MXPA99011676A - New combination of antiasthma medicaments - Google Patents
New combination of antiasthma medicamentsInfo
- Publication number
- MXPA99011676A MXPA99011676A MXPA/A/1999/011676A MX9911676A MXPA99011676A MX PA99011676 A MXPA99011676 A MX PA99011676A MX 9911676 A MX9911676 A MX 9911676A MX PA99011676 A MXPA99011676 A MX PA99011676A
- Authority
- MX
- Mexico
- Prior art keywords
- active ingredient
- rofleponide
- solvate
- patient
- formoterol
- Prior art date
Links
- 239000003814 drug Substances 0.000 title description 4
- 230000001088 anti-asthma Effects 0.000 title description 2
- 239000000924 antiasthmatic agent Substances 0.000 title description 2
- 239000004480 active ingredient Substances 0.000 claims abstract description 48
- 239000000203 mixture Substances 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000011780 sodium chloride Substances 0.000 claims abstract description 19
- 239000012453 solvate Substances 0.000 claims abstract description 18
- BPZSYCZIITTYBL-YJYMSZOUSA-N Formoterol Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-YJYMSZOUSA-N 0.000 claims abstract description 13
- -1 fatty acid ester Chemical class 0.000 claims abstract description 12
- 229960002848 formoterol Drugs 0.000 claims abstract description 12
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 10
- 239000000194 fatty acid Substances 0.000 claims abstract description 10
- 206010038683 Respiratory disease Diseases 0.000 claims abstract description 8
- IXTCZMJQGGONPY-XJAYAHQCSA-N Rofleponide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O IXTCZMJQGGONPY-XJAYAHQCSA-N 0.000 claims description 18
- 229950004432 Rofleponide Drugs 0.000 claims description 18
- 239000000843 powder Substances 0.000 claims description 15
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- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- KQTIIICEAUMSDG-UHFFFAOYSA-K tricarballylate Chemical compound [O-]C(=O)CC(C([O-])=O)CC([O-])=O KQTIIICEAUMSDG-UHFFFAOYSA-K 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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 ropfleponide, or a fatty acid ester thereof. Also disclosed are methods for treating respiratory disorders using this composition or kit.
Description
NOVEDOSA COMBINATION OF ANTI-ASM DRUGS
Field of the Invention The present invention relates to compositions and methods useful in the treatment of respiratory disorders, particularly asthma.
BACKGROUND OF THE INVENTION Despite recent advances in the knowledge of asthma and the introduction of powerful and effective anti-asthma drugs, asthma remains a poorly understood and often poorly treated disease. There have been recent advances in the treatment of the disease which result from the recognition that asthma is a chronic inflammatory disease. The main purpose of therapy now is to control symptoms and reduce inflammation. Symptoms include uncontrolled inflammation of the airways, which can lead to mucosal damage and structural changes that possibly lead to irreversible narrowing of the airways and fibrosis of the lungs. Symptoms can be controlled by β2-adrenoreceptor agonists such as salbutamol, bambuterol,
REF .: 32251
clenbuterol, fenoterol, procaterol, bitolterol, broxaterol, salmeterol, terbutaline and formoterol. Prophylactic therapy is typically provided by spheroids such as beclomethasone dipropionate (BDP), beclomethasone monopropionate (BMP ^ flunisolide, triamcinolone acetonide, dexamethasone, tipredane, ciclesonid, mometasone, RPR 106541, fluticasone or fluticasone propionate and budesonide or sodium cromoglycate or nedocromil sodium.
Brief Description of the Invention The invention is based on the discovery that the esters of formoterol and rofleponide, or their salts or solvates, when administered to a patient concurrently or sequentially, are unexpectedly effective in the treatment of respiratory disorders involving inflammation. , such as asthma. Accordingly, the invention features a composition having, in a mixture: (a) a first active ingredient which is formoterol, a pharmaceutically acceptable formoterol salt or solvate, or a solvate such as a salt; and (b) a second active ingredient which is rofleponide or a fatty acid ester of rofleponide. It is preferred that the molar ratio (a) to (b) is from »1: 1 to 1: 100, preferably from 1: 1 to 1:60, so
more preferable from 1: 1 to 1:35, more preferably from 1:16. The first active ingredient (a) of the composition can be, for example, formoterol fumarate dihydrate, and the second active ingredient (b) of the composition can be, for example, rhoplatinide palmitate. The composition may be provided in the form of a dry powder, the particles of which may have a mass average diameter of less than 10 μ. The invention also includes a device that contains:
(a) a container containing a first active ingredient which is formoterol, a pharmaceutically acceptable salt or solvate thereof, or a solvate such as a salt; (b) a container containing a second active ingredient that is rofleponide or a fatty acid ester of rofleponide; and (c) instructions for the sequential or simultaneous administration of the first and second active ingredients to a patient in need of them. A patient suffering from a respiratory disorder such as asthma can be treated by administering (eg, via inhalation), simultaneously or sequentially, (a) a dose of a first active ingredient selected from the group consisting of formoterol, a salt pharmaceutically acceptable or a solvate thereof, and a solvate of such a salt; and (b) a dose of a second active ingredient selected from the group consisting of rofleponide and a solvate of such a salt; and (b) a dose
of an active ingredient selected from the group consisting of rofleponide and a fatty acid ester of rofleponide. The active ingredients can be provided to the patient to be inhaled in powder form. When administered sequentially, the active ingredients can be administered in any order, such as within a period of two hours. For example, the first active ingredient may be administered to the patient in less than about 30 minutes after the second active ingredient, or the second active ingredient may be administered to the patient less than about 30 minutes after the first active ingredient. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. The combination according to the invention has the advantage that the total dose of each active ingredient can be decreased and is more likely to provide patient acceptance so that it could be exempt from the properties of the individual active ingredients. Detailed Description The invention provides a composition having (a) a first active ingredient selected from the group consisting of formoterol, a salt or solvate of formoterol
pharmaceutically acceptable, and a solvate of such salt; (b) a second active ingredient selected from the group consisting of rofleponide and a fatty acid ester of rofleponide; and, optionally, (c) one or more pharmaceutically acceptable additives, diluents or carriers. It has been found, using an edema model induced by sephadex (Kállstrom et al., Agents and Action, 17: 355-377 (1985)), that the combination of active ingredients provides a significantly improved anti-inflammatory effect compared to the sum of the individual anti-inflammatory effects of the two active ingredients, thereby providing a significant advantage. The first and second active ingredients of the composition can be administered simultaneously or sequentially to treat respiratory disorders. Simultaneously means the first and second active ingredients. (a) and (b) are administered concomitantly, for example as a mixture. Sequential administration generally comprises administering one immediately after the other. They will still have the desired effect if they are administered separately but not separated more than about two hours, for example separated no more than 30 minutes and preferably not more than 5 minutes.
Preferably the composition is administered to provide a daily dose of 0.5 to 200 mmol (preferably 4 to 100 nmol) of (a) and 0.5 to 1140 nmol (preferably 14 to 285 nmol and more preferably preferable from 14 to 285 nmol) of (b) (subject to the molar ratio of (a) to (b) being 1: 1 to 1: 100). When (a) is formoterol fumarate dihydrate, the preferred daily dose is 0.2 to 84 μg (preferably 2 to 42 μg) of (a), and 0.4 to 800 μg (preferably 10 to 400 μg). μg, more preferably 10 to
200 μg) of (b) where (b) is rhoplaponite palmitate (subject to the molar ratio of (a) to (b) being within the range of 1: 1 to 1: 100). Suitable physiologically acceptable salts of formoterol include acid 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 salts or solvates thereof. The active ingredient is preferably formoterol fumarate, especially as the dihydrate.
The rofleponide is preferably esterified by a palmitoyl group. Preferably each of the active ingredients comprises one or more pharmaceutically acceptable additives, diluents or carriers, more preferably in an amount of 50 to 2000 μg in a daily dose, more preferably in an amount of 100 to 1000 μg. . Examples of suitable diluents or carriers include lactose, dextran, mannitol and glucose. Preferably, lactose is used. Since the active ingredient (b) is preferably a fatty acid ester, the formulations containing it are desirably liposomal or proliposomal if they are formulations in the form of a dry powder. Suitable proliposomal formulations of fatty acid esters of rofleponida are described in WO 96/19199. To improve stability the formulation may comprise tocopherol, especially α-tocopherol. The active ingredients (a) and (b) can optionally be formulated together to be administered simultaneously. For example, they can be formulated in admixture as a proliposomic powder, for example of the general type described in WO 96/19199 (which preferably contains tocopherol as a stabilizing agent) or as a mixture.
intimate of (a) in the form of a dry powder and dry powder containing (b). One or more of the active ingredients according to the invention are preferably in the form of a dry powder, more preferably a dry micronized powder, for example, having a mass median diameter of less than 10 μm, for example from 1 to 5 μm, more preferably an agglomerated micronised dry powder. Alternatively, the active ingredient (a) may be in the form of an ordered mixture with the ingredient (c). The ingredients used in the invention can be obtained in those preferred forms using methods known to those skilled in the art. The invention further provides a method for treating a respiratory disorder, which is preferably asthma, chronic obstructive pulmonary disease (COPD) and / or rhinitis, which method comprises applying to a patient suffering from it, or susceptible to suffering from such a disorder , a therapeutically effective amount of a combination according to the invention. According to the invention there is further provided the use of a mixture or equipment according to the invention in the manufacture of a medicament for use in a simultaneous, separate or sequential therapy, preferably in the treatment of a respiratory disorder, for example he
asthma, chronic obstructive pulmonary disease (COPD) and / or rhinitis. The administration can be by oral or intranasal inhalation. The ingredients are preferably adapted to be administered from a dry powder inhaler. The combination can optionally be administered as divided doses of 1 to 4, and preferably once or twice a day, which means unit doses of 0.05 μg to 84 μg (preferably 0.5 μg to 42 μg) of dihydrate formoterol fumarate and from 0.1 to 800 μg (preferably 2.5 μg to 400 μg) of rhoplaponide palmitate.
Example 1 Rylleponide palmitate (10 parts by weight), dipalmitoylphosphatidylcholine (63 parts), dimyristoylphosphatidylcholine (24 parts), dipalmitoyl-phosphatidylglycerol sodium (3 parts) and racemic α-tocopherol (0.1 parts) in tertiary butanol (1300 parts) were dissolved. at 80 ° C. The solution was poured onto the shelves of a lyophilizer cooled to -35 ° C. The solution reached this temperature about 30 minutes later, the pressure in the lyophilizer was then reduced to induce sublimation of the solvent. Although the speed of sublimation can be
adjusted by decreasing the pressure and increasing the temperature, the temperature through the process was not allowed to exceed -10 ° C. The lyophilization continued until all the solvent had been removed. The resulting powder was removed from the freeze dryer shelves and passed through a screen. This powder was micronized in an air jet mill at a powder particle size of less than 5 μm. 0.5 parts of formoterol fumarate dihydrate were mixed with 79.5 parts of lactose monohydrate. The mixture was micronized "using a high pressure air jet mill and then conditioned using the process of EP-A-717 616. This mixture (80 parts) was added to a mixture of steroid / lipid powder (20). parts) by mixing and homogenizing with a low pressure jet mill.The mixture was then spheronized using the process of EP-A-721 331 and filled into an ampule, a capsule or a storage chamber of an inhaler for use in a dry powder inhaler.
Other modalities It should be understood that although the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the invention.
scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.
It is noted that in relation to this date, 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.
Claims (17)
1. A therapeutic composition characterized in that it comprises, in admixture: (a) 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; Y (b) a second active ingredient selected from the group consisting of rofleponide and a fatty acid ester of rofleponide, wherein the molar ratio (a) to (b) in the composition is from 1: 1 to 1: 100.
2. The composition according to claim 1, characterized in that the molar ratio of (a) to (b) in the composition is from 1: 1 to 1:60, preferably from 1: 1 to 1:35.
3. The composition according to claim 1 or 2, characterized in that (a) is formoterol fumarate dihydrate. .
The composition according to any of claims 1 to 3, characterized in that (b) is rofleponide palmitate.
The composition according to any of claims 1 to 4, characterized in that it additionally comprises a pharmaceutically acceptable diluent or carrier suitable for inhalation.
The composition according to any of claims 1 to 5, characterized in that it is in the form of a dry powder of particles which have an average mass diameter of less than 10 μm.
7. A kit, characterized in that 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 salt solvate; (b) a container containing a second active ingredient selected from the group consisting of rofleponide and a fatty acid ester of rofleponide; and (c) instructions for the sequential or simultaneous administration of the first and second active ingredients to a patient in need thereof, the instructions specify that the first and second active ingredients are administered in a molar ratio ranging from 1: 1 to 1. : 100
8. The equipment according to claim 7, characterized in that the first active ingredient is formoterol fumarate dihydrate.
9. The equipment according to claim 7 or 8, characterized in that the second active ingredient is rylcoponide palmitate.
The equipment according to any of claims 7 to 9, characterized in that the instructions specify that the first and second active ingredients are administered in a molar ratio ranging from 1: 1 to 1:60, preferably 1: 1 to 1:35.
11. A method for treating a respiratory disorder, which method is characterized in that it comprises administering simultaneously or sequentially to a patient suffering from the disorder (a) a dose of a first active ingredient selected from the group consisting of formoterol, a salt or solvate pharmaceutically acceptable thereof and a solvate such salt; and (b) a dose of a second active ingredient selected from the group consisting of rofleponide and a fatty acid ester of rofleponide, wherein the molar ratio (a) to (b) is 1: 1 to 1: 100
12. The method according to claim 11, characterized in that the molar ratio of (a) to (b) is from 1: 1 to 1:60, preferably from 1: 1 to 1:35.
The method according to claim 11 or 12, characterized in that the first active ingredient is formoterol fumarate dihydrate.
The method according to any of claims 11 to 13, characterized in that the second active ingredient is rhoplatinide palmitate.
15. The method according to any of claims 11 to 14, characterized in that the first active ingredient is administered to the patient in less than about 30 minutes before and after the second active ingredient.
16. The method according to any of claims 11 to 15, characterized in that the doses are administered to the patient by having the patient inhale them simultaneously.
17. The method according to claim 16, characterized in that the first and second active ingredients are both providing the patient to be inhaled in the form of dry powder.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US883823 | 1997-06-27 |
Publications (1)
Publication Number | Publication Date |
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MXPA99011676A true MXPA99011676A (en) | 2000-05-01 |
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