KR19990071975A - New complex composition - Google Patents

Abstract

In the present invention, the first active ingredient comprises formoterol or a salt or solvate derivative thereof and the budesonide as the second active ingredient (wherein the molar ratio of the first active ingredient to the second active ingredient is 1:30 To 1:36), or compositions and kits, and use of the compositions and kits in the treatment of respiratory disorders.

Description

Novel Composite Compositions

Despite recent advances in awareness of asthma and the introduction of powerful and effective asthma medications, asthma still remains a poorly understood and often poorly treated disease. Recently, the treatment of asthma has advanced in the recognition that asthma is a chronic inflammatory disease. The goal of current treatment is to control symptoms and reduce inflammation. Symptoms of asthma include irreversible narrowing of the airways and inflammation of the unregulated airways that can cause structural damage and mucosal damage that can cause fibrosis of the lungs.

The symptoms can be controlled by β ₂ -adrenoceptor agonists such as salbutamol, salmeterol, terbutalin and formoterol. Formoterol is advantageous because it has a long time to act, rapid onset time, and less awake at night.

Prophylactic treatment typically provides steroids such as beclomethasone, dipropionate, fluticasone propionate and budesonide. Of these, budesonide is advantageous because it has a very low systemic effect and can be provided at high inhalation doses (up to 2 mg per day). Long-term clinical studies in adults and children have shown that inhaled budesonide has an excellent safety profile.

The present invention provides novel complex compositions of pharmaceutically active substances for the treatment of respiratory disorders, in particular asthma.

According to the invention, in the mixture

(a) formoterol, a pharmaceutically acceptable salt or solvate of formoterol, or a solvate of said salt as a first active ingredient; And

(b) providing a composition comprising budesonide as a second active ingredient as a mixture, 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 do.

According to the invention,

(i) a container comprising a first active ingredient;

(ii) a container comprising a second active ingredient; And

(iii) a kit comprising instructions for sequentially or separately administering the first active ingredient and the second active ingredient 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 about 1: 32.5).

By inhalation administration of the complex composition according to the invention it is possible to treat patients suffering from respiratory disorders such as asthma. Alternatively,

(i) a first active ingredient dose; And

(ii) inhaled administration of a second active ingredient dose, wherein the molar ratio of first active ingredient: second active ingredient is from 1:30 to 1:36, preferably about 1: 32.5, sequentially or separately Thereby treating the patient.

It has been found to be advantageous as the combined composition of the active ingredients according to the invention provides a significantly elevated anti-inflammatory effect compared to known treatments. WO 93/11773 discloses a composite composition of budesonide and formoterol with a wide range of weight ratios. The most similar example to the system of the present invention in the composite compositions disclosed in this document is a composite composition in which the weight ratio of formoterol fumarate dihydrate: budesonide is 0.06: 1, ie the molar ratio 1: 16.3. The composite composition of the active ingredients according to the invention provides surprisingly better results when used to treat patients suffering from asthma compared to the above known combination compositions.

The first active ingredient and the second active ingredient of the kit may be administered sequentially or separately to treat a respiratory disorder. "Sequentially" means administering the first active ingredient and the second active ingredient immediately following the administration of one of these ingredients. Although these components are administered separately, however, administration at intervals within about 12 hours, preferably within about 2 hours, and more preferably within about 30 minutes, still has the desired effect.

Preferably, the first active ingredient provides a daily dosage of 10 to 250 nmol (preferably 15 to 120 nmol) such that the molar ratio of the first active ingredient to the second active ingredient is in the range of 1:30 to 1:36. And the second active ingredient is administered to provide a daily dose of 0.1 to 10 μmol (preferably 0.2 to 5 μmol) or 39 to 4300 μg (preferably 86 to 2150 μg).

Suitable physiologically acceptable salts of formoterol are acid addition salts derived from inorganic and organic acids, for example chlorides, bromide, sulfates, phosphates, maleates, fumarates, tartarates, citrates, benzoates, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulfonate, methanesulfonate, ascorbate, acetate, succinate, lactate, glutarate, glue Phosphates, tricarballylates, hydroxynaphthalene-carboxylates or oleates or solvates thereof. The first active ingredient is preferably formoterol fumarate, in particular formoterol fumarate dihydrate.

When the first active ingredient is formoterol fumarate dihydrate, the preferred daily dose of the first active ingredient is 4-100 μg, more preferably 6-50 μg (molar ratio of first active ingredient: second active ingredient). Is in the range of 1:30 to 1:36).

More preferably, the compositions or kits of the invention comprise 6 μg formoterol fumarate dihydrate and 200 μg budesonide, or 4.5 μg formoterol fumarate dihydrate and 160 μg budesonide, both of which are In all cases, up to four times daily.

Alternatively, a composition or kit of the present invention comprises 12 μg formoterol fumarate dihydrate and 400 μg budesonide, or 9 μg formoterol fumarate dihydrate and 320 μg budesonide, both of which Dosing once or twice daily.

Preferably, the active ingredient (s) is preferably in an amount of 50 μg to 25 mg, more preferably in an amount of 50 μg to 10 mg, most preferably in an amount of 100 to 2000 μg, at least one Used in admixture with pharmaceutically acceptable additives, diluents or carriers. Examples of suitable diluents or carriers include lactose, dextran, mannitol and glucose. Preferably, lactose is used, in particular as monohydrate.

When referring to the amount of each active ingredient, it is to be understood that the amount is a metered amount. When administering the active ingredients, the amount of each active ingredient inhaled to the patient may differ from the metered amount, for example due to the retention of the active ingredient in the inhalation device. Moreover, when the active ingredients are formulated separately, the administered amount of each ingredient does not necessarily decrease directly. Thus, the administered rate of the active ingredients may differ from the metered rate. It is preferred that the rate administered is within the metered rate defined above.

The one or more active ingredients used in the present invention are preferably in the form of a dry powder, more preferably finely divided (eg, having a mass average diameter of 10 μm or less (eg 1 to 5 μm)). For example, in the form of a dry powder ground to a micron size, most preferably in the form of agglomerated form of dry powder ground to a micron size. As an alternative to aggregation, the finely divided active ingredients may be in the form of a mixture ordered by size with one or more pharmaceutically acceptable additives, diluents or carriers. Mixtures sorted by size are complex compositions of finely divided active ingredients with coarse particles of pharmaceutically acceptable additives, diluents or carriers. The components used in the present invention can be obtained in these preferred forms using methods known to those skilled in the art.

According to the invention, there is further provided the use of a composition or kit according to the invention in the manufacture of a medicament for the treatment of respiratory disorders (eg asthma). The invention also provides the use of budesonide or formoterol in the manufacture of a kit or composition for treating a respiratory disorder (eg asthma) according to the invention.

Administration can be by oral or nasal inhalation. The components of the invention are preferably suitable for administration from a dry powder inhaler, a pressurized metered dose inhaler or a nebuliser.

If the components of the compositions or kits of the invention are suitable for administration from a pressure inhaler, they may preferably be in the form of milled to micron size. They are dissolved or preferably suspended in the liquid propeland mixture. Propellers that may be used include chlorofluorocarbons, hydrocarbons or hydrofluoroalkanes. Particularly preferred propanes are P134a (tetrafluoroethane) and P227 (heptafluoropropane), which can each be used alone or in combination. They may be used in combination with one or more other propelants and / or one or more surfactants and / or one or more other excipients such as ethanol, lubricants, antioxidants and / or stabilizers.

If the components of the compositions or kits of the invention are suitable for administration via a nebulizer, they may be in the form of a sprayed aqueous suspension or solution, with or without appropriate pH or tonicity adjustments, as unit or multidose devices. .

The compositions or kits of the invention may optionally be administered in one to four divided doses, preferably once or twice daily.

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

Example 1

6 parts by weight of formoterol fumarate dihydrate was mixed with 794 parts by weight of lactose monohydrate. The mixture was ground to micron size using a high pressure air jet mill and then conditioned using the method of EP-A-717 616. 200 parts by weight of micron sized budesonide was added by mixing to the conditioned product and homogenized using a low pressure jet mill. This mixture was then spherical using the method of EP-A-721 331 and filled into a Terbuhaller storage compartment.

Example 2

4.5 parts by weight of formoterol fumarate dihydrate were mixed with 835 parts by weight of lactose monohydrate. The mixture was ground to micron size using a high pressure air jet mill and then conditioned using the method of EP-A-717 616. 160 parts by weight of micron sized budesonide was added by mixing to the conditioned product and homogenized using a low pressure jet mill. This mixture was then spherical using the method of EP-A-721 331 and filled into a Terbuhaller storage compartment.

Example 3

12 parts by weight of formoterol fumarate dihydrate was mixed with 588 parts by weight of lactose monohydrate. The mixture was ground to micron size using a high pressure air jet mill and then conditioned using the method of EP-A-717 616. 400 parts by weight of micron sized budesonide was added by mixing to the conditioned product and homogenized using a low pressure jet mill. This mixture was then spherical using the method of EP-A-721 331 and filled into a Terbuhaller storage compartment.

Example 4

6 parts by weight of formoterol fumarate dihydrate was mixed with 994 parts by weight of lactose monohydrate. The mixture was ground to micron size using a high pressure air jet mill and then conditioned using the method of EP-A-717 616. This mixture was then spherical using the method of EP-A-721 331 and filled into a Terbuhaller storage compartment.

200 parts by weight of micronized ground budesonide was mixed with 800 parts by weight of lactose monohydrate. The mixture was ground to micron size using a high pressure air jet mill and then conditioned using the method of EP-A-717 616. This mixture was then spherical using the method of EP-A-721 331 and filled into a Terbuhaller storage compartment.

Example 5

4.5 parts by weight of formoterol fumarate dihydrate was mixed with 995 parts by weight of lactose monohydrate. The mixture was ground to micron size using a high pressure air jet mill and then conditioned using the method of EP-A-717 616. This mixture was then spherical using the method of EP-A-721 331 and filled into a Terbuhaller storage compartment.

160 parts by weight of micronized ground budesonide was mixed with 840 parts by weight of lactose monohydrate. The mixture was ground to micron size using a high pressure air jet mill and then conditioned using the method of EP-A-717 616. This mixture was then spherical using the method of EP-A-721 331 and filled into a Terbuhaller storage compartment.

Example 6

12 parts by weight of formoterol fumarate dihydrate was mixed with 988 parts by weight of lactose monohydrate. The mixture was ground to micron size using a high pressure air jet mill and then conditioned using the method of EP-A-717 616. This mixture was then spherical using the method of EP-A-721 331 and filled into a Terbuhaller storage compartment.

400 parts by weight of micron sized budesonide was mixed with 600 parts by weight of lactose monohydrate. The mixture was ground to micron size using a high pressure air jet mill and then conditioned using the method of EP-A-717 616. This mixture was then spherical using the method of EP-A-721 331 and filled into a Terbuhaller storage compartment.

Claims (16)

(a) formoterol as a first active ingredient, a pharmaceutically acceptable salt or solvate thereof, and solvate of said salt; And (b) A composition comprising budesonide as a second active ingredient as a mixture, wherein the molar ratio of (a) :( b) in the composition is from 1:30 to 1:36. The composition of claim 1, wherein said molar ratio is about 1: 32.5. The composition of claim 1 or 2, wherein the first active ingredient is formoterol fumarate dihydrate. The composition of any one of claims 1 to 3, further comprising a pharmaceutically acceptable additive, diluent or carrier. The composition according to any one of claims 1 to 4 for use in the treatment of respiratory disorders. (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 said salt, (b) a container comprising budesonide as a second active ingredient, and (c) instructions for sequentially or separately administering the first active ingredient and the second active ingredient 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 kit. The kit of claim 6, wherein the molar ratio is about 1: 32.5. 8. The kit of claim 6 or 7, wherein the first active ingredient is formoterol fumarate dihydrate. The kit of claim 6, further comprising a pharmaceutically acceptable additive, diluent or carrier. 10. The kit according to any one of claims 6 to 9, wherein each component is in the form of finely divided dry powder and each container is a dry powder inhaler. A method of treating a respiratory disorder comprising inhaling the therapeutically effective amount of a composition according to any one of claims 1 to 4 to a patient suffering from a respiratory disorder. (a) formoterol as a first active ingredient, a pharmaceutically acceptable salt or solvate thereof, and a solvate dose of said salt, and (b) inhaled administration of budesonide as a second active ingredient (wherein the molar ratio of (a) :( b) is from 1:30 to 1:36) sequentially or individually to patients suffering from respiratory disorders A method of treating respiratory disorders, comprising. Use of the composition according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of respiratory disorders. Use of the kit according to any one of claims 6 to 10 in the manufacture of a medicament for the treatment of respiratory disorders. Formorol, a pharmaceutically acceptable salt or solvate thereof, and a composition for treating respiratory disorders according to any one of claims 1 to 4 or any one of claims 6 to 10 of the solvate of the salt. Use in the manufacture of a kit for treating respiratory disorders according to claim. Use of budesonide in the preparation of a composition for treating respiratory disorders according to any one of claims 1 to 4 or a kit for treating respiratory disorders according to any one of claims 6 to 10.