MXPA98004357A - New combination - 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

NEW COMBINATION OF PHARMACEUTICALLY ACTIVE SUBSTANCES FIELD OF THE INVENTION The present invention provides a new combination of pharmaceutically active substances, which is of use in the treatment of respiratory disorders / particularly asthma.

BACKGROUND OF THE INVENTION Despite recent advances in the knowledge of asthma and the introduction of potent and effective anti-asthma drugs, asthma remains a disease that is poorly understood and often poorly treated. There have been recent advances in the treatment of the disease, which result from the recognition that asthma is a disease. inflammatory. The therapy is now aimed at controlling symptoms and reducing inflammation. Symptoms include uncontrolled inflammation of the airways, which can lead to damage in the mucous membranes and to structural changes, possibly leading to REP: 27487 irreversible narrowing of the airways and fibrosis of the lungs. Symptoms can be controlled by ß2-adrenoreceptor agonists such as salbuta ol, salmeterol, terbutaline and formoterol. Formoterol is advantageous because the duration of its effect is prolonged; This one has a quick start time and due to this gives few nocturnal awakenings. * Prophylactic therapy is typically provided by steroids such as beclomethasone dipropionate, fluticasone propionate and budesoidide. Of these, budesanide is advantageous because it can be administered in a high dose inhaled (up to .2 mg daily) with very low systemic effects. Long-term clinical studies in adults and children have shown that inhaled budesonide has an excellent safety profile.

DESCRIPTION OF THE INVENTION According to the invention there is provided a composition comprising, in a mixture: < H.H a) a first active ingredient which is formoteral, a pharmaceutically acceptable salt or a 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 1:30 to 1:36, preferably from about 1: 32.5. According to the invention, additional equipment is provided comprising: i) a container containing the first active ingredient; ii) a container containing the second active ingredient; and iii) instructions for the 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, preferably from about 1: 32.5. A patient suffering from a respiratory disorder such as asthma can be treated. By administration via inhalation, of a composition. according to the invention. Alternatively, such a patient may be treated by administration via 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 from about 1: 32.5. It has been found that the combination of active ingredients according to the invention is advantageous because it gives a significantly improved anti-inflammatory effect, compared to known treatments. International Patent Publication No. W093 / 11773 discloses a combination of budesonide and formoterol having a wide weight ratio range. The closest example of a combination described in this document to the system of the invention has a weight ratio of formoterol fumarate dihydrated to budesonide of 0.06: 1, for example a molar ratio of 1: 16.3. The combination of active ingredients according to the invention gives surprisingly better results when used to treat patients suffering from asthma, compared to this known combination. The first and second active ingredients of the equipment can be administered sequentially or separately to treat respiratory disorders. By sequential it is understood that the first and second active ingredients are administered one immediately after the other. These still have the desired effect if they are administered separately, but with less than about 12 hours apart, preferably less than about 2 hours apart, more preferably less than about 30 minutes apart. Preferably, the first active ingredient is administered to provide a daily dose of 10 to 250 nmol (preferably 15 to 120 nmol) 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 from 39 to 4300 μg of the second active ingredient (preferably 86 to 2150 μg), subject to the molar ratio of the first active ingredient to the second active ingredient, which is within the range of, 1. : .3.0, at 1:36 .. Suitable physiologically acceptable salts of formotere, include the acid addition salts derived from inorganic and organic acids, for example, the salts of chloride, bromide, sulfate, phosphate, maieate, fumarate, tartrate, citrate, benzoate, 4-metaxibenzaate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulfonate, methansulfonate, .ascorbate, .acetate, .succinate, lactate, glutarate , gluconate, tricarbalylate, idroxinaphthalene-carboxylate or oleate or solvates thereof. The first active ingredient is preferably the fumarate of the latex, especially the dihydrate. When the first active ingredient is fumarate, or, preferably, dihydrate, the preferred daily dose of the first active ingredient is from 4 to 100 μa, more preferably from 6 to 50. . μg . { subject to the molar ratio of the first active ingredient to the second active ingredient, which is within the range of 1: 3Q to 1:36). More preferably the composition or equipment of the invention comprises 6, μg of formoterol fumarate dihydrate and 200 μg of budesonide, or 4.5 μg of formoterol fumarate dihydrate and 160 μg of budesonide, any of which is administered up to four times a day. Alternatively, the composition or equipment of the invention comprises .12 μg. Of formoterol dihydrate and 400 μg of budesonide, or 9 μg of formol fumarate dihydrate and .320 μg. Of budesonide, any of which It is administered once or twice a day. * Preferably, the active ingredients are used. in admixture with, one or more pharmaceutically acceptable diluents or carriers, preferably in an amount of 50 μg to 25 g per dose, more preferably in an amount of 50 μg to 10 mg, more. preferably in an amount of 100 to 2000 μg. Examples of suitable diluents or carriers include lactose, dextran, .manitol and glucose. Preferably lactose is used, especially as the monohydrate. It should be understood that where reference is made to the amounts of each active ingredient, these are measured quantities. When the active ingredients are administered, the amount of each ingredient inhaled by the patient may differ in the amount measured, for example, by the patient. the retention of the active ingredient in the inhalation device. In addition, when the active ingredients are formulated separately, the amount administered of each is not necessarily reduced proportionally. Thus, the proportion administered of the active ingredients could differ from the proportion measured. Preferably, the proportion administered is within the specified proportion specified. above. One or more of the active ingredients used in the invention is preferably in the form of a dry powder, more preferably a finely divided powder, for example a dry powder, micronized, having for example an average mass diameter of less than 10 μm, for example from 1 to 5 μm, more preferably an agglomerated micronised dry powder. As an alternative to agglomeration, finely divided active ingredients can is in the form of an ordered mixture with one or more pharmaceutically acceptable additives, diluents or carriers. An ordered mixture is the combination of the finely divided active ingredient with coarse particles of the additive, diluent or pharmaceutically acceptable carrier.

The ingredients used in the invention can be obtained in these preferred forms using methods known to those of skill in the art. According to the invention, there is further provided the use of a composition or equipment according to the invention in the manufacture of a medicament for the 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 an equipment or a composition according to the invention for use in the treatment of a respiratory disorder, for example asthma. The administration can be by inhalation orally or intranas.almenta. The ingredients are preferably adapted to be administered from a dry powder inhaler, a pressurized metered dose inhaler, or a nebulizer. When the ingredients of the composition or equipment are adapted to be administered from a pressurized inhaler, they are preferably in the micronized form .. These are dissolved or, preferably, suspended in a liquid propellant mixture. The propellants that can be used include chlorofluorocarbons, hydrocarbons or hydrofluoroalkanes. Especially preferred propellants are P134a (tetrafluoroethane) and P227 (heptafluoropropane) each of which can be used alone or in combination. These are optionally used in combination with one or more other propellants and / or one or more surfactants and / or one or more other excipients, for example ethanol, a lubricant, an antioxidant and / or. .a stabilizing agent. When the ingredients of the composition or equipment of the invention are adapted to be administered via a nebulizer, they may be in the form of a. a nebulized aqueous suspension, or a solution, with or without an adequate pH or tonicity adjustment, ... whether as a single dose or as a multiple dose device. The composition or team may optionally be administered as divided doses from 1 to 4, and preferably once or twice daily. The invention is illustrated by the following Examples, which are not intended to limit the scope of the application. In the Examples, micronization is carried out in a conventional manner, such that the particle size range for each component is adequate for administration by inhalation. Turbuhaler is a trading name of Astra AB.

EXAMPLE 1 Six parts were mixed in the weight of formoterol dihydrate with 794 parts by weight of lactose, monohydrate. The mixture was micronized using a high pressure air jet mill and then conditioned using the process of European Patent EP-A-717, 616. 200 parts by weight of budesonide. micronized products were added to the conditioned product, by mixing and homogenization with a .molino. cho xo ..a-low. The mixture was then spheronized using the process of the European Patent. EPTA-721, .331 and filling .dentxo of the storage compartment of a Turbuhaler.

EXAMPLE 2 4 parts of the formoterol fumarate dihydrate were mixed with 835 parts by weight of monohydrated lactose. The mixture was icronized using a high pressure air jet mill and then conditioned, using the process of European Patent EP-A-717,616. 160 parts by weight of budesonide .. micronized = j were added .. added to the conditioned product, by mixing and homogenization with a mill., of .chorrea ba ..px.esion. The mixture was then spheronized using the process of the European Patent EP-A-7.21.331 .and filling ... into ... the storage compartment of a Turbuhaler.

EXAMPLE 3 HE. mixed .12 .parts ..in ..weight of. fu formoterol axate dihydrate with 588 parts by weight of lacto a .. monohydrate - The mixture. it was heated using a high pressure air jet mill and then conditioned using. the .. process .. of the European Patent EP-A-717, 616. 400 parts by weight of micronized budesonide = were .. added .. to the conditioned product, by mixing and homogenization with a. low jet. The mixture was then spheronized using the process of the European Patent .. EP-A-721, .331 and filling of the storage compartment of a Turbuhaler.

EXAMPLE 4 6 parts of the dehydrated fumarate dihydrate were mixed with 994 parts by weight of lactose monohydrate. The mixture was micronized by filtering a high pressure air jet mill and then conditioned using the process of European Patent EP-A-717, 616. The mixture was then spheronized using the process of the European Patent EP-A. -721,331 and filled into the storage compartment of a Turbuhaler. 200 parts by weight of micronized budenoside were mixed with 8.00 parts by weight of monohydrated lactose. The mixture was micronized by filtering a .chorro. high, and then it was conditioned using the process of European Patent EP-A-717, 616. The mixture was then spheronized using the process of European Patent EP-A-721.3-3-1. It was filled into the storage compartment of a Turbuhaler.

EXAMPLE 5 4. 5 parts by weight of formoterol fumarate dihydrate were mixed with 935 parts by weight of lactose monohydrate. The mixture was micronized by filtering a. This was then transferred to a high-pressure vessel and then conditioned using the process of European Patent EP-A-717 ^ 616. The mixture was then spheronized using the process of the European Patent EP-A- 721 ,,. 331 and ... was found in the storage compartment of a Turbuhaler. 160 parts of the weight of budenoside micronizer were mixed with 840 parts by weight of lactose hydrolyzate. The mixture was micronized by filtering a high pressure air jet mill and then conditioned using the process of European Patent EP-A-717,616. The mixture was then spheronized using the. process .de .la .Patiente .European EP-A-721,331 and was filled inside the storage compartment of a Tuxbuhaler.

EXAMPLE 6 The parts in the weight of the dihydrate formulation were mixed with 988 parts by weight of the lactose hydrolyzate. The mixture was micronized by filtering a high pressure air jet mill and then it was. conditioned by using the process of European Patent EP-A-717, 616. The mixture was then spheronized using the process of European Patent EP-A-.721, .331 and was filled into the storage compartment of a Turbuhaler. 400, arts. in, that .micronized budenoside was mixed with 600 parts by weight of lactose monohydrate. The mixture was micronized by filtering a high pressure air jet mill and then conditioned using the process of the European Patent EP-A-717, 616. The mixture was then spheronized using. The process of the .European .EP-A-721,331 and was filled inside the storage compartment of a Turbuhaler.It is noted that with regard to this concept, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

The invention having been described as above, .. is claimed .co or property. Contained in the following:

Claims (11)

1. A composition, characterized in that it comprises, in admixture: (a) a first selected active ingredient, of the group consisting of .foxmo.terol, a pharmaceutically acceptable salt or solvate thereof, and a salty-salt.; and (b) a second active ingredient which is budesonide; where the molar ratio of (a) to (b) in the composition. is,. of..1.:. 30.a.1: 3.6.

2. A composition according to claim 1, characterized because the molar proportion is approximately 1: 32.5.

3. A composition of conformity with claim 1, characterized in that the first active ingredient is fumarate deformotexol dihydrate.

4. A composition according to claim .1, .characterized. Because .comprende additionally. an additive,. pharmaceutically acceptable carrier or carrier ..

5. U, n .. equipment, .. characterized ... because it comprises: (a) a container containing a first active ingredient selected from the group consisting of formoterol, a pharmaceutically acceptable salt or solvate thereof, and a. .sol.vato of such salt; (b) a container containing a second active ingredient, which is budesonide; (c) the instructions for sequential administration .. or .. separated from 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.

6. A device according to claim 5, characterized in that the molar proportion is approximately 1: 32.5.

7. A kit according to claim 5 characterized in that the first active ingredient is formoterol fumarate dihydrate.

8. A kit according to claim 5, characterized in that it comprises a pharmaceutically acceptable additive, diluent or carrier, suitable for inhalation.

9. A device according to claim 5, characterized in that each ingredient is in the form of a finely divided dry powder and each container is a dry powder inhaler.

10. A method for the treatment of a respiratory disorder, characterized in that the method comprises administering via inhalation to a patient suffering from the disorder, a therapeutically effective amount of a composition as defined in accordance. with claim .1.

11. A method of treating a respiratory disorder, characterized the method - because it comprises administering sequentially or separately via inhalation to a patient suffering from the disorder: (a) a dose of the first active ingredient which is selects from the group which consists of formoterol, a pharmaceutically acceptable salt or solvate thereof, and a solvate thereof. Salt; and (b) a dose of a second active ingredient which is budesonide; where the molar ratio of (a.) to (b) is from 1:30 to 1: 36.