away from the mice, leaving the vast majority of the pulmonary airways in the mice, the trachea contained almost exclusively β alone1Adrenergic receptors, and the remainder of the airway is β1And β2A mixture of adrenergic receptors. In contrast, the human airways, including both the trachea and the smaller airways, are almost exclusively linedIt is prepared by mixing together β2A receptor. Thus, the experiments reported in PCT patent publication No. WO02/29534 have little predictive value for human asthma. The experiments reported in this application more closely reflect human physiology.
β -adrenergic antagonist drugs or "β blockers" are treated as having the same activity in conventional compression mechanics β blockers are further classified as β based on their selectivity or lack of selectivity1(referred to as "cardioselectivity") or β1/β2("non-selective") or β alone2The latter definition is based on the novel recognition set forth in this application that many G-coupled protein receptors, including β -adrenergic receptors, exhibit low levels of spontaneous activity that can be further prevented by binding of inverse agonists to the receptor.
Despite the knowledge in the art of this subclass of beta blockers, many scientists continue to treat compounds from different subclasses as a class. An example of this is the clinical trial of the beta blocker bucindolol for congestive heart failure, conducted in 1998-1999. Previously, two other beta blockers metoprolol and carvedilol have been clinically tested in patients with CHF and showed significant mortality reduction. Bucindolol failed to show any benefit over placebo and therefore the clinical trial was discontinued. The inventors of the present application noted that metoprolol and carvedilol are both beta-inverse agonists, while bucindolol is a neutral antagonist with partial agonist activity. Thus, the inventors of the present application predicted that only beta-adrenergic inverse agonists would be effective in the treatment of CHF. As such, the inventors of the present application predicted that only beta-adrenergic inverse agonists would be effective for long-term treatment of asthma airways with high responsiveness. Such a distinction is not made or suggested in PCT patent publication No. WO 02/29534. This prediction is demonstrated in the present invention by the finding that the beta blocker alprenolol, a partial agonist previously considered to be the preferred drug in the deficient murine asthma model, was found to be devoid of any activity in the present invention.
In contrast, the present invention provides the use of an active β -adrenergic receptor-binding form of a β -adrenergic inverse agonist in the prevention or inhibition of mucus hypersecretion, resulting in a new therapeutic modality for aiding smoking cessation. This treatment modality is in contrast to other methods of smoking cessation that are primarily directed at psychological or behavioral aspects, treating the physiological effects of smoking cessation such as tremors, coughs, and mucus hypersecretions. Inverse agonists may take the form of pure or substantially pure enantiomers or diastereomers, or may be racemic mixtures. In many cases, the active form of such compounds is the L-form when only one chiral center is present. In the case of nadolol having three chiral centers and possibly 12 isomers, the most active form is the RSR form of nadolol, although only two are usually formed during synthesis.
Particularly preferred for use according to the invention are the beta-adrenergic inverse agonists: nadolol, for example as the hydrochloride salt; bucindolol, for example, as the hydrochloride salt; butoxamine, for example, as the hydrochloride salt; caramolol, for example as the hydrochloride salt; carvedilol, for example, as the hydrochloride salt; ICI-118,551, for example as the hydrochloride salt; levobunolol, for example as the hydrochloride salt; metoprolol as the tartrate or succinate salt; propranolol, for example as the hydrochloride salt; sotalol, for example as the hydrochloride salt; timolol, for example, as the hydrochloride salt; and salts, solvates, analogs, homologues, mimetics, bioisosteres, stereoisomers, hydrolysates, metabolites, precursors and prodrugs thereof. Particularly preferred inverse agonists are carvedilol, nadolol and ICI-118,551. The most particularly preferred inverse agonists are nadolol and ICI-118,551. As used herein, the recitation of an inverse agonist compound or agonist compound where applicable, includes all pharmaceutically acceptable salts of said inverse agonist compound or agonist compound, unless excluded. Thus, the recitation of nadolol or ICI-118,551 as the hydrochloride salt does not exclude other pharmaceutically acceptable salts that are or can be prepared.
Inverse agonists useful in the methods and compositions of the invention have been shown generally to be β2Inverse agonism of adrenergic receptors, which as shown to β1-adrenergic receptors and β2Non-selective inverse agonists of inverse agonism of both adrenergic receptors, or as selective β2-inverse agonists.
Preferably, the inverse agonists useful in the methods and compositions of the present invention reduce airway hyperresponsiveness and also do not shift methacholine response to the left (i.e., to lower methacholine concentrations) when tested in an asthmatic mouse model.
Specifically, and also contemplated within the scope of the present invention, are nadolol analogs of formula (I) wherein R is1Is hydrogen or lower alkyl, R2Is hydrogen or lower alkyl, and m and n are 1 to 3, with the proviso that when R1And R2Both are hydrogen and when m is 1, n is not 1. The term "lower alkyl" as used herein is defined as a straight or branched chain hydrocarbyl residue of 1 to 6 carbon atoms.
Furthermore, particularly contemplated within the scope of the invention are carvedilol analogs of formula (II) wherein R is1Is hydrogen or lower alkyl, R2Is hydrogen or lower alkyl, and R3Is hydrogen or lower alkyl, provided that R1、R2And R3Not all are hydrogen.
Furthermore, contemplated within the scope of the present invention are timolol analogs of formula (III), wherein R1Is hydrogen or lower alkyl and R2Is hydrogen or lower alkyl, provided that R1And R2Both are not hydrogen.
Furthermore, contemplated within the scope of the invention are metoprolol analogs of formula (IV) wherein R is1Is hydrogen or lower alkyl and R2Is hydrogen or lower alkyl, provided that R1And R2Both are not hydrogen.
Also contemplated within the scope of the invention are ICI-118,551 analogs of formula (V) wherein R1Is lower alkyl, R2Is hydrogen or lower alkyl, R3Is hydrogen or lower alkyl, R4Is hydrogen or lower alkyl, R5Is lower alkyl and R6Is lower alkyl, provided that R1、R3、R5And R6Not all are methyl, and R2And R4Not all are hydrogen.
In the case of salts, it is known that organic compounds, including compounds having an activity suitable for the process of the invention, have a plurality of groups which can accept or donate protons, depending on the pH of the solution in which they are present. These groups include carboxyl, hydroxyl, amino, sulfonic acid and other groups known to participate in acid-base reactions. Recitation of a compound or analog includes such salt forms as they exist at physiological pH or the pH of a pharmaceutical composition, unless specifically excluded. Pharmaceutically acceptable salts include, but are not limited to, the salts described below.
Likewise, prodrug esters may be formed by ester-forming reaction of a carboxyl or hydroxyl group on a compound or analog suitable for the methods of the invention with an acid or alcohol. The acid or alcohol typically includes lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. These groups may be substituted, for example, with hydroxy substituents or other substituents. Such prodrugs are well known in the art and need not be described further herein. Prodrugs are usually converted to the active compound by intracellular enzymes through hydrolysis of the ester bond. Other suitable groups that can be used to form prodrug esters are well known in the art. For example, prodrugs may include amides prepared by reaction of the parent acid compound with a suitable amine. In some cases, it is desirable to prepare a prodrug of the diester type, such as an (acyloxy) alkyl ester or an ((alkoxycarbonyl) oxy) alkyl ester. Suitable esters as prodrugs include methyl, ethyl, propyl, isopropyl, N-butyl, isobutyl, tert-butyl, morpholinoethyl and N, N-diglycolamido, to the extent necessary. The methyl ester prodrugs can be prepared by acid-forming the compound with the appropriate carboxylic acid group in a medium such as one containing an acid or base esterification catalyst (e.g., NaOH, H)2SO4) By reaction in methanol. Ethyl ester prodrugs were prepared in a similar manner using ethanol instead of methanol. Morpholinoethyl ester prodrugs can be prepared by the reaction of the sodium salt of a suitable compound (in a medium such as dimethylformamide) with 4- (2-chloroethyl) morpholine hydrochloride (available from aldrich chemical co., Milwaukee, wis.
Pharmaceutically acceptable salts include inorganic or organic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, fumarate, maleate, acetate, citrate, lactate, tartrate, sulfamate, malonate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, quinic acid salt, formate, cinnamate, picrate, propionate, succinate, glycolate, gluconate, ascorbate, benzoate, anthranilate, p-hydroxybenzoate, phenylacetate, mandelate, pamoate, pantothenate, 2-hydroxyethanesulfonate, sulfanilate, stearate, cyclohexylsulfamate, alginate beta-hydroxybutyrate, salicylate, hemi-lactobionate, galacturonate, and other suitable salts. Such salts can be derived using acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid, as well as the other corresponding acids listed above.
Pharmaceutically acceptable salts also include salts formed with bases such as alkali metal salts, e.g., sodium or potassium salts, as well as pyridine, ammonium, piperazine, diethylamine, nicotinamide, calcium, magnesium, zinc, lithium, methylammonium, triethylamino, dimethylamido, Ν' -benzhydrylethylenediamine, choline, diethanolamine, chloroprocaine, ethylenediamine, meglumine, procaine and tris (hydroxymethyl) aminomethane salts. Such salts may be derivatized using a suitable base.
The subject to be treated may be a human patient or a socially or economically important animal including, but not limited to, a dog, cat, horse, cow, sheep, goat or pig. The methods of the invention are not limited to treatment of humans. However, since it is known that only humans smoke, methods and compositions relating to smoking cessation are considered herein to be directed only to treatment of humans.
The methods of administering the beta-adrenergic inverse agonists of the invention are generally directed to one or more physiological symptoms associated with smoking cessation, including but not limited to tremors, mucus hypersecretion, and coughing. This activity provides a unique method of quitting smoking and supplements other methods of treating psychological and behavioral problems.
Methods of administering β -adrenergic inverse agonists of the invention will generally produce continuous levels of said β -adrenergic inverse agonists in the bloodstream of a subject2-a responsive therapeutic effect of an adrenergic agonist drug. This provides a combination therapy discussed in detail below.
The methods of the invention generally inhibit or reverse the transformation of airway epithelial cells into mucus-producing goblet cells.
The beta-adrenergic inverse agonist can be administered in combination with one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients may include, but are not necessarily limited to, calcium carbonate, calcium phosphate, various sugars or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and physiologically compatible solvents. Other pharmaceutically acceptable excipients are well known in the art. The beta-adrenergic inverse agonist can be administered in combination with one or more pharmaceutically acceptable carriers. Exemplary pharmaceutically acceptable carriers include, but are not limited to, any and/or all solvents, including aqueous and non-aqueous solvents, dispersion media, coatings, antibacterial and/or antifungal agents, isotonic and/or adsorption delaying agents, and the like. The use of such media and/or agents in pharmaceutically active substances is well known in the art. Any conventional media, carrier, or agent is contemplated for use in the compositions of the present invention, except insofar as it is incompatible with one or more active ingredients. Supplemental active ingredients may also be incorporated into the compositions, particularly under combination therapy as described below. For administration of any of the compounds used in the present invention, the formulation should meet sterility, non-pyrogenicity, general safety and purity standards required by the FDA office of biologicals standards (FDA), or other regulatory organizations that manage pharmaceuticals.
Thus, the beta-adrenergic inverse agonist can be formulated for oral, sustained release oral, buccal, sublingual, inhalation, spray or parenteral administration. However, for the treatment or prevention of mucus hypersecretion associated with smoking cessation, oral administration of beta-adrenergic inverse agonists is generally preferred. Other relevant routes of administration within the scope of the present invention include administration via a transdermal patch or as a chewing gum.
If the beta-adrenergic inverse agonist is administered orally in a conventional or sustained release formulation, it is usually administered in a conventional unit dosage form such as a tablet, capsule, pill, lozenge, tablet, powder, or liquid such as a solution, suspension, tincture, or syrup. Oral formulations typically include conventional excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and other conventional pharmaceutical excipients. In certain embodiments, the oral pharmaceutical compositions comprise an inert diluent and/or an assimilable edible carrier, and/or they may be enclosed in a hard or soft shell gelatin capsule. Alternatively, they may be compressed into tablets. As another alternative, they may be incorporated directly into the food, particularly for veterinary practice. For oral therapeutic administration, they may be combined with excipients or used in the form of swallowable tablets, troches, dragees, pills, lozenges, capsules, wafers, chewing gums or other conventional dosage forms.
Tablets, pills, lozenges, capsules, wafers, chewing gums or other conventional dosage forms may also contain the following: binders such as gum tragacanth, gum acacia, corn starch, sorbitol, starch mucilage, polyvinylpyrrolidone or gelatin; excipients or fillers, such as dicalcium phosphate, lactose, microcrystalline cellulose or sugars; disintegrants, for example potato starch, croscarmellose sodium or sodium starch glycolate or alginic acid, lubricants, for example magnesium stearate, stearic acid, talc, polyethylene glycol or silicon dioxide; sweetening agents, such as sucrose, lactose or saccharin; wetting agents, such as sodium lauryl sulfate; or a flavoring agent such as peppermint, oil of wintergreen, orange flavoring, or cherry flavoring. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form and properties of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both. The pharmaceutical compositions of the invention may be manufactured in a manner known per se, for example by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing processes. One important dosage form is gums, such as chewing gums, gum forming agents and excipients are well known in the art. Chewing gums generally comprise a natural or synthetic gum base, coloring, flavoring and other conventional ingredients.
Pharmaceutical formulations for oral use can be obtained as follows: the active compounds are mixed with solid excipients, the resulting mixture is optionally ground, and the mixture of granules is worked up, if desired with the addition of suitable auxiliary materials, to obtain tablets or sugar-coated tablet cores. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Sugar-coated tablet cores may be provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or dragee inclusions to identify or characterize different combinations of active compound agents.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
In one alternative, a sustained release formulation is used. Sustained release formulations are well known in the art. For example, they may include the use of polysaccharides such as xanthan and locust bean gum in combination with a carrier such as dimethylsilane, silicic acid, a mixture of mannan and galactan, xanthan and micronized seaweed, as described in U.S. Pat. No. 6,039,980 to Baichwal, which is incorporated herein by reference. Other sustained release formulations incorporate biodegradable polymers such as the lactic-glycolic acid polymers described in U.S. patent No. 6,740,634 to Saikawa et al, which is incorporated herein by reference. Other sustained release formulations incorporate expandable grids comprising polyvinyl alcohol and polyethylene glycol based polymers, as described in U.S. Pat. No. 4,428,926 to Keith, which is incorporated herein by reference. Other sustained release formulations are based on Rohm&Eudragit of HaasTMPolymers comprising copolymers of acrylates and methacrylates with quaternary ammonium groups as functional groups and ethyl acrylate-methyl methacrylate copolymers with neutral ester groups. Particularly preferred extended release compositions suitable for use in the methods of the present invention are extended release compositions comprising nadolol or ICI-118,551 as their active ingredients.
Oral liquid preparations may take the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, tinctures or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, glucose/sucrose syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifiers such as lecithin, sorbitan monolaurate or gum arabic; non-aqueous media (which may include edible oils), such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethylene glycol; or preservatives, for example methyl paraben, propyl paraben or sorbic acid. If desired, the formulations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents (e.g. mannitol).
Those skilled in the art recognize that the route of administration is an important determinant of the rate of absorption efficiency. For example, the digestive tract route, such as the mouth or cheek, is generally considered the safest route of administration. The delivery of the drug in the circulation is slow, eliminating the rapid high blood levels of the drug that can potentially have acute side effects. Although this is considered the safest route of administration, several disadvantages remain. An important drawback is that the rate of absorption is variable, which is a significant problem if the blood level range over which the desired therapeutic effect of the drug is separated from its toxic effects is small, i.e. if the drug has a relatively low therapeutic index. Furthermore, patient compliance may not always be ensured, particularly if the patient perceives that oral administration is unpleasant. In addition, with oral administration, extensive hepatic metabolism may occur before the drug reaches its target site.
Solutions of the active compounds as the free base or pharmaceutically acceptable salts can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and/or mixtures thereof and/or in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Suitable non-sensitizing and non-sensitizing preservatives are well known in the art.
The carrier can also be a solvent and/or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and/or liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of a suitable particle size in the case of dispersions, and/or by the use of surfactants. Prevention of the action of microorganisms can be achieved by the inclusion of various antibacterial and/or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, or thimerosal. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. In many cases, it is preferred to prepare the solution in a physiologically compatible buffer such as Hanks's solution, Ringer's solution, or physiological saline buffer.
Another route of administration of the compositions of the present invention is nasal, using a dosage form such as a nasal solution, nasal spray, aerosol or inhalant. Nasal solutions are typically aqueous solutions designed to be administered in drops or spray form to the nasal passages. Nasal solutions are typically prepared so that they resemble nasal secretions in many respects in order to maintain normal ciliary activity. Thus, aqueous nasal solutions are typically isotonic and/or slightly buffered in order to maintain a pH of about 5.5 to about 6.5. In addition, antimicrobial preservatives similar to those used in ophthalmic formulations and/or suitable pharmaceutical stabilizers, if desired, may be included in the formulations. Various commercial nasal formulations are known and may include, for example, antibiotics or antihistamines. The spray composition may be formulated, for example, as an aqueous solution or suspension, or as an aerosol delivered from pressurized packs using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2,3,3, 3-heptafluoropropane, 1,1,1, 2-tetrafluoroethane, carbon dioxide, or other suitable gas.
Aerosol therapy allows for nearly ideal benefit to risk ratios, since very small doses of inhaled drugs provide the most appropriate therapy with the lowest side effects. However, the therapeutic effect of a drug administered by aerosolization depends not only on the pharmacological properties of the drug itself, but also on the characteristics of the delivery device. The characteristics of the delivery device affect the amount of drug deposited in the lungs and the distribution pattern of the drug in the airways.
Aerosols are suspensions of fine particles carried in air. The particles may be solid or liquid. The aerosol particles are multi-phase dispersed (i.e., the particles have various sizes), and the aerosol particle size distribution is best described by a log-normal distribution. The particles tend to precipitate (settle), adhere to each other (coagulate), and adhere to structures such as pipes and mucous membranes (sediment). Particles delivered by aerosol can be conveniently characterized according to their aerodynamic behavior. One parameter is Mass Median Aerodynamic Diameter (MMAD). By definition, a particle distribution with an MAD of 1 μm has the same average settling rate as a droplet with a unit density and a diameter of 1 μm.
The size of the aerosol particles and variables that affect the respiratory system affect the deposition of inhaled aerosols in the airways. On the one hand, particles larger than 10 μm are unlikely to deposit in the lung. However, particles smaller than 0.5 μm may reach the alveoli or may be exhaled. Thus, particles between 1 μm and 5 μm in diameter are most efficiently deposited in the lower respiratory tract. Particles of these sizes are most effective for delivery of therapeutic agents, including beta-adrenergic inverse agonists.
Therapeutic aerosols are typically produced by nebulizing a liquid in a jet nebulizer or by vibration of a static liquid pool (ultrasonic nebulization). Preformed aerosols may also be administered. Examples of the latter include MDI and dry powder devices. Regardless of the delivery device used, the patient should be instructed to use it correctly.
All spray atomizers work by similar operating principles, which can be explained in the familiar perfume sprayers. The liquid is placed at the bottom of the closed container and the aerosol is generated by injecting air from a compressor or compressed gas canister through the device. Ultrasonic nebulizers produce aerosols by vibrating a liquid located above a transducer at a frequency of about 1 mHz. This creates a mist of particles which is carried out of the device by the air flow and towards the patient. Depending on the design of the nebulizer and its manner of operation, aerosols of different particle numbers, sizes and distributions may be produced by the nebulizer. It should be noted that not all atomizers have the specification indices (MMAD, flow rate, output) required to provide optimal performance. Recent studies compared the pulmonary deposition of 4 nebulizers in healthy volunteers and showed that the median pulmonary aerosol deposition, expressed as a percentage of the medicament initially loaded in the nebulizer, ranged from 2 to 19%. To minimize side effects, the pH and osmolarity of the atomized solution should be controlled.
Metered Dose Inhalers (MDIs) are probably the most widely used therapeutic aerosols for delivering inhaled drugs to outpatients due to their convenience and effectiveness. Most of the MDIs currently used contain a suspension of the drug in the propellant. MDI has 2 main components: (i) a canister, which is a sealed plastic or metal cylinder containing a propellant, an active drug and a metering chamber; and (ii) a driver that is a molded plastic container that holds the canister and directs the released aerosol to the airway of the patient.
The propellant mixture is selected to achieve the vapor pressure and spray properties required for optimal drug delivery. Chlorofluorocarbons have been used previously, but due to environmental concerns, chlorine-free propellants are now used. Finely divided particles of medicament, typically less than 1 μm, are suspended in a pressurised (liquefied) propellant. In order to prevent coagulation of the drug, a surfactant such as sorbitan oleate, lecithin or oleic acid is usually added; other surfactants are known in the art. The metering chamber typically has a volume of 2 to 100. mu.L. When the canister is depressed into the drive, the contents of the metering chamber are released. Almost simultaneously, the propellant begins to evaporate, causing the discharged liquid to disintegrate into particles that are propelled forward with great momentum. In order to obtain optimal pulmonary drug deposition, the drug should be released at the beginning of a slow inspiration lasting about 5 seconds, followed by a 10 second breath hold. Several inhalation aids have been designed to improve the effectiveness of MDIs. They are most useful in patients with poor hand-breathing coordination. A short tube (e.g., a cone or sphere) can introduce the aerosol directly into the mouth, or a collapsible bag can act as an aerosol reservoir, keeping the particles suspended for 3 to 5 seconds, during which time the patient can inhale the drug. However, when using any of these devices, the aerosol velocity decreases after entering the oropharynx and the drug availability to the lungs and deposition in the oropharynx decreases.
Dry powder inhalers have been designed for delivering medicament to a user MPatients with DI difficulties (e.g. children and elderly patients). Generally, the appropriate dosage is placed in a capsule with a flow aid or filler such as large lactose or glucose particles. Inside the device, the capsule is first pierced by the needle (e.g. by piercing it with the needle)) Or cut in half (e.g. by cutting)). During inhalation, the capsule rotates or the propeller rotates, creating small particles that cause the contents of the capsule to enter the inhaled air and break up into pieces suitable for delivery to the airway. The energy required to disperse the powder is derived from the inspiratory activity of the patient. More recently, more convenient multi-dose dry powder inhalers have been described (e.g. dry powder inhalers). Potential problems associated with dry powder inhalers include esophageal irritation and thus cough caused by the direct effect of the powder in the airway. Furthermore, the walls of the capsule may become encapsulated by the drug as a result of failure of the capsule to release the drug or failure of the agglomerated powder to disintegrate. This may cause virtually all of the drug to be deposited in the mouth. These powder units are free of chlorofluorocarbons and may provide an alternative to MDI.
Due to the nature of the interaction between inverse agonists and the beta-adrenergic receptors with which they interact, therapeutic response occurs gradually over time as receptor concentrations in diseased tissue increase in response to administration of inverse agonists. Therefore, inverse agonists are usually administered chronically over a considerable period of time. Thus, in a particularly preferred alternative, the dose is titrated at the beginning of administration and gradually increased. In other words, the beta-adrenergic inverse agonist is administered over time in a series of progressively varying doses beginning with the lowest dose and increasing to the highest dose. When the highest dose is reached, the β -adrenergic inverse agonist continues to be administered at that dose (maintenance dose). For example, with orally administered nadolol, treatment may begin at a 1mg dose, then gradually go through 3mg, 5mg, 10mg, 15mg, and then reach higher maintenance doses such as 25mg, 30mg, 50mg, 75mg, 100mg, 150mg or more as needed, depending on the particular condition to be treated, the severity and the response of the condition to the treatment. A particularly preferred dosage regime begins with 10mg and then progresses through 25, 50, 75, 100 and 150mg based on established dose escalation criteria determined by pulmonary function, symptoms, heart rate and blood pressure, as described in further detail below. Criteria relating to the effect of beta-adrenergic inverse agonist treatment on a subject's physiological condition, mood, behavior, or addiction to nicotine craving may also be included in the dose escalation calculation when the beta-adrenergic inverse agonist is administered for the treatment or prevention of mucus hypersecretion in a subject attempting to quit smoking. Similar dosage regimes are available for other inverse agonists, and the exact starting dose will generally depend on the affinity of the inverse agonist for the binding site of the β -adrenergic receptor.
Various factors must be taken into account in setting the appropriate dose for the beta-adrenergic inverse agonist. These factors include whether the patient is taking other drugs that alter the pharmacokinetics of the beta-adrenergic inverse agonists, causing them to be degraded more quickly or more slowly. In particular, if a patient is taking the antibiotic erythromycin or neomycin, it is often necessary to reduce the maintenance dose.
β -adrenergic inverse agonist toxicity and therapeutic efficacy can be determined, for example, by use in cell cultures or experimental animals50(lethal dose for 50% of the population) and ED50(dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as LD50/ED50The ratio of (a) to (b). Compounds that exhibit large therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used to formulate various dosages for use in humans. The dosage of such compounds is preferably such that ED is included50And has little or no toxicityCirculating concentration range. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
For any compound used in the methods of the invention, a therapeutically effective dose can be initially estimated from cell culture assays. For example, the agent can be formulated to obtain an IC in an animal model that is determined to be included in cell culture50(i.e., the concentration of test compound that achieves the half-maximal increase in receptor signaling when long-term effects are considered). Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured by, for example, HPLC.
The exact formulation, route of administration and dosage can be selected by the individual physician according to the condition of the patient (see, e.g., Fingl et al, pharmacological basis of therapeutics, 1975, Ch.1p.1). It should be noted that the attending physician knows how and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician also knows that treatment can be adjusted to higher levels (to exclude toxicity) if the clinical response is inadequate. In the management of target disorders, the magnitude of the administered dose varies with the severity of the condition to be treated and the route of administration. The severity of the condition can be assessed, for example, in part, by standard prognostic assessment methods. In addition, the dosage, and possibly the frequency of administration, also varies with the age, presentation and response of the individual patient. For the case where the subject is a non-human mammal and can be treated by administration of a beta adrenergic inverse agonist, procedures comparable to those discussed above can be used in veterinary medicine, if appropriate.
Such agents may be formulated and administered systemically or topically depending on the particular condition to be treated. Administration is usually systemic. Techniques for formulation and administration can be found in Remington pharmacy (Remington's pharmaceutical sciences) 18 th edition, Mack publishing Co., Easton, Pa. (1990). Suitable routes may include oral, oral controlled release, nasal, buccal or transdermal routes. Oral administration is generally preferred, particularly when administering a beta-adrenergic inverse agonist to treat or prevent mucus hypersecretion in a subject attempting to quit smoking. Buccal administration using chewing gum and transdermal administration, for example using a transdermal patch, are also important routes of administration within the scope of the present invention.
It is within the scope of the present invention to formulate the compounds disclosed herein for use in the practice of the present invention in dosages suitable for systemic administration using a pharmaceutically acceptable carrier. After a proper choice of carrier and suitable manufacturing methods, the composition of the invention, in particular the combination formulated as a solution, can be administered parenterally, for example by intravenous injection. The compounds can be readily formulated into dosages suitable for oral administration using pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredient is contained in an amount effective to achieve its intended purpose. Determination of an effective amount is well within the ability of those skilled in the art, particularly in light of the detailed disclosure provided herein. In addition to the active ingredient, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Formulations formulated for oral administration may take the form of tablets, dragees, capsules or solutions. The pharmaceutical compositions of the invention may be manufactured in a manner known per se, for example by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or freeze-drying processes.
Pharmaceutical formulations for oral use can be obtained as follows: the active compounds are mixed with solid excipients, the resulting mixture is optionally ground, and the mixture of granules is worked up, if desired with the addition of suitable auxiliary materials, to obtain tablets or sugar-coated tablet cores. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Sugar-coated tablet cores may be provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or dragee inclusions to identify or characterize different combinations of active compound agents.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
Methods of formulating compounds such as β -adrenergic inverse agonists for transdermal administration are well known in the art and are described, for example, in k.d&Bunge, pharmacokinetic model of skin absorption (pharmacokinetic models of dermalabsorption),J.Pharm.Sci.1699 (2001) and P.Morgani et al, transdermal absorption and delivery systems (percutaneous absorption systems),Clin.Dermatol.19: 489-. Generally, transdermal delivery systems involve the incorporation of a drug into a carrier, such as a polymer and/or pressure sensitive adhesive formulation or other form of carrier. The pressure sensitive adhesive must adhere effectively to the skin and allowTransdermal administration of active ingredients such as β -adrenergic inverse agonists from a carrier through the skin and into the bloodstream of a patient is described in U.S. Pat. Nos. β to Zaffatroni, 3,731,683 to Zaffatroni, β to Urquhart et al, β to Higuchi et al, 4,201,211 to Chandrasekaran et al, β to Chandrasekara, β to Chandrasekaran, β to Campbell et al, β to Leeper, 4,559,222 to Enscor et al, 4,568,343 to Leeper et al, β to Chan et al, β to Gale et al, Galbernevoid β to Lemphee et al, Galbere β, Lemphee et al, Galnee β to Lemphee et al, Galnee β, Lemphee β, Lesclere β, Lemphee et al, Lemphee β, Lemphe et al, Lemphe β, and Lemphe β, all references thereto, Lemphe et al.
Another route of administration that may be used is by use of chewing gum, which is a suitable route for buccal administration of beta-adrenergic inverse agonists. The use of chewing gums for the administration of pharmacologically active substances is well known in the art and is described, for example, in the following U.S. patent nos.: 7,101,579 by Athanikar et al, 6,537,525 by West, 6,344,222 by Cherukuri et al, 5,922,347 by Hausler et al, and 4,971,079 by Talapin et al, all of which are incorporated herein by reference.
In the methods of the invention, the inverse agonist is typically administered as a daily dose or multiple times per day, depending on the half-life of the inverse agonist and other factors described above. Alternatively, the inverse agonist may be administered less frequently, e.g., every other day, every third day, every fourth day, weekly, etc. Less frequent administration can be achieved by developing an in vivo drug depot that causes the drug to be released over a long sustained period of time. Such depot may be administered orally or by injection. One skilled in the art of pharmacokinetics will recognize the importance of understanding the bioavailability and half-life of a drug for the administration of a particular drug. It is well known that if the time interval between administrations is less than 4 half-lives, the drug will accumulate in the body, in which case the total body reserve index of the drug increases to a plateau or steady state concentration. The average total body reserve of drug at the plateau is a function of the dose, the interval between administrations, the bioavailability of the drug, and the elimination rate of the drug. Thus, one of ordinary skill in the art will be able to determine the dosage and time between administrations that will achieve the desired effect for a given drug.
Another embodiment of the invention encompasses a method of preventing or controlling mucus hypersecretion in the respiratory tract, said method comprising administering to a subject suffering from or at risk of mucus hypersecretion:
(1) a therapeutically effective amount of a beta-adrenergic inverse agonist; and
(2) a therapeutically effective amount of an additional compound for treating mucus hypersecretion.
In this method, the subject suffering from or at risk of mucus hypersecretion may be a subject attempting to quit smoking.
Additional compounds for the treatment of hypersecretion of mucus may be, but are not limited to, antibiotics, DNases, bronchodilators, corticosteroids, expectorants, (2R,3R,4S,5R) -2- [ 6-amino-2- (1S-hydroxymethyl-2-phenyl-ethylamino) -purin-9-yl ] -5- (2-ethyl-2H-tetrazol-5-yl) -tetrahydrofuran-3, 4-diol, 4-hydroxy-7- [2- [ [2- [ [3- (2-phenylethoxy) propyl ] sulfonyl ] ethyl ] amino ] ethyl-2- (3H) -benzothiazolone, cis-20, 4-cyano-4- [3- (cyclopentyloxy) -4-methoxybenzene Alkyl cyclohexanecarboxylic acid or a PDE4 inhibitor.
Antibiotics can be, but are not limited to: (1) aminopenicillins, including but not limited to ampicillin and amoxicillin; (2) quinolones, including but not limited to, cinoxacin, norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, lomefloxacin, fleroxacin, pefloxacin, levofloxacin, trovafloxacin, gatifloxacin, moxifloxacin, clinafloxacin, and sitafloxacin; or (3) trimethoprim-sulfamethoxazole.
The DNase may be, but is not limited to, a recombinant human DNase.
The bronchodilator may be, but is not limited to, methylxanthine, having a strong β2Methylxanthines include, but are not limited to, theophylline, aminophylline, theobromine, enprophylline, dyphylline, isobutyltheophylline, choline theophylline, abiphylline, arophylline, pamiteine and caffeine have β2Sympathomimetic agents of adrenergic stimulatory nature include, but are not limited to, salbutamol, bitolterol, clenbuterol, chlorpropanaline, dobutamine, fenoterol, formoterol, isoetharine, isoproterenol, levalbuterol, mabuterol, metaproterenol, pirbuterol, ritodrine, salbutamol, salmeterol, terbutaline and salts, solvates, analogs, congeners, bioisosteres, hydrolysates, metabolites, precursors and prodrugs. Anticholinergics include, but are not limited to ipratropium bromide, tiotropium bromide, and oxitropium bromide and salts, solvates, analogs, congeners, bioisosteres, hydrolysates, metabolites, precursors, and prodrugs thereof.
In addition, the additional compound may be a corticosteroid, including but not limited to beclomethasone, mometasone, braytone, ciclesonide, flunisolide, fluticasone, methylprednisolone, prednisolone, prednisone, and fluprednisolone, and salts, solvates, analogs, congeners, bioisosteres, hydrolysates, metabolites, precursors, and prodrugs thereof.
In addition, the additional compound may be an epidermal growth factor receptor (EGF-R) antagonist, as described in Nadel et al, U.S. Pat. No. 6,846,799, incorporated herein by reference. Epidermal growth factor receptor antagonists include, but are not limited to: anti-EGF-R antibodies, tyrosine kinase inhibitors, antioxidants, inhibitors of mitogen-activated protein kinase (MEK), inhibitors of transmembrane Metalloproteases (MP), and antibodies that bind to factors that stimulate EGF production or EGF-R production. Specific inhibitors include tyrosine kinase inhibitors such as quinazolines, e.g., PD153035, 4- (3-chloroanilino) quinazoline, or CP-358,774; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP59326, CGP60261 and CGP62706 and pyrazolopyrimidines; 4- (phenylamino) 7H-pyrrolo [2,3-d ] pyrimidines; curcumin (diferuloylmethane); 4, 5-bis (4-fluoroanilino) phthalimide; tyrosine phosphorylation inhibitors containing nitrothiophene moieties; protein kinase inhibitor ZD-1839 (AstraZeneca); CP-358774(Pfizer, Inc.); PD-0183805 (Warner-Lambert); or an antisense molecule.
Furthermore, the additional compound may be a PDE4 inhibitor, such as, but not limited to, cilomilast, felast, ibudilast, piracetat, or roflumilast. Particularly preferred PDE4 inhibitors include roflumilast and cilomilast.
The beta-adrenergic inverse agonist and the additional compound for treating mucus hypersecretion may be administered simultaneously or at different times. If the beta-adrenergic inverse agonist is administered concurrently with the additional compound, they can be administered in a single pharmaceutical composition or dosage form that includes both the beta-adrenergic inverse agonist and the additional compound for treating mucus hypersecretion.
The administration of beta-adrenergic inverse agonists and additional compounds to treat mucus hypersecretion can follow several different patterns. Examples of such patterns include: (1) formulating together a beta-adrenergic inverse agonist and an additional compound for the treatment of mucus hypersecretion to give a single formulation for administration; (2) formulating a β -adrenergic inverse agonist and an additional compound for treating mucus hypersecretion in two different formulations that are administered simultaneously, or close in time, by the same route of administration; (3) formulating a β -adrenergic inverse agonist and an additional compound for treating mucus hypersecretion in two different formulations that are administered by the same route of administration but at different times; (4) formulating a β -adrenergic inverse agonist and an additional compound for treating mucus hypersecretion in two different formulations that are administered simultaneously, or close in time, by different routes of administration; (5) the beta-adrenergic inverse agonist and the additional compound for treating mucus hypersecretion are formulated in two different formulations which are administered by different routes of administration at different times, in the possible order of administration.
Pharmaceutical compositions and dosage forms comprising both a beta-adrenergic inverse agonist and an additional compound for the treatment of mucus hypersecretion may be prepared according to methods well known in the art, such as that disclosed in U.S. patent application publication No. 2005/0080113 to Ohkawa et al, which is incorporated herein by reference.
Thus, various pharmaceutical compositions and dosage forms can be prepared as is well known in the art, including both a beta-adrenergic inverse agonist and an additional compound that treats hypersecretion of mucus. For example, the beta-adrenergic inverse agonist and the additional compound for treating mucus hypersecretion can be mixed with a pharmaceutically acceptable carrier to give a pharmaceutical composition that can be safely administered orally, such as tablets (including sugar-coated tablets or film-coated tablets), powders, granules, capsules (including soft capsules), solutions, sustained-release agents, and the like.
Suitable pharmaceutically acceptable carriers are known in the art. For example, they may be conventional organic or inorganic supports. The solid preparation may include an excipient, a lubricant, a binder and a disintegrant. Liquid formulations may include solvents, solubilizers, suspending agents, agents to provide isotonicity, buffers, soothing agents, and other ingredients. In addition, additives such as conventional preservatives, antioxidants, colorants, sweeteners, absorbents, wetting agents, and the like may be used, if appropriate, and as is well known in the art.
Suitable excipients include, but are not limited to, lactose, sucrose, D-mannitol, starch, corn starch, microcrystalline cellulose, and light anhydrous silicic acid. Suitable lubricants include, but are not limited to, magnesium or calcium stearate, talc, and colloidal silicon dioxide. Suitable binders include, but are not limited to, microcrystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose. Suitable disintegrants include, but are not limited to, starch, carboxymethyl cellulose calcium, sodium carboxymethyl starch, and L-hydroxypropyl cellulose. Suitable solvents include, but are not limited to, water, alcohols, propylene glycol, ethylene glycol, sesame oil, corn oil, olive oil, soybean oil, and other oils. Suitable solubilizing agents include, but are not limited to, ethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triaminomethane, cholesterol, triethylamine, sodium carbonate, and sodium citrate. Suitable suspending agents include, but are not limited to, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. Suitable agents for providing isotonicity include, but are not limited to, glucose, D-sorbitol, sodium chloride, glycerol and D-mannitol. Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, carbonate buffers, and citrate buffers. Suitable soothing agents include, but are not limited to, benzyl alcohol. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Suitable antioxidants include, but are not limited to, sulfites, ascorbic acid, and alpha-tocopherol.
For an oral administration preparation containing both a β -adrenergic inverse agonist and another compound for treating mucus hypersecretion, for example, an excipient (e.g., lactose, sucrose, starch, etc.), a disintegrant (e.g., starch, calcium carbonate, etc.), a binder (e.g., starch, gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, etc.), a lubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000, etc.), etc. may be added to the combination of the β -adrenergic inverse agonist and the other compound according to a method known in the art, and the mixture may be compression-molded, and then, if necessary, the molded product may be coated for the purpose of taste masking, enteric properties, or persistence to obtain a preparation for oral administration by a conventional method. As such a coating agent, for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween80, pluronic f68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (methacrylic acid-acrylic acid copolymer), pigments (e.g., iron oxide red, titanium dioxide, etc.), or other conventional ingredients can be used. Formulations for oral administration may be rapid release formulations or sustained release formulations.
The ratio of beta-adrenergic inverse agonist to additional compound for the treatment of mucus hypersecretion in a combination may be selected depending on the route of administration, the clinical course of the patient and the particular disease or condition to be treated. As described in detail above, in one embodiment of the invention, the disease or condition to be treated is mucus hypersecretion associated with nicotine withdrawal in a subject attempting to quit smoking.
For example, β -adrenergic inverse agonists and additional compounds for the treatment of mucus hypersecretion can be formulated into formulations suitable for aqueous injection solutions, along with other agents such as, for example, Tween80 (manufactured by atlas powder, US), HCO60 (manufactured by nikko chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose, dextrin, or other dispersing agents known in the art), stabilizers (such as ascorbic acid, sodium metabisulfite, or other stabilizers known in the art), surfactants (such as polysorbate 80, ethylene glycol, or other surfactants known in the art), solubilizing agents (such as glycerol, ethanol, or other solubilizing agents known in the art), buffers (such as phosphoric acid/alkali metal salts thereof, citric acid/alkali metal salts thereof, or other buffers or buffer systems known in the art), An agent that provides isotonicity (e.g., sodium chloride, potassium chloride, mannitol, sorbitol, glucose, or other agents known in the art that provide isotonicity), a pH adjusting agent (e.g., hydrochloric acid, sodium hydroxide, or other pH adjusting agents known in the art), a preservative (e.g., ethyl paraben, benzoic acid, methyl paraben, propyl paraben, benzyl alcohol, or other preservatives known in the art), a solubilizing agent (e.g., concentrated glycerol, meglumine, or other solubilizing agents known in the art), a solubilizing aid (e.g., propylene glycol, sucrose, or other solubilizing aids known in the art), a soothing agent (e.g., glucose, benzyl alcohol, or other soothing agents known in the art), or can be dissolved, suspended, or emulsified in a vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, or other oils or solubilizing aids such as propylene glycol, and molded into an oily formulation.
Thus, another aspect of the invention is a pharmaceutical composition comprising:
(1) a therapeutically effective amount of a beta-adrenergic inverse agonist; and
(2) at least one pharmaceutically acceptable carrier;
wherein the pharmaceutical composition is formulated for the treatment of mucus hypersecretion.
Such pharmaceutical compositions are typically formulated for the treatment of mucus hypersecretion associated with nicotine withdrawal.
Accordingly, a further aspect of the invention is a pharmaceutical composition comprising:
(1) a therapeutically effective amount of a beta-adrenergic inverse agonist;
(2) a therapeutically effective amount of an additional compound that treats hypersecretion of mucus; and
(3) at least one pharmaceutically acceptable carrier;
wherein the pharmaceutical composition is formulated for the treatment of mucus hypersecretion.
Such pharmaceutical compositions are typically formulated for the treatment of mucus hypersecretion associated with nicotine withdrawal.
Yet another aspect of the present invention is a pharmaceutical composition comprising:
(1) a therapeutically effective amount of a beta-adrenergic inverse agonist;
(2) a therapeutically effective amount of an additional compound that promotes smoking cessation; and
(3) at least one pharmaceutically acceptable carrier;
wherein the pharmaceutical composition is formulated for treating mucus hypersecretion associated with nicotine withdrawal.
Pharmaceutical compositions, including the features of a pharmaceutically acceptable carrier, the particular beta-adrenergic inverse agonist used, the amount of beta-adrenergic agonist, the particular additional compound for treating hypersecretion of mucus, and the amount of the additional compound for treating hypersecretion of mucus, as described above.
The pharmaceutical composition comprises an amount of the beta-adrenergic agonist and an amount of the additional compound that treats hypersecretion of mucus, each being therapeutically effective for treating hypersecretion of mucus, particularly mucus hypersecretion associated with nicotine withdrawal, in a subject attempting to quit smoking.
In another aspect of the invention, a β -adrenergic inverse agonist may be administered to a subject seeking smoking cessation, along with one or more additional compounds that promote smoking cessation. In contrast to the above-mentioned further compounds for treating mucus hypersecretion, the further compounds for promoting smoking cessation do not directly treat mucus hypersecretion, the pharmacological activity of which is directed against another physiological or psychological process affected by smoking. Such additional compounds that promote smoking cessation include, but are not limited to, bupropion, varenicline, clonidine and nortriptyline, and salts, solvates, analogs, congeners, mimetics, bioisosteres, stereoisomers, hydrolysates, metabolites, precursors and prodrugs thereof.
Thus, when one or more additional compounds that promote smoking cessation are used, another aspect of the invention is a method of preventing or controlling mucus hypersecretion in the respiratory tract in a subject at risk of mucus hypersecretion who is attempting to quit smoking, said method comprising administering to the subject:
(1) a therapeutically effective amount of a beta-adrenergic inverse agonist; and
(2) a therapeutically effective amount of an additional compound that promotes smoking cessation.
Likewise, when one or more additional compounds that promote smoking cessation are used, the pharmaceutical compositions of the present invention may comprise:
(1) a therapeutically effective amount of a beta-adrenergic inverse agonist as described above;
(2) a therapeutically effective amount of an additional compound that promotes smoking cessation as described above; and
(3) at least one pharmaceutically acceptable carrier.
Pharmaceutical compositions comprising both: (i) at least one additional compound as described above for the treatment of mucus hypersecretion; and (ii) at least one additional compound as described above that promotes smoking cessation. Thus, in such an alternative, such a pharmaceutical composition may comprise:
(1) a therapeutically effective amount of a beta-adrenergic inverse agonist as described above;
(2) a therapeutically effective amount of an additional compound as described above for the treatment of mucus hypersecretion;
(3) a therapeutically effective amount of an additional compound that promotes smoking cessation as described above; and
(4) at least one pharmaceutically acceptable carrier.
In the pharmaceutical compositions of the present invention, one or more beta-adrenergic inverse agonists, one or more additional compounds for treating mucus hypersecretion, if present, and one or more additional compounds for promoting smoking cessation, if present, may be included in the pharmaceutical composition. However, for most purposes it is generally preferred to include in the pharmaceutical composition only one beta-adrenergic inverse agonist, only one additional compound (if present) to treat mucus hypersecretion, and only one additional compound (if present) to promote smoking cessation.
A method of preventing or controlling mucus hypersecretion in the respiratory tract in a subject at risk of mucus hypersecretion who is attempting to quit smoking, when both an additional compound that treats mucus hypersecretion and an additional compound that promotes smoking cessation are used, comprising administering to the subject:
(1) a therapeutically effective amount of a beta-adrenergic inverse agonist;
(2) a therapeutically effective amount of an additional compound that treats hypersecretion of mucus; and
(3) a therapeutically effective amount of an additional compound that promotes smoking cessation.
The same general principles described above for administering a β -adrenergic inverse agonist and another compound for treating hypersecretion of mucus to such a subject apply to the dosage, frequency of dosage and route of administration when the additional compound for promoting smoking cessation or both the additional compound for treating hypersecretion of mucus and the additional compound for promoting smoking cessation are administered to the subject attempting to cease smoking. The beta-adrenergic inverse agonist and the additional compound that promotes smoking cessation may be administered simultaneously or at different times. If (i) a beta-adrenergic inverse agonist; (ii) additional compounds for treating mucus hypersecretion; and (iii) an additional compound for the treatment of smoking cessation, the three compounds may be administered simultaneously, or both components may be administered simultaneously and the third administered at a different time, or all three compounds may be administered at different times. Various schedules are known to those of ordinary skill in the art and, therefore, would be within the scope of the present invention. Likewise, if used, the administration of the beta-adrenergic inverse agonist, the additional compound that promotes smoking cessation, and the additional compound that treats mucus hypersecretion may follow a number of different patterns. If only two compounds are used (i.e., a beta-adrenergic inverse agonist and an additional compound that promotes smoking cessation), the mode of administration may be similar to that described above for the beta-adrenergic inverse agonist and the additional compound that treats hypersecretion of mucus, except that the additional compound that promotes smoking cessation is substituted for the additional compound that treats hypersecretion of mucus in the above mode of administration. When all three compounds (i.e., a beta-adrenergic inverse agonist, an additional compound to treat mucus hypersecretion, and an additional compound to promote smoking cessation) are used, all possible modes of administration are within the scope of the invention with respect to time of administration, route of administration, simultaneity of administration of more than one compound, and application of the formulation comprising one or more than one compound.
The invention is illustrated by the following examples. This example is included for illustrative purposes only and is not intended to limit the invention.