WO1992016173A1

WO1992016173A1 - Methods and compositions for treating pulmonary disorders using optically pure terbutaline

Info

Publication number: WO1992016173A1
Application number: PCT/US1992/002342
Authority: WO
Inventors: James T. Young
Original assignee: Sepracor, Inc.
Priority date: 1991-03-19
Filing date: 1992-03-18
Publication date: 1992-10-01
Also published as: AU1658992A

Abstract

A method and composition are disclosed utilizing the pure (-) isomer of terbutaline, which is a potent bronchodilator with reduced adverse effects, has a low incident of the development of tolerance and has increased bronchial distribution when administered by inhalation.

Description

METHODS AND COMPOSITIONS FOR TREATING PULMONARY DISORDERS USING OPTICALLY PURE TERBUTALINE

1. BACKGROUND OF THE INVENTION This invention relates to novel compositions of matter containing optically pure (-) terbutaline. These compositions possess potent bronchodilating activity as a β- adrenergic receptor agonist while avoiding or reducing adverse effects including but not limited to cardiovascular stimulation and muscle tremor 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. Also disclosed are methods to treat asthma, bronchitis, emphysema and alleviate bronchospasms as well as other ailments in patients ₁₅ 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.

The active compound of this composition and method _₀ is an optical isomer of the compound terbutaline. Chemically this isomer is (-)α-( (tert-butylamino)-1- (3 , 5- dihydroxy)benzyl alcohol (hereinafter referred to as (-) terbutaline) .

Many organic compounds exist in optically active ₅ forms, i.e. , 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 0 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 5 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.

Stereochemical 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.

Terbutaline, 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 enantio ers.

Terbutaline is administered as a sulfate salt. Terbutaline-^*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.

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 decide 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 combination of these factors. Although obstruction 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 (eg, changes in barometric pressure or temperature) , inhalation of cold air or irritants (eg, 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- ediated 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 (eg, 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.

The racemic mixture of terbutaline, in addition to its use as an bronchodilator, has been shown to have a spectrum of action which includes:

- Treatment of HDL - cholesterol levels (U.S. Patent No. 4,472,436)

- Treatment of ocular hypotension (U.S. Patent Nos. 3,985,897 and 3,885,047)

Treatment of glaucoma (U.S. Patent No/ 4,415,564)

- Treatment of Spasticity (GB 1,453,034)

- Treatment of breathing disorders (U.S. Patent No. 4,564,626)

Whereas the foregoing U.S. patents, recognize that compounds such as terbutaline have optically active forms, only U.S. Patent Nos. 3,985,897 and 3,885,047 issued to

Seidehamel et al. give an example of an optically active form. These patents disclose and claim the topical administration of d-terbutaline and other d-phenethanolamines to lower intraocular pressure. It has been hypothesized that levorotatary .-adrenergic stimulating compounds had a high order of adrenergic activity while the dextrorotatory compound was pharmacologically "inactive" with respect to adrenoreceptors. Subsequently, Seidehamel et al. proposed that such dextrorotatory compounds would reduce intraocular pressure and would be suitable for ophthalmogical use because of the reduced adrenergic activity. As stated above, it has been hypothesized that

(-) terbutaline was in large part responsible for the activity of the racemic mixture. For example, Wetterlin J.Med.Chem. , 1972 Vol. 15(11) p. 1182-1183 has reported that the (-) isomer of terbutaline is about 200 times more potent as an adrenergic .„ receptor stimulator than the (+) isomer. Similarly, Jeppsson et al. , Brit J. Pharmacol., 1982, Vol. 77 Suppl. , 402P. have reported that (+) terbutaline was about 3,000 times less potent than the (-) isomer. Additional results by Jeppsson et al., Acta Pharmacol. et Toxicol, 1984 Vol. 54, p. 285-291, show that the (+) isomer has virtually no affinity for ^-adrenoceptors and is devoid of any blocking activity. Pharmacokinetic data from Borgstro et al., Br. J. Clin. Pharmac. 1989 Vol. 27 p. 49-56, demonstrated that (-) terbutaline governs the absorption properties of the racemate, however, the (+) isomer governs the elimination behavior.

While the racemic mixture of terbutaline has certain medical advantages, it also has disadvantages. Terbutaline causes adverse effects common to β -agonists which effect the central nervous system, such as hand tremors, muscle tremors, nervousness, dizziness, headache and drowsiness. It is also known that terbutaline causes adverse effects in the cardiovascular system, such as palpitations, increased heart rate, and tachycardia. Like other sympatho imetic agents, terbutaline can cause adverse effects in the respiratory system such as dyspnea, wheezing, drying or irritation of the oropharynx and chest discomfort. In addition, terbutaline can cause angina, vertigo, central stimulation and insomnia. Terbutaline also effects the 5 gastrointestinal system and causes nausea and vomiting. As with other pharmaceuticals terbutaline sometimes causes systemic adverse effects such as weakness, flushed feeling, sweating, unusual taste and muscle cramps.

Furthermore, patients have a tendency to develop a 10 tolerance to the bronchodilating effect of the racemic mixture to terbutaline. 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 15 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. 0 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 5 mixture of terbutaline. These agonists mediate brochodilation and promote easier breathing. Asthmatic patients utilizing .-agonists, such as the racemic mixture of terbutaline, 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 terbutaline by inhalation, because of particle size and 5 air flow distribution characteristics of the racemic mixture of terbutaline, 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 10 the therapeutic characteristics of terbutaline which would not have the above described disadvantages.

2. SUMMARY OF THE INVENTION It has now been discovered that the (-) isomer of

15 terbutaline is an effective bronchodilator that does not have certain adverse effects associated with the administration of the racemic mixture of terbutaline. The present invention includes administering to a human (-) terbutaline to cause bronchodilation without causing said adverse effects.

20 Furthermore, it has also been discovered that by administering only the (-) isomer of terbutaline there is not an increase in tolerance to the compound, which is seen when the racemic mixture of terbutaline is administered. In addition, it has been discovered that by administering the

25 (-) isomer of terbutaline by inhalation, it is possible to obtain improved distribution of the compound in the smaller bronchioles which results in an increased bronchodilating effect. The present invention also includes novel compositions of matter containing optically pure (-) on . . .

^ terbutaline which is useful as a bronchodilator. These novel compositions also avoid the above described adverse effects, increased tolerance or limited pattern of distribution when administered by inhalation, associated with the racemic mixture of terbutaline. 5 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 bronchospasms, but insufficient to cause said adverse effects, development of tolerance or limited pattern of bronchial distribution when administered by inhalation, of (-) terbutaline or a pharmaceutically acceptable salt thereof, substantially free of its (+) stereoisomer. The bronchodilator effect is achieved by utilizing the highly potent β-adrenergic effects of the (-) isomer of terbutaline 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 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

(-) terbutaline or a pharmaceutically acceptable salt thereof, substantially free of its (+) stereoisomer. The racemic mixture of terbutaline (i.e. , a mixture of R and S stereoisomers) cause 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 terbutaline 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 terbutaline when treating asthma, bronchitis, emphysema or to alleviate bronchospasms.

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 terbutaline it is possible to accomplished a more "targeted" therapy. A more "targeted" therapy means that by using the (-) isomer of terbutaline the compound's broad activity can be taken advantage of without also having adverse effects, development of tolerance, or limited pattern of bronchial distribution when administered by inhalation. These effects are associated with administration of the racemic mixture of terbutaline. This is important since it is not desirable for all patients to be administered a compound with such a multifaceted spectrum of activity. Thus by administering to a patient the (-) isomer of terbutaline, significant bronchodilating activity is obtained without adverse effects, development of tolerance, or limited pattern of bronchial distribution when administered by inhalation, which are associated with the racemic mixture of terbutaline.

In addition, in the methods and compositions of the present invention, (-) terbutaline can be administered in a form suitable for inhalation, such that because of decreased particle size and favorable flow patterns, an efficacious amount of the compound is delivered to the smaller airways in the lungs which results in increased bronchodilation.

The term "adverse effects" includes but is not limited to hand tremors, muscle tremors, nervousness, palpitations, tachycardia, increased heart rate, dyspnea, chest discomfort, drying or irritation of the oropharynx and wheezing. Also included in the term "adverse effects" is headaches, dizziness, 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 (-) terbutaline and 10% by weight or less of (+) terbutaline. In the most preferred embodiment the term "substantially free of the (+) stereoisomer" means that the composition contains at least 99% by weight (-) terbutaline and 1% or less of (+) terbutaline.

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 terbutaline 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 stereoisomers of terbutaline may be prepared by resolution, eg. , by the method of Wetterlin, J. Med. Chem. , Vol. 15, pg. 1182-3 (1972). Alternatively, (+) and (-) terbutaline may be prepared by direct asymetric synthesis as described below. According to the choice of hydride reducing agent employed in the second step, either of these two stereoisomers can be prepared in high optical purity.

(2)

(1) Bn=Benzyl

(3)

(2) 5

(4)

(3)

5

5 With regard to the above synthesis, the benzyl protected acetophenone (1) is brominated to give bromoketone (2) . Ketone (2) can be stereoselectively reduced according to Corey's or Brown's boron hydride reduction procedures to alcohol (3) . Both isomers of (3) can be prepared by changing the hydride reagents. The bromohydrin

(3) is then treated with N-benzyl protected tert-butylamine

(use of N-benzyl protection to prevent double alkylation) .

The resulting amino alcohol (4) is then deprotected by Pd catalysed hydrogenolysis to give the title compound terbutaline (5). See, Corey et al., J. Org. Chem. , 56, pg.

442-44 (1991) and Brown et al., J. Org. Chem. , 47 pg. 1606

(1982) .

The magnitude of a prophylactic or therapeutic dose of (-) terbutaline 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 15 mg per day, preferably 1.0 mg to 10 mg per day orally, and most preferably from about 1.5 mg to 7 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 terbutaline. Preferably, each oral dosage administered by actuation contains about 0.05 mg to about

0.15 mg of the (-) isomer of terbutaline. Concerning subcutaneous injection or intravenous infusion the amount administered is from about 0.1 mg to about 5.0 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.

Any suitable route of administration may be employed for providing the patient with an effective dosage of (-) terbutaline. For example, oral, rectal, parenteral, transdermal, subcutaneous, intramuscular, inhalation and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, aerosols, patches and the like. The pharmaceutical compositions of the present invention comprise (-) terbutaline 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, ca phorsulfonic, citric, ethenesulfonic, 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 hydrobromic, hydrochloric, phosphoric and sulfuric acids.

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 nature and severity of the condition being treated. 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 15 mg (-) isomer of terbutaline per day, preferably from about 1.0 mg to about 10 mg per day and most preferably from about 1.5 mg to about 7 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 terbutaline. Preferably, each inhalation delivers about 0.05 mg to about 0.15 mg of the (-) isomer of terbutaline. In practical use, (-) terbutaline 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 and

4,008,719, 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. Inhalator devices used for oral inhalation of the (-) isomer of terbutaline 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.

EXAMPLES

4.1 EXAMPLE 1

ORAL FORMULATION

Capsules:

Quantity per Capsule

Formula (Mg.)

A B

Active ingredient 1.0 2.5 Lactose 104.75 103.25 Corn Starch 18.75 18.75 Magnesium Stearate 0.50 0.50

125.00 125.00

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

Active ingredient 0.0375g Sorbitan trioleate 0.105g

Trichloromonofluoromethane NF 2.58g Dichlorotetrafluoroethane NF 2.58g Dichlorodifluoromethane NF 5.16g

The metered dose dispenser contains micronized (-) terbutaline sulfate, in suspension. Each actuation delivers O.lOmg of (-) terbutaline sulfate 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 5 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 10 by inhalation, of (-) terbutaline or a pharmaceutically acceptable salt thereof, substantially free of its (+) stereoisomer.

2. The method of claim 1 wherein (-) terbutaline 15 is administered by subcutaneous injection, intravenous infusion, oral inhalation, transdermal delivery, orally as a tablet or orally as a capsule.

3. The method according to claim 2 wherein the 0 amount administered is about 0.01 mg to about 15 mg.

4. The method according to claim 3 wherein the amount administered by subcutaneous injection or intravenous infusion is about 0.1 mg to about 5 mg. 5

5. The method according to claim 3 wherein the amount administered orally as a tablet or orally as a capsule is 0.25 mg to 15 mg per day.

^{^ 6. The method according to claim 5 wherein the amount administered is about 1 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 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 (-) terbutaline or a pharmaceutically acceptable salt thereof is greater than approximately 90% by weight.

10. The method according to claim 1 wherein (-) terbutaline 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 (-) terbutaline sulfate 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 (-) terbutaline or a pharmaceutically acceptable salt thereof, substantially free of its (-I-) stereoisomer.

13. A composition according to claim 12 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.

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 (-) terbutaline sulfate.

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

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

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

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

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