KR20060135873A - Salmeterol inhalation formulations - Google Patents

Abstract

A metered dose inhalation formulation for once daily administration comprises salmeterol, or a physiologically acceptable salt thereof; and a propellant. A dry powder inhalation formulation for once daily administration comprises salmeterol or a physiologically acceptable salt thereof and a diluent. Also provided is a unit dose inhalation formulation for once daily administration comprising salmeterol or a pharmaceutically acceptable salt, ester of other derivative thereof, wherein the formulation comprises from 25 to 50 mcg of active.

Description

Salmeterol inhalation formulations

The present invention relates to salmeterol preparations and the use thereof for the treatment of respiratory diseases, including asthma and related diseases.

Pathophysiology of asthma and related diseases involves bronchoconstriction resulting from airway infections with bronchial smooth muscle spasm and muscle edema. Treatment of asthma and other related diseases has been known to utilize β-2 agonists, also known as β-2 adrenergic receptor agonists. Such β-2 adrenergic receptor agonists are known to provide bronchodilating effects to patients, which alleviate the symptoms of dyspnea. More specifically, β-2 adrenergic receptor agonists have been shown to increase the conductance of potassium channels in airway muscle cells, leading to membrane hyperpolarization and alleviation.

Examples of β-2 adrenergic receptor agonists include terbutalin, salbutamol, lev-albuterol, R, R-formoterol, metaproterol sulfate, pybuterol acetate, bitolterol mesylate, phenoterol, procaterol , Salmeterol, bambuterol hydrochloric acid, clenbuterol, and formoterol. Among these, salmeterol, formoterol, and bambuterol hydrochloric acid are long acting β-2 adrenergic receptor agonists, of which salmeterol has long been approved as a treatment for asthma. The long acting subgroup of β-2 adrenergic receptor agonists acts through relaxation of the airway smooth muscle and thereby bronchial dilatation. Drugs of the long acting subgroup may slow the onset of action and are therefore used for long-term regular treatment of reversible airway obstruction of asthma, and especially bronchial dilators used for the management of persistent asthma symptoms. Among these groups, salmeterol, available as xinafoate salt, in particular as a sympathomimetic amine, is a relatively selective long acting β-2 agonist.

Chemically (±) 4-hydroxy-α ¹ -[[[6- (4-phenylbutoxy) hexyl] amino] methyl] -1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxyl Laterate salmeterol xinapoate is used as a bronchodilator for long-term prevention of bronchial contraction and prevention of exercise-induced bronchial contraction in patients with reversible obstructive airway disease, including night asthma symptoms. Salmeterol is also used as a bronchodilator for long-term symptomatic therapy of reversible bronchial contractions associated with chronic obstructive disease (COPD), including chronic bronchitis and emphysema. Salmeterol is used alone or in combination with a therapeutic steroid.

Chronic obstructive pulmonary disease (COPD) is a generic term that includes chronic bronchitis, emphysema, and chronic obstructive airway disease. COPD is a chronically progressive disease characterized by airway obstruction that does not change noticeably over several months. Symptoms of COPD with varying degrees of disease include cough with or without sputum and dyspnea with or without wheezing.

Helium propellant compositions for use with aerosols are discussed in US patent application US 20030199594 to Larson & Taylor. US patent application 20030064097 to Patel et al. Discloses a solid carrier for improved delivery of hydrophobic active ingredients of pharmaceutical compositions. U.S. Patent Application 20030062042 to Wensley et al. Relates to a method and apparatus for producing aerosols for producing desirable particles having a size of molecules to 10 microns. Methods and devices for delivering physiologically active compounds are discussed in US patent application 2003005728 to Lloyd et al. Delivery via the inhalation route of aerosols containing small particles is discussed in US patent application 20030035776 to Hodges et al. United States patent application 20030015197 to Hale et al. Discloses a method of forming an aerosol for inhalation administration. Aerosol formers for use in inhalation therapy are claimed in US patent application 20030015196 to Hodges et al.

Aerosol compositions containing finely divided solid materials and preferred propellants around them are discussed in US Pat. No. 4,352,789 to Thiel et al. WO 9311743 (Glaxo Group Ltd) discloses aerosol preparations for drug administration by inhalation, in particular salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate, and physiologically acceptable salts thereof. And certain drugs selected from the group comprising solvates, and pharmaceutical aerosol formulations comprising a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, substantially free of surfactant. Also described is a method for treating respiratory disease comprising inhalationally administering a pharmaceutical aerosol formulation as described above in an effective amount.

GB2235627 describes a combination of corticosteroid fluticasone propionate with salmeterol or a pharmaceutically acceptable salt thereof for use in treating asthma and other respiratory diseases by therapy twice daily. A combination of salmeterol xinafoate and fluticasone propionate is currently used clinically for the treatment of asthma. It is indicated to administer twice a day.

Patent GB2140800 describes penethanolamine compounds which are β-2 agonists, including salmeterol xinapoate, which are used clinically in the treatment of bronchial asthma and related diseases. Salmeterol is used clinically in the treatment of bronchial asthma and related diseases. It is indicated to administer twice a day.

WO 9632150 of Glaxo Wellcome Inc. for dispensing inhaled drug formulations comprising salmeterol or a physiologically acceptable salt thereof, and a fluorocarbon propellant, optionally one or more pharmacologically active compounds or one or more excipients, Some or all of the inner surface discloses a quantitative spray inhaler (MDI) coated in combination with one or more fluorocarbon polymers, optionally with one or more nonfluorocarbon polymers.

Patent US2003125313 describes a combination of salmeterol and budesonide, and its use for preventing and treating respiratory diseases. The amount of salmeterol and budesonide required to achieve a therapeutic effect depends on the particular compound, the route of administration, the patient being treated, and the particular condition and disease to be treated. As a monotherapy, salmeterol xinapoate is generally administered to adults by aerosol inhalation at a dose of 50 mcg to 100 mcg, twice daily.

Therefore, these documents report the use of salmeterol and its salts twice a day for the prevention or treatment of asthma.

The inventors have surprisingly found that asthma can be satisfactorily controlled by administering salmeterol, especially lower doses of salmeterol or its salts once a day.

It is an object of the present invention to provide a new method comprising an effective amount of salmeterol or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, for the prevention or treatment of mild or moderate asthma in a daily administration. To provide a unit dosage form.

It is another object of the present invention to provide a method for preparing a formulation comprising an effective amount of salmeterol or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient.

Another object of the present invention is to provide a method for preventing or treating asthma, comprising administering an effective amount of salmeterol or a combination of pharmaceutically acceptable salts thereof once daily.

The present invention relates to salmeterol or a physiologically acceptable salt thereof; And a propellant, a quantitative spray inhalation (MDI) formulation for once-daily administration.

The invention also provides a dry powder inhalation (DPI) formulation for once-daily administration comprising salmeterol or a physiologically acceptable salt thereof, and a diluent.

The invention also relates to salmeterol or a physiologically acceptable salt thereof as the active ingredient; Propellant; A quantitative spray inhalation (MDI) formulation for once daily administration comprising a cosolvent and optionally a surfactant.

The present invention also relates to a dry powder inhalation (DPI) formulation for once-daily administration, comprising as an active ingredient salmeterol or a physiologically acceptable salt thereof and a diluent.

The invention also

Weighing the active ingredient in a can;

If necessary, adding a cosolvent and / or a surfactant;

Sonicating the solution (preferably about 5 minutes);

Mounting a metering valve into the can and crimping (preferably with a vacuum crimpier) and then filling the propellant through the metering valve. It is about.

In addition, the present invention

Mixing the active ingredient with the lactose; And

A method of making a dry powder inhalation formulation comprising the step of filling the mixture into a capsule.

The present invention relates to a method for preventing or treating asthma, comprising administering an effective amount of salmeterol or a physiologically acceptable combination thereof, once daily.

The present invention also provides a unit dose inhalation formulation for once-daily administration comprising salmeterol, or a pharmaceutically acceptable salt thereof, or an ester of another derivative thereof, so that the active ingredient is 25-50 mcg. inhalation formulation).

Accordingly, the present invention provides a method of preventing or treating asthma comprising administering an effective amount of a physiologically acceptable salt thereof, such as salmeterol or xinapoate salt, once daily. In particular, there is provided a method for preventing or treating mild to moderate asthma, especially persistent asthma, comprising administering an effective amount of a physiologically acceptable salt thereof, such as salmeterol or xinapoate salt, once daily. .

There are several advantages to administering once daily. If administration in b.i.d is necessary, it may hinder effective patient compliance. Once daily administration can provide a more convenient dosing regimen for the patient, thereby improving patient compliance. In addition, administration of a combination of salmeterol once daily is particularly suitable for the prevention or treatment of mild to moderate asthma, especially persistent asthma. Treatment can be initiated once daily, or reduced to once daily, beginning with b.i.d. once the patient's asthma is stabilized. Once the patient's asthma stabilizes, it is desirable to titrate the least effective amount to reduce the likelihood of any potential side effects. Once daily administration also allows more flexibility for physicians in prescribing continuous treatment of asthma. This may be particularly important for pediatric patients.

The inventors have found that once a day administration lower doses of salmeterol can minimize the potential side effects that can occur at higher doses while providing a sufficient therapeutic effect.

In countries where salmeterol is used clinically, inhalation administration twice a day has been recommended. In studies comparing salmeterol with 25, 50, and / or 100 mcg twice daily with MDI in mild to severe asthma patients, pulmonary function, criteria of action, and duration of action are generally Dose-related improvements have been found in.

The addition of salmeterol to the dosage regimen of asthma patients selected for the double-blind study resulted in a rapid, statistically and clinically significant improvement in the measurement of morning and evening peak expiratory flow rates. Most studies measured bronchodilation for 12 hours after a single dose of salmeterol showed that patients who received salmeterol maintained a 15-20% improvement in FEV ₁ over baseline. In performing the present inventors study, the present inventors have the following, FEV ₁ 15% smaller by measuring the FEV ₁ repeatedly, the pressing amount spray-inhaler (pressurized metered dose inhaler) until than administration of a single dose of The bronchial dilatation effect of salmeterol formulations administered with each other was compared. Four treatments, Salmeterol HFA 25 and 50 mcg and Salmeterol CFC 25 and 50 mcg, were studied by randomized double blind, double placebo, crossover trials. After 24 hours, FEV ₁ averaged 15% improvement over baseline.

Various pharmacologically predictable systemic effects are associated with beta-2 agonists. This includes headaches, tremors, palpitations, and muscle spasms. In phase III clinical studies, the incidence of this effect was low, with salmeterol 50 mcg bid and 200-400 mcg q.d.s. There was no significant difference between the livers. Higher doses of salmeterol, ie 100 mcg b.i.d. Tremor occurred more frequently than patients receiving placebo or salbutamol q.d.s. Therefore, side effects were thought to decrease significantly when administered at 25 mcg or 50 mcg once a day.

The evidence obtained in this study suggests that salmeterol has a 24-hour duration of action in asthma patients, so the recommended regimen of twice daily administration is controversial. The prolongation of the action duration of salmeterol is believed to be related to the binding of salmeterol to a site adjacent to a traditional beta-receptor called exosite, resulting in long-lasting receptor occupancy.

In summary, salmeterol is effective at clinically recommended doses of 25 and 50 mcg and can be proven effective in the treatment of bronchial asthma through its ability to expand the airway for more than 24 hours.

As used herein, the term "once a day" means that a patient's asthma is administered approximately once every 24 hours with a physiologically acceptable salt thereof, such as a lower dose of salmeterol or xinapoate salt, in which the patient is effective. This means that the patient's asthma is properly controlled. Preferably the patient will receive an effective amount of drug at the same time in each 24 hour period.

The dose of physiologically acceptable salts thereof, such as salmeterol or xinapoate salt, required to achieve a therapeutic effect will depend on the particular salt form, route of administration, the patient being treated, and the particular disease to be treated. Drugs and / or formulations comprising physiologically acceptable salts thereof such as salmeterol or xinapoate salt may be administered by inhalation with salmeterol at a dosage of 25 mcg to 50 mcg per day. The formulations of the present invention may preferably be administered to adults by inhalation of a physiologically acceptable salt thereof, such as salmeterol or, optionally, xinapoate salt, at a dose of 25 mcg to 50 mcg per day. The total daily dose may be inhaled or administered by one operation of an inhaler, for example a dry powder inhaler or a metered spray inhaler, or by one or more operations. The daily dosage is preferably about 25 mcg or about 50 mcg.

1 and 2 show FEV ₁ curves in patients receiving a single dose of salmeterol. In the figure, one puff translates to 25 mcg of salmeterol. The baseline determining the therapeutically effective concentration of drug was 15% baseline. The first column of each figure represents the first visit of the patient and the second column describes the second visit of that particular patient. After the first visit, the patient's FEV ₁ curve was still observed to be above the 15% baseline and therefore it was determined to continue the study further. Therefore, for that particular patient in FIG. 1, the study continued for 24 hours. And in FIG. 2, the second visit study was continued for 48 hours. From both figures it is clear that a single dose of salmeterol administration once a day provides a therapeutically effective drug concentration for at least 24 hours.

According to the present invention, the compositions and methods disclosed herein include the use of unit doses of salmeterol in appropriate inhalation formulations.

Ease of use, multi-dose capacity, low dose to absorb systemically, little or no taste of evil administration, can be used for alleviation and prophylaxis, can be used by most individuals with appropriate added devices Because of the many advantages of using an inhaler as a delivery system, this route of administration allows salbutamol to be used to control patients with asthma and related respiratory diseases.

Accordingly, according to the present invention, salbutamol may be formulated into any suitable inhalation formulation suitable for administering the drug to the respiratory tract, including a quantitative spray inhaler (MDI) and a dry powder inhaler (DPI).

In a preferred embodiment, the pharmaceutical composition of the invention is an inhaler, i.e. may be MDI or DPI. Pharmaceutical compositions and formulations may conveniently be embodied in unit dosage form and may be prepared by methods well known to those skilled in the art.

Preferably, the pharmaceutical composition according to the present invention comprises an inhalation formulation delivered from a pressurized container using a suitable propellant as a carrier or excipient. Suitable propellants include 1,1,1,2-tetrafluoroethane (HFA 134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), or a combination of both, Or mono-fluoro trichloromethane and dichlorodifluoromethane, or chlorofluorocarbons and derivatives thereof, in particular 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2 , 3,3,3-heptafluoropropane (HFA 227), preferably HFA 134a.

A pharmaceutical inhalation formulation according to the invention is preferably a C _{2 -6} aliphatic alcohol and a polar co-solvent, such as polyols: may further comprise a (e.g., ethanol, isopropanol, and propylene glycol), among them, ethanol is preferred. Preferably, the concentration of cosolvent is in the range of about 0.1 to 15% by weight relative to the total formulation.

The formulations according to the invention may further comprise one or more surfactants. Such surfactants may be included to stabilize the formulation and reduce friction of the valve system. The most commonly used surfactants in inhalation formulations are phospholipids such as lecithin and oils derived from natural fuels such as corn oil, olive oil, cottonseed oil, and sunflower seed oil. Preferred surfactants for use in the present invention are oleic acid. Surfactants used in the formulations of the present invention are generally present in the range of about 0.0001% to 0.5% by weight, preferably 0.01 to 0.1% by weight relative to the therapeutic agent present in the formulation.

Preferred inhalation formulations of the invention are in the form of suspensions, particulate suspensions, or clear solutions. In the case of particulate suspensions or solutions, the cosolvent used should have a higher polarity than the propellant used. The most commonly used cosolvent is ethanol substantially as described above.

Another preferred inhalation formulation of the present invention is a dry powder for inhalation. The active ingredient is suitably mixed with a known diluent to prepare the formulation. Preferred diluent is lactose. The formulation may be filled into a blistered cartridge or capsule. Such blister cartridges or capsules may then be used using any known inhaler.

Preferably, the therapeutic agent present in the inhalation formulation according to the invention is present in the formulation at a concentration in the range of about 25-50 mcg.

Therefore, the present invention also provides a method of preparing a pharmaceutical formulation as substantially described herein, comprising providing a salmeterol formulation for use in the treatment of asthma and related diseases.

The present invention also provides a method of preparing a pharmaceutical formulation as substantially described herein, comprising mixing a pharmaceutically acceptable carrier or excipient with salmeterol or a functional derivative thereof.

Pharmaceutical inhalation formulations according to the invention are particularly suitable for use in DPIs or MDIs. Substantially the MDIs as described above utilize liquefied propellants as mentioned above to propel the droplets containing the therapeutic agent used according to the invention. Suitably, the preparations according to the invention are filled into aluminum cans via a suitable metering device, typically the cans can be coated with plastic, coated with lacquer or allowed to produce an oxide film.

The method for preparing an inhalation preparation claimed in claim 1

Weighing the active ingredient in a plain aluminum can;

If necessary, adding a cosolvent and / or a surfactant;

Crimping the metering valve and then filling the propellant through the valve.

The invention also

Mixing the active ingredient drug and diluent; And

Disclosed is a method of making an inhalation formulation comprising using the inhalation formulation with the aid of any known container used for inhalation.

The invention will now be further illustrated by the following examples which do not in any way limit the scope of the invention.

1 and 2 show FEV ₁ curves in patients receiving a single dose of salmeterol.

In the examples below, the total weight of the propellant-based formulations is 9.6 g and for DPI the total weight is 25 mg per capsule.

In Examples 1 to 6 above, the active ingredient was first weighed into an ordinary can of aluminum (with a capacity to accommodate 120 doses). Then ethanol (and surfactant if needed) was added and the solution was sonicated for 5 minutes. A metering valve was then mounted to the can and crimped with a vacuum crimpier. The propellant 134a was then filled through a metered valve.

Way:

1. The drug and diluent (lactose) were mixed.

2. The mixture was then filled into capsules.

3. The capsules were then used using any well known inhaler.

Claims (16)

A quantitative spray inhalation (MDI) formulation for once-daily administration comprising salmeterol or a physiologically acceptable salt thereof, and a propellant. A dry powder inhalation (DPI) formulation for once-daily administration, comprising salmeterol or a pharmacologically acceptable salt thereof, and a diluent. The inhalation formulation according to claim 1 or 2, wherein the physiologically acceptable salt thereof is salmeterol xinafoate. The inhalation formulation of claim 1, 2 or 3, wherein the dose of salmeterol or physiologically acceptable salt thereof administered is 25 mcg to 50 mcg. The method of claim 1, wherein the propellant comprises 1,1,1,2-tetrafluoroethane (HFA 134a); 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), or a combination thereof; Mono-fluoro trichloromethane; Dichlorodifluoromethane; Chlorofluorocarbons or derivatives thereof; Inhalation formulation, characterized in that it is preferably selected from HFA 134a. 6. The inhalation formulation of claim 1, wherein the formulation comprises a cosolvent and a surfactant. The inhalation formulation of claim 6, wherein the cosolvent is ethanol, isopropanol, or propylene glycol. 8. The inhalation formulation of claim 7, wherein the amount of cosolvent is from 0.1 to 15% by weight relative to the total formulation. 9. Inhalation preparation according to claim 6, 7, or 8, wherein the surfactant is oleic acid or lecithin. 10. The inhalation according to claim 6, wherein the amount of surfactant is from 0.0001% to 0.5% by weight, preferably from 0.01% to 0.1% by weight relative to the therapeutic drug present in the formulation. Formulation. The inhalation formulation of claim 2 wherein the diluent is lactose. Weighing the active ingredient in a can; If necessary, adding a cosolvent and / or a surfactant; Crimping the metering valve and then filling the propellant through the valve, A method for preparing an inhalation formulation according to any one of claims 1 and 3 to 10. Mixing the active ingredient with a diluent; And A method of making an inhalation formulation according to claim 2 comprising filling the singer mixture into a suitable blistered cartridge or capsule. A method of preventing or treating asthma and related diseases comprising administering an effective amount of salmeterol or a physiologically acceptable salt thereof once daily. 15. The method of claim 14, wherein the daily dose of salmeterol is 25-50 mcg. A unit dose inhalation formulation for once-daily administration, comprising 25-50 mcg of salmeterol, or esters of pharmaceutically acceptable salts or other derivatives thereof.

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