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WO1992016173A1 - Procedes et compositions de traitement de troubles pulmonaires utilisant de la terbutaline optiquement pure - Google Patents

Procedes et compositions de traitement de troubles pulmonaires utilisant de la terbutaline optiquement pure Download PDF

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Publication number
WO1992016173A1
WO1992016173A1 PCT/US1992/002342 US9202342W WO9216173A1 WO 1992016173 A1 WO1992016173 A1 WO 1992016173A1 US 9202342 W US9202342 W US 9202342W WO 9216173 A1 WO9216173 A1 WO 9216173A1
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WIPO (PCT)
Prior art keywords
terbutaline
administered
inhalation
composition according
pharmaceutically acceptable
Prior art date
Application number
PCT/US1992/002342
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English (en)
Inventor
James T. Young
Original Assignee
Sepracor, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sepracor, Inc. filed Critical Sepracor, Inc.
Publication of WO1992016173A1 publication Critical patent/WO1992016173A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline

Definitions

  • compositions of matter containing optically pure (-) terbutaline possess potent bronchodilating activity as a ⁇ - 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.
  • the active compound of this composition and method _ 0 is an optical isomer of the compound terbutaline. Chemically this isomer is (-) ⁇ -( (tert-butylamino)-1- (3 , 5- dihydroxy)benzyl alcohol (hereinafter referred to as (-) terbutaline) .
  • optically active 5 forms i.e. , they have the ability to rotate the plane of plane-polarized light.
  • 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.
  • 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
  • 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.
  • COPD chronic Obstructive Pulmonary Diseases
  • 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.
  • viral respiratory infection e.g, 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 eg, and ingestion of aspirin or sulfites in sensitive individuals.
  • irritants eg, gasoline fumes, fresh paint and noxious odors, or cigarette smoke
  • 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.
  • 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
  • (+) isomer has virtually no affinity for ⁇ -adrenoceptors and is devoid of any blocking activity.
  • terbutaline causes adverse effects common to ⁇ -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.
  • 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.
  • beta-adrenergic agonists such as the racemic 5 mixture of terbutaline.
  • 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.
  • the present invention also includes novel compositions of matter containing optically pure (-) on . . .
  • 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 ⁇ -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
  • the racemic mixture of terbutaline i.e. , a mixture of R and S stereoisomers
  • terbutaline 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 terbutaline results in diminished adverse effects, decreased development of tolerance and increased bronchial distribution when the compound is administered by inhalation.
  • it is much more desirable to use the (-) isomer of terbutaline when treating asthma, bronchitis, emphysema or to alleviate bronchospasms.
  • 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.
  • (-) 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.
  • abnormal 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.
  • compositions contain 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.
  • 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.
  • 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.
  • stereoisomers of terbutaline may be prepared by resolution, eg. , by the method of Wetterlin, J. Med. Chem. , Vol. 15, pg. 1182-3 (1972).
  • (+) and (-) terbutaline may be prepared by direct asymetric synthesis as described below.
  • either of these two stereoisomers can be prepared in high optical purity.
  • 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.
  • 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.
  • 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.
  • each dosage administered by actuation should contain about 0.01 mg to about 0.50 mg of the (-) isomer of terbutaline.
  • each oral dosage administered by actuation contains about 0.05 mg to about
  • the amount administered is from about 0.1 mg to about 5.0 mg.
  • the amount administered is about 0.01 mg to about 10 mg per day.
  • any suitable route of administration may be employed for providing the patient with an effective dosage of (-) terbutaline.
  • 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.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • 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.
  • 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.
  • 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.
  • 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.
  • each inhalation delivers about 0.05 mg to about 0.15 mg of the (-) isomer of terbutaline.
  • (-) 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Procédé et composition utilisant l'isomère pur (-) de terbutaline, qui est un puissant bronchodilatateur avec peu d'effets négatifs, présente une faible incidence sur le développement de la tolérance et permet une meilleure diffusion dans les bronches lorsqu'il est administré par inhalation.
PCT/US1992/002342 1991-03-19 1992-03-18 Procedes et compositions de traitement de troubles pulmonaires utilisant de la terbutaline optiquement pure WO1992016173A1 (fr)

Applications Claiming Priority (2)

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US67156391A 1991-03-19 1991-03-19
US671,563 1991-03-19

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2289842A (en) * 1991-04-05 1995-12-06 Sepracor Inc Bronchodilator enantiomers
EP0892639A4 (fr) * 1996-01-29 1999-06-09 Savor Evelyn PROCEDE DE TRAITEMENT DES CONTRACTIONS UTERINES INDESIRABLES PAR UTILISATION D'ISOMERES R OU RR OPTIQUEMENT PURS D'AGONISTES -g(b)-2 ADRENERGIQUES
CN101475497B (zh) * 2008-11-02 2012-04-18 李勤耕 制备满足药用要求的硫酸特布他林晶型b的方法
CN104069497A (zh) * 2014-06-27 2014-10-01 东莞市凯法生物医药有限公司 一种降低药物耐受性的组合物、方法及其应用
CN106667974A (zh) * 2017-02-15 2017-05-17 杭州百诚医药科技股份有限公司 一种吸入用硫酸特布他林溶液制备方法
WO2020247136A3 (fr) * 2019-05-07 2021-03-25 Wen Tan UTILISATION DE β2-AGONISTES DE R-ÉNANTIOMÈRES POUR LA PRÉVENTION ET LE TRAITEMENT DE L'INFLAMMATION PULMONAIRE ET LE REMODELAGE INFLAMMATOIRE POUR DES EFFETS INDÉSIRABLES RÉDUITS

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3985897A (en) * 1973-12-21 1976-10-12 Mead Johnson & Company Ocular hypotensive process employing dextrorotatory sulfonamidophenethanolamines
US4415564A (en) * 1981-06-30 1983-11-15 Dispersa Ag Pharmaceutical preparation for treating glaucoma and ocular hypertension
US4472436A (en) * 1982-12-06 1984-09-18 Neo-Bionics, Inc. Increasing HDL-cholesterol levels with phenylethylamine derivatives
US4564626A (en) * 1983-04-01 1986-01-14 Schering Corporation Methods of inducing bronchodilation
US4963367A (en) * 1984-04-27 1990-10-16 Medaphore, Inc. Drug delivery compositions and methods

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3985897A (en) * 1973-12-21 1976-10-12 Mead Johnson & Company Ocular hypotensive process employing dextrorotatory sulfonamidophenethanolamines
US4415564A (en) * 1981-06-30 1983-11-15 Dispersa Ag Pharmaceutical preparation for treating glaucoma and ocular hypertension
US4472436A (en) * 1982-12-06 1984-09-18 Neo-Bionics, Inc. Increasing HDL-cholesterol levels with phenylethylamine derivatives
US4564626A (en) * 1983-04-01 1986-01-14 Schering Corporation Methods of inducing bronchodilation
US4963367A (en) * 1984-04-27 1990-10-16 Medaphore, Inc. Drug delivery compositions and methods

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2289842A (en) * 1991-04-05 1995-12-06 Sepracor Inc Bronchodilator enantiomers
GB2289842B (en) * 1991-04-05 1996-01-31 Sepracor Inc Improved use of ß2 bronchodilator drugs
EP0892639A4 (fr) * 1996-01-29 1999-06-09 Savor Evelyn PROCEDE DE TRAITEMENT DES CONTRACTIONS UTERINES INDESIRABLES PAR UTILISATION D'ISOMERES R OU RR OPTIQUEMENT PURS D'AGONISTES -g(b)-2 ADRENERGIQUES
CN101475497B (zh) * 2008-11-02 2012-04-18 李勤耕 制备满足药用要求的硫酸特布他林晶型b的方法
CN104069497A (zh) * 2014-06-27 2014-10-01 东莞市凯法生物医药有限公司 一种降低药物耐受性的组合物、方法及其应用
CN106667974A (zh) * 2017-02-15 2017-05-17 杭州百诚医药科技股份有限公司 一种吸入用硫酸特布他林溶液制备方法
WO2020247136A3 (fr) * 2019-05-07 2021-03-25 Wen Tan UTILISATION DE β2-AGONISTES DE R-ÉNANTIOMÈRES POUR LA PRÉVENTION ET LE TRAITEMENT DE L'INFLAMMATION PULMONAIRE ET LE REMODELAGE INFLAMMATOIRE POUR DES EFFETS INDÉSIRABLES RÉDUITS

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