WO1993000090A1

WO1993000090A1 - Methods and compositions for treating pulmonary and cardiac disorders using optically pure (+) pirbuterol

Info

Publication number: WO1993000090A1
Application number: PCT/US1992/005378
Authority: WO
Inventors: James W. Young
Original assignee: Sepracor, Inc.
Priority date: 1991-06-26
Filing date: 1992-06-25
Publication date: 1993-01-07
Also published as: AU2305092A

Abstract

A method and composition are disclosed utilizing the pure (+) isomer of pirbuterol, which is a potent bronchodilator and a potent cardiovascular stimulant with reduced adverse effects, having a low incidence of the development of tolerance and having increased bronchial distribution when administered by inhalation.

Description

METHODS AND COMPOSITIONS FOR TREATING PULMONARY AND CARDIAC DISORDERS USING OPTICALLY PURE (+ PIRBUTEROL

1. BACKGROUND OF THE INVENTION This invention relates to novel compositions of matter containing optically pure (+) pirbuterol. These compositions possess potent bronchodilating activity and potent cardiovascular activity as β- adrenergic receptor agonists while avoiding or reducing adverse effects including but not limited to muscle tremor and tachycardia as well as avoiding or reducing the development of tolerance on repeated administration. The compositions also provide an improved pattern of bronchial distribution when administered by inhalation. This invention also relates to methods of treating asthma, bronchitis, emphysema, bronchospasms, and other ailments in patients with obstructive airway or allergic disorders while avoiding adverse effects, development of tolerance on repeated administration or a limited pattern of bronchial distribution when administered by inhalation'. In addition the invention includes methods of treating congestive heart failure utilizing optically pure (+) pirbuterol in order to decrease adverse effects.

The active compound of this composition and method is an optical isomer of the compound pirbuterol. Chemically this isomer is written as (+)- 2-hydroxymethyl-3-hydroxy-6-(l-hydroxy-2-ter- butylaminoethyl) pyridine, or (+)-α⁶-[[ (1,l- di ethylethyl)amino]methyl]-3-hydroxy-2,6- pyridinedi ethanol, hereinafter referred to as (+)pirbuterol. 1.1. Stereochemistry

Many organic compounds exist in optically active forms, i.e. _r they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule, about its chiral center(s) . The prefixes (+) and (-) or d and 1 are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1_. meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.

Stereoche ical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of propranolol, which is known to be 100 times more potent than the D- enantiomer.

Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy and that the corresponding L-enantiomer, a potent teratogen.

Pirbuterol which is the subject of the present invention, is available only as a racemic mixture. That is, it is a mixture of optical isomers, called enantiomers. Pirbuterol is administered as a monoacetate or dihydrochloride salt. Pirbuterol's primary use. is as a bronchodilator for the relief of reversible bronchospasm in patients with obstructive airway disease such as asthma, bronchitis and emphysema. Pirbuterol, its preparation and its bronchodilator activity were originally described by Barth in U.S. Patent Nos. 3,700,681; 3,763,173; 3,772,314; 3,786,160. Additional processes and intermediates useful for the preparation of pirbuterol and its derivatives are disclosed in U.S. Patent Nos. 3,948,919, 4,011,231, 4,031,108 and 4,477,671. Pirbuterol also has utility in the treatment of congestive heart failure.

1.2. Pulmonary Diseases Asthma, bronchitis and emphysema are known as Chronic Obstructive Pulmonary Diseases (COPD) . COPD is characterized as generalized airways obstruction, particularly of small airways, associated with varying degrees of symptoms of chronic bronchitis, asthma, and emphysema. The term COPD was introduced because these conditions often coexist, and it may be difficult in an individual case to dε . ide which is the major condition producing the obstruction. Airways obstruction is defined as an increased resistance to airflow during forced expiration. It may result from narrowing or obliteration of airways secondary to intrinsic airways disease, from excessive collapse of airways during a forced expiration secondary to pulmonary emphysema, from bronchospasm as in asthma, or may be due to a combine Ion of these factors. although o ε ruction of large airways may occur in all these disorders, particularly in asthma, patients with severe COPD characteristically have major abnormalities in their small airways, namely those less than 2 mm internal diameter, and much of their airways obstruction is situated in this zone. The airways obstruction is irreversible except for that which can be ascribed to asthma.

Asthma is a reversible obstructive lung disorder characterized by increased responsiveness of the airways. Asthma can occur secondarily to a variety of stimuli. The underlying mechanisms are unknown, but inherited or acquired imbalance of adrenergic and cholinergic control of airways diameter has been implicated. Persons manifesting such imbalance have hyperactive bronchi and, even without symptoms, bronchoconstriction may be present. Overt asthma attacks may occur when such persons are subjected to various stresses, such as viral respiratory infection, exercise, emotional upset, nonspecific factors (e.g.. changes in barometric pressure or temperature) , inhalation of cold air or irritants (e.g. , gasoline fumes, fresh paint and noxious odors, or cigarette smoke) , exposure to specific allergens, and ingestion of aspirin or sulfites in sensitive individuals. Psychologic factors may aggravate an asthmatic attack but are not assigned a primary etiologic role.

Persons whose asthma is precipitated by allergens (most commonly airborne pollens and molds, house dust, animal danders) and whose symptoms are IgE-mediated are said to have allergic or "extrinsic" asthma. They account for about 10 to 20% of adult asthmatics; in another 30 to 50%, symptomatic episodes seem to be triggered by non-allergenic factors (e.g. , infection, irritants, emotional factors) , and these patients are said to have nonallergic or "intrinsic" asthma. In many persons, both allergenic and nonallergenic factors are significant. Allergy is said to be a more important factor in children than in adults, but the evidence is inconclusive.

Chronic bronchitis (unqualified) is a condition associated with prolonged exposure to nonspecified bronchial irritants and accompanied by mucus hypersecretion and certain structural changes in the bronchi. Usually associated with cigarette smoking, it is characterized clinically by chronic productive cough. The term chronic obstructive bronchitis is used when chronic bronchitis is associated with extensive abnormalities of the small airways leading to clinically significant airways obstruction. (Pulmonary emphysema is enlargement of the air spaces distal to terminal nonrespiratory bronchioles, accompanied by destructive changes of the alveolar walls.) The term chronic obstructive emphysema is used when airways obstruction is also present and where it is clear that the major features of the disease can be explained by emphysematous changes in the lungs.

1.3. Cardiac Disorders Congestive heart failure (CHF) or heart failure is a state in which circulatory congestion exists as a result of a distention of the myocardial tissue of the left and/or right ventricles of the human heart. Circulatory congestion occurs when the blood is sent into systemic and/or pulmonary circulation with low efficiency.

CHF involves a decrease in the myocardial contractile state such that cardiac output is inadequate for the body's needs. This syndrome may be caused by many different etiologies. A review of CHF and related disorders can be found in The Merck Manual, 15th Edition, R. Berkow, et al. Eds., Chapter 27, 1987, Merck Sharp & Dohme Research Laboratories, Rahway, N.J.

As mentioned above, the utility of pirbuterol is not limited to bronchodilation. Taylor discloses the method of treating congestive heart failure using pirbuterol salts in U.S. Patent No. 4,175,128. Similarly, Leveier et al., Clin. Pharmacol. Ther.. 1982, 3(1): 89-94, reports on the utility of intravenous pirbuterol in treating low- output congestive heart failure. Pa elia, Am. Heart J.. 1983, 106(6): 1369-1376 confirms the beneficial hemodynamic effects of oral pirbuterol on acute hemodynamics of patients with chronic severe CHF, however they also report on the presence of typical beta adrenergic adverse effects. Webster and Sharpe Medical Toxicology, 1986, 1: 335-342 include pirbuterol in their report on the adverse effects associated with inotropic agents such as the β agonists which include pirbuterol and terbutaline. All the above references report on the use of racemic pirbuterol in congestive heart failure; only Taylor recognizes that pirbuterol is a racemic mixture which can be resolved into pure enantiomers. However, Taylor does not give specific examples of the enantiomers and does not disclose the benefit of using the pure (+) isomer of pirbuterol in order to decrease adverse effects while sustaining the therapeutic effects.

The racemic mixture of pirbuterol, in addition to its use as an bronchodilator and a cardiac stimulant, has been shown to have synergetic action in antiinflammatory compositions demonstrated by the U.S. Patents 4,874,757 and 4,812,455. These patents disclose the administration of compositions which contain the bronchodilator pirbuterol in combination with the antiinflam atory piroxicam and other pharmaceuticals for the treatment of various inflammations, such as gastrointestinal inflammation.

While the racemic mixture of pirbuterol has certain medical advantages, it also has disadvantages. Pirbuterol causes adverse effects common to ₂-agonists which effect the central nervous system, such as hand tremors, muscle tremors, nervousness, dizziness, headache and drowsiness. It is also known that pirbuterol causes adverse effects in the cardiovascular system, such as palpitations, increased heart rate, and tachycardia. Like other sympathomimetic agents, pirbuterol can cause adverse effects in the respiratory system such as dyspnea, wheezing, drying or irritation of the oropharynx, coughing, chest pain and chest discomfort. In addition, racemic pirbuterol can cause angina, vertigo, central stimulation and insomnia. Pirbuterol also effects the gastrointestinal system and causes nausea, diarrhea, dry mouth and vomiting. As with other pharmaceuticals pirbuterol sometimes causes systemic adverse effects such as weakness, fatigue, flushed feeling, sweating, unusual taste, hoarseness, muscle cramps and backaches.

Furthermore, patients have a tendency to develop a tolerance to the bronchodilating effect of the racemic mixture to pirbi erol. This is related to desensitization, which is one of the most clinically significant phenomena involving the beta-adrenergic receptor. It has been observed that patients in prolonged beta-agonist therapy have a tendency to increase the dosage of drug they use. This occurs because after prolonged administration, the beta- receptor appears to become desensitized to the agonist, thus requiring larger doses of the compound to effect an equivalent physiological response.

The problem of desensitization is especially significant in the treatment of diseases involving bronchospasms, such as asthma. The treatment of asthma usually involves the self-administration either orally or by aerosol, of beta-adrenergic agonists such as the racemic mixture of pirbuterol. These agonists mediate brochodilation and promote easier breathing. Asthmatic patients utilizing 0-agonists, such as the racemic mixture of pirbuterol, for a prolonged time gradually increase the self-administered dose in order to get a sufficient amount of bronchodilation and relief in breathing. As a result of this increased dosage, the agonist concentration builds to a sufficient level so as to enter the peripheral circulation where it acts on the beta receptors of the heart and vasculature to cause cardiovascular stress and other adverse effects.

Moreover, when administering the racemic mixture of pirbuterol by inhalation, because of particle s.ze and air flow distribution characteristics of the racemic mixture of pirbuterol, the distribution of the compound into the smaller bronchioles is limited, which results in a decreased effectiveness of the compound.

It is therefore desirable to find a compound with the therapeutic characteristics of pirbuterol which would not have the above described disadvantages. 2. SUMMARY OF THE INVENTION

It has now been discovered that the (+) isomer of pirbuterol is an effective bronchodilator that does not have certain adverse effects associated with the administration of the racemic mixture of pirbuterol. The present invention includes administering to a human (+) pirbuterol to cause bronchodilation and to decrease said adverse effects.

Furthermore, it has also been discovered that by administering only the (+) isomer of pirbuterol there is not an increase in tolerance to the compound, which is seen when the racemic mixture of pirbuterol is administered. In addition, it has been discovered that by administering the (+) isomer of pirbuterol by inhalation, it is possible to obtain improved distribution of the compound in the smaller bronchioles which results in an increased bronchodilating effect. Further, it has now been discovered that (+) isomer of pirbuterol is effective in the treatment of congestive heart failure while avoiding or reducing certain adverse effects associated with the administration of the racemic mixture of pirbuterol. The present invention includes administering to a human (+) pirbuterol to cause an _c inotropic and/or vasodilating effects on the heart b without causing said adverse effects. The present invention also includes novel compositions of matter containing optically pure (+) pirbuterol which is useful as a bronchodilator. These novel compositions _Q also avoid the above described adverse effects, increased tolerance or limited pattern of distribution when administered by inhalation, associated with the racemic mixture of pirbuterol. Furthermore, the present invention also includes novel compositions of 5 matter containing optically pure (+) pirbuterol which is also useful as an inotropic agent and/or vasodilator for treating heart failure.

3. DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a method of eliciting a bronchodilator effect while avoiding the concomitant liability of adverse effects, development of tolerance, or limited pattern of bronchial distribution when administered by inhalation, which compromises administering to a human in need of bronchodilation an amount sufficient to alleviate bronchospas s, but insufficient to cause said adverse effects, development of tolerance or limited pattern of bronchial distribution when administered by inhalation, of (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer. The bronchodilator effects are achieved by utilizing the highly potent β-adrenergic effects of the (+) isomer of pirbuterol while substantially limiting the adverse effects, development of tolerance or limited pattern of bronchial distribution when administered by inhalation, by decreasing or eliminating the amount of (-) isomer in the composition. The present invention also includes a method of treating congestive heart failure while avoiding concomitant liability of adverse effects or development of tolerance, which comprises administering to a human in need for cardiovascular stimulation an amount sufficient to alleviate congestive heart failure, but insufficient to cause said adverse effects or development of tolerance, of (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer. The cardiac stimulating effects are achieved by utilizing the highly potent 0-adrenergic effects of the (+) isomer of pirbuterol while substantially limiting adverse effects and development of tolerance, by decreasing or eliminating the amount of (-) isomer in the composition.

The present invention also encompasses a bronchodilator composition for the treatment of a patient in need of bronchodilating therapy which comprises an amount sufficient to alleviate bronchospasms but insufficient to cause adverse effects, development of tolerance or limited bronchial distribution when administered by inhalation, of (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its {-) stereoisomer.

The racemic mixture of pirbuterol (i.e.. a mixture of (+) and (-) εtereoiso εrs) causes bronchial smooth muscle relaxation and modulates inhibition of mediator release effect; however this racemic mixture causes adverse effects, leads to the development of tolerance and results in a limited pattern of bronchial distribution when administered by inhalation. Utilizing the (+) isomer of pirbuterol results in diminished adverse effects, decreased development of tolerance and increased bronchial distribution when the compound is administered by inhalation. Thus, it is much more desirable to use the (+) isomer of pirbuterol when treating asthma, bronchitis, emphysema or to alleviate bronchospasms.

The present invention also encompasses a inotropic and/or vasodilator composition for the treatment of a patient suffering from congestive heart failure which comprises an amount sufficient to treat heart failure but insufficient to cause adverse effects or development of tolerance of (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer.

Additionally, the racemic mixture of pirbuterol can be used to treat congestive heart failure however this racemic mixture causes adverse effects and leads to development of tolerance. Utilization of the (+) isomer of pirbuterol results in diminished adverse effects, and decreased development of tolerance. Thus, it is much more desirable to use the (+) isomer of pirbuterol when treating congestive heart failure.

Furthermore, although there is some variability from one patient to another, it is generally observed that, by administering an effective amount of only the (+) isomer of pirbuterol it is possible to accomplish a more "targeted" therapy. A more "targeted" therapy means that by using the (+) isomer of pirbuterol the compound's activity can be taken advantage of without also having consequences of the pharmacologic effects of the (-) isomer which are observed upon administration of the racemic mixture of pirbuterol. This is important since it is not desirable for all patients to be administered a compound with such a multifaceted spectrum of activity.

In addition, in the methods and compositions of the present invention, (+) pirbuterol can be administered in a form suitable for inhalation.

The term "adverse effects" includes but is not limited to hand tremors, muscle tremors, hand tremors, nervousness, palpitations, tachycardia, increased heart rate, dyspnea, coughing, chest pain, chest discomfort, drying or irritation of the oropharynx and wheezing. Also included in the term "adverse effects" are headaches, dizziness, fatigue, hoarseness, backaches, nausea, vomiting, drowsiness, weakness, flushed feeling, sweating, unusual taste, muscle cramps, weakness, angina, vertigo, central stimulation and insomnia.

The term "substantially free of the (-) stereoisomer" as used herein means that the composition contains at least 90% by weight of (+) pirbuterol and 10% by weight or less of (-) pirbuterol. In the most preferred embodiment the term "substantially free of the (-) stereoisomer" means that the composition contains at least 99% by weight (+) pirbuterol and 1% or less of (-) pirbuterol.

The term "eliciting a bronchodilator effect" means relief from the symptoms associated with obstructive airway diseases, which include but are not limited to respiratory distress, wheezing, coughing, shortness of breath, tightness of pressure in the chest and the like.

The term "development of tolerance" means that when administering the racemic mixture of pirbuterol in repeated dosage or over a period of time, the amount of the compound given to the patient must be increased in order to achieve the same effect as the lower dosage given at an earlier time.

The term "limited pattern of bronchial distribution when administered by inhalation" means that therapeutically efficacious quantities cannot penetrate into smaller bronchioles.

The term "a human in need of cardiovascular stimulation" means that said human suffers from congestive heart failure and needs therapy or treatment of this condition.

The term "alleviate congestive heart failure" means that the contractility of that part of the heart which is inefficiently operating (i.e. , including but not limited to the left or right ventricles) is markedly augmented.

The racemic mixture of pirbuterol can be prepared according to United States Patent Nos. 3,763,173 and 3,786,160 by Barth, W.E. The individual enantiomers of pirbuterol may be obtained by resolution of a mixture of enantiomers (i.e. _r the racemic mixture) using conventional means, such as an optically active resolving acid. Other standard methods of resolution known to those skilled in the art including but not limited to simple crystallization and chromatographic resolution can be used. (See for example, Stereochemistry of Carbon Compounds. E.L. Eliel, McGraw Hill 1962; "Tables of Resolving Agents," S.A. Wilen and Lochmuller, L.H. et al., 1975, J. Chromatogr. 113(3): 283-302.)

The magnitude of a prophylactic or therapeutic dose of (+) pirbuterol will, of course, vary with the nature of the severity of the condition to be treated and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range for bronchodilating use lie within the range of from about 0.01 mg to about 30 mg per day. Preferably the oral dosage is about 1.0 mg to about 15 mg per day orally, and most preferably from about 5 mg to about 10 mg per day orally, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. With regard to inhalation, each dosage administered by actuation should contain about 0.01 mg to about 0.50 mg of the (+) isomer of pirbuterol. Preferably, each inhalation dosage administered by actuation contains about 0.05 mg to about 0.25 mg of the (+) isomer of pirbuterol. Concerning subcutaneous injection or intravenous infusion the amount administered is from about 0.0375 mg to about 1.0 mg. When administered as a transdermal patch, the amount administered is about 0.01 mg to about 10 mg per day. The term "an amount sufficient to alleviate bronchospasms but insufficient to cause said adverse effects, development of tolerance or limited pattern of bronchial distribution when administered by inhalation", is encompassed by the above-described amounts.

The term "an amount sufficient to treat congestive heart failure, but insufficient to cause adverse effects or development of tolerance" is also encompassed by the above described amounts.

Any suitable route of administration may be employed for providing the patient with an effective dosage of (+) pirbuterol. For example, oral, rectal, parenteral, transdermal, subcutaneous, intramuscular, inhalation and the like may be employed. Each of these routes of administration can also be in the sustained release form. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, aerosols, patches and the like.

The pharmaceutical compositions of the present invention comprise (+) pirbuterol an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.

Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzene- sulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Particularly preferred are the monoacetate salt and the dihydrochloride salt.

The compositions include compositions suitable for oral, rectal, parenteral (including subcutaneous, transdermal, intramuscular, and intravenous) and inhalation, although the most suitable route in any given case will depend on the condition being treated and the nature and severity of that condition. The most preferred route of the present invention is oral by either tablets or capsules, oral inhalation or transdermal patch. They may be conveniently presented in.unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In the case where an oral composition is employed, a suitable dosage range for use is, e.g. , from about 0.25 mg to about 30 mg of the (+) isomer of pirbuterol per day, preferably from about 1.0 mg to about 5 mg per day and most preferably from about 5 mg to about 10 mg per day.

In the case where inhalation is employed, a suitable dosage is two inhalations separated by 60 second intervals, repeated every 4 to 6 hours. Each inhalation should deliver about 0.01 mg to about 0.50 mg of the (+) isomer of pirbuterol. Preferably, each inhalation delivers about 0.05 mg to about 0.15 mg of the (+) isomer of pirbuterol.

In practical use, (+) pirbuterol can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g.. oral or parenteral (including intravenous) . In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or aerosols or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is capsules. Because of their ease of administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200, 4,008,719, and EPA 295,113, the disclosures of which are hereby incorporated by reference.

Furthermore, the methods and compositions of the present invention are particularly suited for administration by the transdermal routes, including, but not limited to, transdermal patches, electrically stimulated transdermal delivery systems and metered injection systems. (+) Pirbuterol can be administered transder ally as a salt or a free base. Inhalator devices used for oral inhalation of the (+) isomer of pirbuterol are also included within the novel methods and compositions of the present invention.

Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets or aerosol sprays each containing a - predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in- water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 0.5 mg to about 5 mg of the active ingredient and each cachet or capsule contains from about 0.5 mg to about 5 mg of the active ingredient. Most preferably the tablet, cachet or capsule contains 1 mg or 2.5 mg of active ingredient.

The invention is further defined by reference to the following examples describing in detail the preparation of the compound and compositions of the present invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.

All temperatures are in degrees Celsius.

The active ingredient, lactose and corn starch are blended until uniform; then the magnesium stearate is blended into the resulting powder. The resulting mixture is incapsulated into suitably sized two-piece hard gelatin capsules.

4 . 2 . EXAMPLE 2 ORAL FORMULATION

Tablets :

Formula Quantity per Tablet

Active Ingredient Lactose Corn Starch Water (per thousand Tablets) Corn Starch Magnesium Stearate

* The water evaporates during manufacture

The active ingredient is blended with the lactose until a uniform blend is formed. The smaller quantity of cornstarch is blended with the water to form the resulting corn starch paste. This is then mixed with said uniform blend until a uniform wet mass is formed. The remaining corn starch is added to the resulting wet mass and mix until uniform granules are obtained. The granules are then screened through a suitable milling machine, using a 1/4 inch stainless steel screen. The milled granules are then dried in a suitable drying oven until the desired moisture content is obtained. The dried granules are then milled through a suitable milling machine using 1/4 mesh stainless steel screen. The magnesium stearate is then blended and the resulting mixture is compressed into tablets of desired shape, thickness, hardness and disintegration. 4.3. EXAMPLE 3 ORAL INHALATION

Formula Quantity Contained in Each

Metered Dose Dispenser

7.5 ml (10.5g) Canister

Active Ingredient 0.075 g trichloromonofluoromethane 5.16 g dichlorodifluoro ethane 5.16 g sorbitan trioleate 0.105 g

The metered dose dispenser contains micronized (+) pirbuterol monoacetate, in suspension. Each actuation delivers O.lOmg of (+) pirbuterol monoacetate from the mouthpiece. Each canister provides about 300 inhalations.

Claims

What is claimed is:

1. A method of eliciting a bronchodilator effect while avoiding concomitant liability of adverse effects, development of tolerance or limited pattern of bronchial distribution when administered by inhalation, which comprises administering to a human in need of bronchodilation an amount sufficient to alleviate bronchospasms, but insufficient to cause said adverse effects, development of tolerance or limited pattern of bronchial distribution when administered by inhalation, of (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer.

2. The method of claim 1 wherein (+) pirbuterol is administered by subcutaneous injection, intravenous infusion, oral inhalation, transdermal delivery, orally as a tablet or as a capsule.

3. The method according to claim 2 wherein the amount administered is about 0.01 mg to about 30 mg.

4. The method according to claim 3 wherein the amount administered by subcutaneous injection or intravenous infusion is about 0.0375 mg to about 1.0 mg.

5. The method according to claim 3 wherein the amount administered orally as a tablet or as a capsule is about 1.0 mg to about 15 mg per day.

6. The method according to claim 5 wherein the amount administered is about 5 mg to about 10 mg per day.

7. The method according to claim 3 wherein the amount administered by oral inhalation is about 0.01 mg to about 0.50 mg.

8. The method according to claim 3 wherein the amount administered by transdermal patch is about 0.01 mg to about 10 mg.

9. The method according to claim 1 wherein the amount of (+) pirbuterol or a pharmaceutically acceptable salt thereof is greater than approximately 90% by weight.

10. The method according to claim 1 wherein (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer is administered together with a pharmaceutically acceptable carrier.

11. A method according to claim 2, 3, 4, 5 , 6, 7 or 8 wherein (+) pirbuterol monoacetate is administered.

12. A bronchodilator composition adapted for the treatment of a human in need of bronchodilator therapy which comprises an amount sufficient to alleviate bronchospasms, but insufficient to cause adverse effects, development of tolerance or limited pattern of bronchial distribution when administered by inhalation, of (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer.

13. A composition according to claim 12 c wherein the amount is about 0.1 mg to about 15 mg.

14. A composition according to claim 13 wherein said composition is administered from one to four times a day. 0

15. A composition according to claim 14 wherein said composition is administered twice a day.

16. A composition according to claim 14 wherein said composition is administered once a day.

17. A composition according to claim 13 which comprises (+) pirbuterol monoacetate.

0 18. A composition according to claim 17 adapted for oral administration.

19. A composition according to claim 17 adapted for use by oral inhalation. 5

20. A composition according to claim 17 adapted for use in a transdermal delivery formulation.

21. A composition according to Claim 20 0 adapted for use as a transdermal patch.

22. The composition according to claim 12, wherein (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its (-) 5 stereoisomer is administered together with a pharmaceutically acceptable carrier.

23. A method of treating congestive heart failure while avoiding concomitant liability of adverse effects or development of tolerance, which comprises administering to a human in need of cardiovascular stimulation an amount sufficient to alleviate congestive heart failure, but insufficient to cause said adverse effects or development of tolerance, of (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer.

24. The method of claim 23 wherein (+) pirbuterol is administered by subcutaneous injection, intravenous infusion, transdermal delivery, orally as a tablet or orally as a capsule. •

25. The method according to claim 24 wherein the amount administered is about 0.01 mg to about 15 mg.

26. The method according to claim 24 wherein the amount administered by subcutaneous injection or intravenous infusion is about 0.0375 mg to about 1.0 mg.

27. The method according to claim 24 wherein the amount administered orally as a tablet or orally as a capsule is about 1.0 mg to about 15 mg per day.

28. The method according to ciaim 27 wherein the amount administered is about 5 mg to about 10 mg per day.

29. The method according to claim 24 wherein the amount administered by oral inhalation is about 0.01 mg to about 0.50 mg.

30. The method according to claim 24 wherein the amount administered by transdermal patch is about 0.01 mg to about 10 mg.

31. The method according to claim 23 wherein the amount of (+) pirbuterol or a pharmaceutically acceptable salt thereof is greater than approximately 90% by weight.

32. The method according to claim 23 wherein (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer is administered together with a pharmaceutically acceptable carrier.

33. A method according to claim 24, 25, 26, 27, 28, 29 or 30 wherein (+) pirbuterol dihydrochloride is administered.

34. A method according to claim 24, 25, 26, 27, 28, 29 or 30 wherein (+) pirbuterol monoacetate is administered.

35. A composition adapted for the treatment of a human having congestive heart failure and in need of cardiovascular therapy which comprises an amount sufficient to treat congestive heart failure, but insufficient to cause adverse effects or development of tolerance of (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer.

36. A composition according to claim 35 wherein the amount is about 0.1 mg to about 15 mg.

37. A composition according to claim 36 wherein said composition is administered from one to four times a day.

38. A composition according to claim 37 wherein said composition is administered twice a day.

39. A composition according to claim 37 wherein said composition is administered once a day.

40. A composition according to claim 36 which comprises (+) pirbuterol monoacetate.

41. A composition according to claim 40 adapted for oral administration.

42. A composition according to claim 40 adapted for use in a transdermal delivery formulation.

43. A composition according to Claim 42 adapted for use as a transdermal patch.

44. The composition according to claim 35, wherein (+) pirbuterol or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer is administered together with a pharmaceutically acceptable carrier.

45. A composition according to claim 36 which comprises (+) pirbuterol dihydrochloride.

46. A composition according to claim 45 g adapted for oral administration.

47. A composition according to claim 45 adapted for use in transdermal delivery.

_ 48. A composition according to claim 47 adapted for use as a transdermal patch.

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