CZ176198A3 - Novel preparation - Google Patents

Abstract

The invention provides a composition or kit having as a first active ingredient formoterol, or a salt or solvate derivative thereof, and having as a second active ingredient budesonide, wherein the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36, and the use of the composition and kit in the treatment of respiratory disorders.

Description

The invention relates to a novel combination of pharmaceutically active substances which is useful in the treatment of respiratory disorders, in particular asthma.

BACKGROUND OF THE INVENTION

Despite recent advances in asthma knowledge and the introduction of powerful and effective anti-asthma drugs, asthma remains a poorly understood and often undertreated disease. Recently, progress has been made in the treatment of this disease as a result of the finding that asthma is a chronic inflammatory disease. Treatment is currently aimed at both managing symptoms and alleviating inflammation. Symptoms include uncontrolled airway inflammation, which can lead to mucosal damage, and structural changes that can lead to irreversible airway narrowing and lung fibrosis.

Symptoms may be controlled by β-adrenoreceptor agonists such as salbutamol, salmeterol, terbutaline and formoterol. Formoterol is preferred because its duration of action is long-lasting. It has a rapid onset of action and requires little wake-up at night.

Prophylactic treatment is usually provided by steroids such as beclomethasone diproprionate, fluticasone propionate and budesonide. Of these, budesonide is preferred as it can be administered in a high dose for inhalation (up to 2 mg per day) with very low systemic effects. Long-term clinical studies in adults and children have shown that inhaled budesonide has an excellent safety profile.

• ·

SUMMARY OF THE INVENTION

The present invention provides a composition comprising:

(a) a first active ingredient that is formoterol, a pharmaceutically acceptable salt or solvate of formoterol, or a solvate of such a salt, and (b) a second active ingredient that is budesonide, wherein the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1 : 36, preferably about 1: 32.5.

The invention further provides a kit comprising:

(i) a container containing a first active ingredient, (ii) a container containing a second active ingredient, and (iii) instructions for sequential or separate administration of the first and second active ingredients to a patient in need thereof, wherein the molar ratio of the first active ingredient to the second active ingredient is 1:30 to 1:36, preferably 1: 32.5.

A patient suffering from a respiratory disorder such as asthma may be treated by inhalation of the composition of the invention. Alternatively, the patient may be treated sequentially or separately by inhalation:

(i) a dose of the first active ingredient; and (ii) a dose of the second active ingredient, wherein the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36, preferably about 1: 32.5.

It has been found that the combination of the active ingredients of the invention is advantageous as it provides a significantly better anti-inflammatory effect compared to known treatments. International Patent Application No. WO 93/11773 discloses a combination of budesonide and formoterol with a wide range of weight ratios. The closest example of the combination described herein to the system of the invention has a weight ratio of formoterol fumarate dihydrate to budesonide of 0.06: 1, i.e. a molar ratio of 1: 16.3. The combination of active ingredients according to the invention gives surprisingly better results when used

999 _ ·· 9 999 99

About 9 · · ··· · 9 9 ·

9,999 · · ··· · 9 ··

9 9 9 · · · 99 99 · 9 ·

9 9999999

9 · 9 9 · 99 · 9 99 to treat patients with asthma compared to this known combination.

The first and second active ingredients of the kit may be administered sequentially or separately in the treatment of respiratory disorders. By sequential it is meant that the first and second active ingredients are applied immediately one after the other. They also have the desired effect when applied separately, but before about 12 hours in a row, preferably before about 2 hours in a row, more preferably before about 30 minutes in a row.

Preferably, the first active ingredient is applied to provide a daily dose of from 10 to 250 nmol (preferably from 15 to 120 nmol), and the second active ingredient is administered to provide a daily dose of from 0.1 to 10 pmol ( preferably 0.2 to 5 pmol) or from 39 to 4300 pg of the second active ingredient (preferably from 86 to 2150 pg), provided that the molar ratio of the first active ingredient to the second active ingredient is in the range of 1:30 to 1: 36.

Suitable physiologically acceptable salts of formoterol include addition salts derived from inorganic and organic acids, for example chloride, bromide, sulfate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or

4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulfonate, methanesulfonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalenecarboxylate or oleate or solvates thereof. The first active ingredient is preferably formoterol fumarate, especially its dihydrate.

If the first active ingredient is formoterol fumarate dihydrate, the preferred daily dose of the first active ingredient is from 4 to 100 pg, more preferably 6 to 50 pg (provided that the molar ratio of the first active ingredient to the second active ingredient is in the range of 1:30 to 1: 36).

• ♦ ···································································· 9 · • · · ·······

Most preferably, the composition or kit of the invention comprises 6.5 µg formoterol fumarate dihydrate and 160 µg budesonide, each administered up to four times a day.

Alternatively, the composition or kit of the invention comprises 12 µg of formoterol fumarate dihydrate and 400 µg of budesonide or 9 µg of formoterol fumarate dihydrate and 320 µg of budesonide, each applied once or twice daily.

The active ingredient (s) are preferably used with one or more pharmaceutically acceptable excipients, diluents or carriers, preferably in an amount of 50 to 25 mg per dose, more preferably in an amount of 50 to 10 mg, most preferably in an amount of 100 to 50 mg. 2000 yg. Examples of suitable diluents or carriers include lactose, dextran, mannitol and glucose. Preferably lactose is used, especially in the form of the monohydrate.

When reference is made in the specification to the amounts of the individual components, it is to be understood that these amounts are dosed amounts. When the active ingredients are administered, the amount of each of the ingredients inhaled by the patient may differ from the dosage administered, e.g. due to the retention of the active ingredient in the inhaler. Further, when the active ingredients are assembled separately, the application rate need not necessarily be reduced proportionally. Thus, the ratio of active ingredients applied could be different from that of the prior art. The applied ratio is preferably within the aforementioned dosage ratio.

One or more of the active ingredients used according to the invention is preferably in the form of a dry powder, more preferably a finely divided, eg micronized, dry powder, eg having an average diameter of less than 10 µm, e.g. from 1 to 5 µm, most preferably agglomerated micronized dry powder. . As an alternative to agglomeration, the finely divided active ingredients may be in the form of an ordered mixture with one or more pharmaceutically acceptable excipients, diluents, or carriers. An ordered composition is a combination of a finely divided active ingredient with coarse particles of a pharmaceutically acceptable excipient, diluent or carrier. The components used according to the invention can be obtained in these preferred forms using methods known to those skilled in the art.

The invention further provides the use of a composition or kit of the invention in the manufacture of a medicament for use in the treatment of a respiratory disorder, for example asthma. The invention also provides the use of budesonide or formoterol in the manufacture of a kit or composition of the invention for use in the treatment of a respiratory disorder such as asthma.

Administration can be by inhalation oral or intranasal. The ingredients are preferably adapted to be delivered from a powder inhaler, a pressurized metered dose inhaler, or a nebulizer.

When the ingredients of the composition or kit are adapted to be delivered from a pressurized inhaler, they are preferably comminuted into fine particles. They are dissolved or preferably suspended in a liquid propellant mixture. CFCs, hydrocarbons or hydrofluoroalkanes can be used as propellants. Particularly preferred propellants are P 134a (tetrafluoroethane) and P 227 (heptafluoropropane), each of which may be used alone or in combination. They are optionally used in combination with one or more other propellants and / or one or more surfactants and / or one or more excipients, for example ethanol, a lubricant, an antioxidant and / or a stabilizing agent.

When the ingredients of the composition or kit are adapted for nebulizer administration, they may be in the form of a nebulized aqueous suspension or solution with or without appropriate pH or tonicity adjustments, either in a single dose or multi dose device.

Optionally, the composition or kit may be administered in separate doses of from 1 to 4, and preferably once or twice daily.

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention. In the examples, the grinding into fine particles is carried out in a conventional manner so that the particle size range for each component is suitable for administration by inhalation. Turbuhaler is a trademark of Astra AB.

Example 1 parts by weight of formoterol fumarate dihydrate was mixed with 794 parts by weight of lactose monohydrate. The mixture was comminuted to fine particles by a high-pressure air jet mill according to EP-A-717 616. 200 parts by weight of the finely divided micronesonide were added to the treated product by mixing and homogenizing by a low-pressure air jet mill. The mixture was then spheronized using the procedure of EP-A-721 331 and filled into a Turbuhaler container.

Example 2

4.5 pbw of formoterol fumarate dihydrate was mixed with 835 pbw of lactose monohydrate. The mixture was pulverized using a high pressure air jet mill and conditioned using the procedure of EP-A-717 616. 160 parts by weight of the fine particle budesonide was added to the treated product by mixing and homogenizing with a low pressure air jet mill. The mixture was then spheronized using the procedure of EP-A-721 331 and filled into a Turbuhaler container.

ΦΦΦΦ

Ί φ φ φ φ φφφφ

φ φ φ φ φφφ

Example 3 parts by weight of formoterol fumarate dihydrate was mixed with 588 parts by weight of lactose monohydrate. The mixture was pulverized using a high pressure air jet mill and then treated using the procedure of EP-A-717 616. 400 parts by weight of the fine particle budesonide was added to the treated product by mixing and homogenizing with a low pressure air jet mill. The mixture was then spheronized using the procedure of EP-A-721 331 and filled into a Turbuhaler container.

Example 4 parts by weight of formoterol fumarate dihydrate was mixed with 994 parts by weight of lactose monohydrate. The mixture was pulverized using a high pressure air jet mill and then treated using the procedure of EP-A-717 616. The mixture was then spheronized using the procedure of EP-A-721 331 and filled into a Turbuhaler container.

200 pbw of finely divided budesonide was mixed with 800 pbw of lactose monohydrate. The mixture was pulverized using a high pressure air jet mill and then treated using the method of EP-A-717 616. The mixture was then spheronized using the procedure of EP-A-721 331 and filled into a Turbuhaler container.

Example 5

4.5 pbw of formoterol fumarate dihydrate was mixed with 995 pbw of lactose monohydrate. The mixture was pulverized using a high pressure air jet mill and then treated using the procedure of EP-A-717 616. The mixture was then spheronized using the procedure of EP-A-721 331 and filled into a Turbuhaler container.

9

160 parts by weight of finely divided budesonide was mixed with 840 parts by weight of lactose monohydrate. The mixture was pulverized using a high pressure air jet mill and then treated using the method of EP-A-717 616. The mixture was then spheronized using the procedure of EP-A-721 331 and filled into a Turbuhaler container.

Example 6 parts by weight of formoterol fumarate dihydrate was mixed with 988 parts by weight of lactose monohydrate. The mixture was pulverized using a high pressure air jet mill and then treated using the procedure of EP-A-717 616. The mixture was then spheronized using the procedure of EP-A-721 331 and filled into a Turbuhaler container.

400 parts by weight of finely divided budesonide was mixed with 600 parts by weight of lactose monohydrate. The mixture was pulverized using a high pressure air jet mill and then treated using the method of EP-A-717 616. The mixture was then spheronized using the procedure of EP-A-721 331 and filled into a Turbuhaler container.

Claims (14)

PATENTOV E N Á R OKY 1. A new device, v y z n and no u s e by that contains in mixture (and) the first active ingredient, which is formoterol, j eho farm- a pharmaceutically acceptable salt or solvate or solvate of such a salt; and (b) a second active ingredient that is budesonide, wherein the molar ratio of (a) to (b) in the composition is from 1:30 to 1:36. The composition of claim 1, wherein the molar ratio is about 1: 32.5. Composition according to claims 1 or 2, characterized in that the first active ingredient is formoterol fumarate dihydrate. The composition of claim 1, 2 or 3, further comprising a pharmaceutically acceptable excipient, diluent or carrier. The composition of claims 1 to 4 for use in treating a respiratory disorder. A kit comprising (a) a container comprising a first active ingredient selected from the group consisting of formoterol, a pharmaceutically acceptable salt or solvate thereof, and a solvate of such a salt, and (b) a container comprising a second active ingredient that is budesonide, ( c) instructions for sequential or separate administration of the first and second active ingredients to a patient in need thereof, wherein the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36. Kit according to claim 6, characterized in that the molar ratio is 1: 32.5. Kit according to claim 6 or 7, characterized in that the first active ingredient is formoterol fumarate dihydrate. A kit according to claim 6, 7 or 8, further comprising a pharmaceutically acceptable excipient, diluent or carrier suitable for inhalation. Kit according to claims 6 to 9, characterized in that each component is in the form of a finely divided dry powder and each container is a dry powder inhaler. Use of a composition according to claims 1 to 4 in the manufacture of a medicament for use in the treatment of a respiratory disorder. Use of a kit according to claims 6 to 10 for the manufacture of a medicament for use in the treatment of a respiratory disorder. Use of formoterol, a pharmaceutically acceptable salt thereof, or a solvate thereof or a solvate of such a salt in the manufacture of a composition according to claims 1 to 4 or a kit according to claims 6 to 10 for use in the treatment of a respiratory disorder. Use of budesonide for the manufacture of a composition according to claims 1 to 4 or a kit according to claims 6 to 10 for use in the treatment of a respiratory disorder.