SK75198A3 - Pharmaceutical composition - 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 pharmaceutical composition based on a novel combination of pharmaceutically active substances which is needed 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 poorly understood and often undertreated. 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 constriction and lung fibrosis.

Symptoms can be controlled by β ₂ -adrenoreceptor agonists such as salbutamol, salmeterol, terbutaline and formoterol. Formoterol is suitable because its duration of action is long-lasting. It has a rapid onset of action and does not require frequent standing at night.

Prophylactic treatment is usually provided with steroids such as beclomethasone dipropionate, fluticasone propionate and budesonide. Of these, budesonide is preferred as it can be administered at 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, which is formoterol, a pharmaceutically acceptable salt or solvate of formoterol or a solvate of such a salt; and (b) a second active ingredient, which is budesonide, wherein the molar ratio of the first active ingredient to the second active ingredient is from: 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 by inhalation sequentially or separately:

(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.

The combination of the active ingredients of the invention has been found to be 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 over a wide range of weight ratios. The closest example of a combination described herein to a system of the invention has a weight ratio of formoterol fumarate dihydrate to budesonide of 0.06: 1, i. molar ratio 1: 16.3.

The combination of the active ingredients according to the invention surprisingly gives better results when used for the treatment of patients suffering from 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 earlier than 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 applied to provide a daily dose of from 0.1 to 10 gmol (preferably 0 to 10 nmol). , 2 to 5 gmol) or from 39 to 4300 gg of the second active ingredient (preferably from 86 to 2150 gg) with the proviso 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, tricarbalylate, hydroxynaphthalenecarboxylate or oleate or solvates thereof. The first active ingredient is preferably formoterol fumarate, especially its dihydrate.

When the first active ingredient is formoterol fluorate dihydrate, the preferred daily dose of the first active ingredient is from 4 to 100 gg, more preferably 6 to 50 gg (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).

Most preferably, the composition or kit of the invention comprises 6.5 gg formoterol fumarate dihydrate and 160 gg will be 4 sonides, each administered up to four times a day.

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

The alternative component (s) are preferably used with one or more pharmaceutically acceptable excipients, diluents or carriers, preferably in an amount of 50 pg to 25 mg per dose, more preferably in an amount of 50 pg to 10 mg, most preferably in an amount of 100 to 2000 pg . 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 quantities. When the active ingredients are administered, the amount of each of the ingredients inhaled by the patient may differ from the dosage amount, e.g. due to the retention of the active ingredient in the inhalation device. When the active ingredients are formulated separately, the application rate need not necessarily be proportionally reduced. Thus, the applied ratio of active ingredients could be different from the dosage ratio. The applied ratio is preferably within the above 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 finely divided, e.g. micronized, dry powder, e.g. with a mean diameter of less than 10 µm, for example from 1 to 5 µm, most preferably an 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 mixture 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 such as 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 oral or intranasal inhalation. 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 for administration 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 may be used as propellants. Particularly preferred are propellants 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 administration by nebulizers, 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.

The composition or kit may optionally 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 milling 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 wt. parts of formoterol fumarate dihydrate was mixed with 794 wt. parts of lactose monohydrate. The mixture was comminuted into fine particles by a high-pressure air jet mill according to EP-A-717 616. parts of budesonide pulverized into fine particles were 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 2

4.5 wt. parts of formoterol fumarate dihydrate was mixed with 835 wt. parts of lactose monohydrate. The mixture was comminuted to fine particles using a high pressure air jet mill and conditioned using the procedure of

EP-A-717 616. parts of budesonide pulverized into fine particles were 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 3 wt. parts of formoterol fumarate dihydrate was mixed with 588 wt. parts of lactose monohydrate. The mixture was milled into fine particles using a high pressure metal air jet mill and then treated using the procedure of EP-A-717 616. parts of budesonide pulverized into fine particles were 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 wt. parts of formoterol fumarate dihydrate was mixed with 994 wt. parts of lactose monohydrate. The mixture was comminuted into fine air particles and then EP-A-717 616. The mixture using a high pressure jet mill was adjusted using the procedure of then it was spheronized using the procedure of EP-A-721 331 and filled into a Turbuhaler container.

200 wt. parts of budesonide pulverized into fine particles were mixed with 800 wt. parts of lactose monohydrate. The mixture was crushed into fine particles 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 wt. parts of formoterol fumarate dihydrate was mixed with 995 wt. parts of lactose monohydrate. The mixture was comminuted into fine particles 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.

160 wt. parts of budesonide pulverized into fine particles were mixed with 840 wt. parts of lactose monohydrate. The mixture was comminuted to fine particles 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 wt. parts of formoterol fumarate dihydrate was mixed with 988 wt. parts of lactose monohydrate. The mixture was comminuted into fine particles 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 wt. parts of budesonide pulverized into fine particles were mixed with 600 wt. parts of lactose monohydrate. The mixture was crushed into fine particles 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)

PATENT CLAIMS A composition comprising in mixture (a) a first active ingredient that is formoterol, a pharmaceutically acceptable salt thereof, or a solvate or solvate thereof, and (b) a second active ingredient which is budesonide, wherein the molar ratio (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 additive, 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 which 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. The kit of claim 6, wherein the molar ratio is about 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 for 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 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. 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.