JP2004500431A - Pharmaceutical composition comprising (R, R) -formoterol and rofleponide - Google Patents

Abstract

The invention relates to pharmaceutical preparations comprising a combination of (R, R) -formoterol and rofleponide, and to the use of such preparations in medicine, in particular in the prevention and treatment of respiratory diseases.

Description

微細化した活性成分を計量してアルミニウム缶に入れ、続いて１，１，１，２−テトラフルオロエタンを真空フラスコから加え、計量バルブを所定の位置に取り付けた。
【００３２】
同じ方法を実施例２の製剤のために使用し得る：
実施例２
【表２】

【００３３】
Ｂ： 乾燥粉末吸入器
実施例３
【表３】

活性成分を微細化して、上記の割合にて大スケールでラクトースと混合した。該混合物を、硬ゼラチンカプセル若しくはカートリッジ、又は、Ｒｏｔａｈａｌｅｒ、Ｄｉｓｋｈａｌｅｒ又はＤｉｓｋｕｓ吸入器（それぞれＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄの商標である）のような吸入器により投与するために特別に作製した二重フォイルブリスター包装に充填した。
【００３４】
同様の方法を実施例４の製剤のために使用し得る：
実施例４
【表４】

[0001]
The present invention relates to a combination of (R, R) -formoterol and rofleponide, in particular a composition comprising a combination of (R, R) -formoterol and rofleponide, and the medical treatment of such a composition, especially for the treatment of respiratory diseases. It relates to its use in prevention and treatment.
[0002]
Formoterol, 2′-hydroxy-5 ′-[(RS) -1-hydroxy-2 {[(RS) -p-methoxy-α-methylphenethyl] amino} ethyl] formanilide, especially its fumarate, It is a well-known adrenergic receptor agonist currently used clinically in the treatment of bronchial asthma and related disorders. Formoterol has two asymmetric centers and in certain forms exists as the (R, R) -isomer. The (R, R) -isomer of formoterol has already been described, for example, in WO 98/21175 and US Pat. No. 5,795,564.
[0003]
WO92 / 13872 discloses rofleponide, namely 16α, 17α-butylidenedioxy-6α, 9α-difluoro-11β, 21-dihydroxypregna-4-en-3,20-dione, salts and esters thereof, and pharmaceutical preparations thereof. Is described. Rofleponide is an anti-inflammatory corticosteroid and has been proposed for use in the treatment of bronchial asthma and related disorders.
[0004]
WO 99/00134 describes combinations of formoterol and rofleponide, but does not disclose the usefulness of (R, R) -formoterol.
[0005]
Although formoterol fumarate and rofleponide can be effective therapeutic agents, there is a clinical need for asthma treatments that have a strong, selective action and an advantageous action profile.
[0006]
Thus, according to the present invention, (R, R) -formoterol or a pharmaceutically acceptable salt thereof, a solvate or a derivative having a physiological function, and rofleponide or a pharmaceutically acceptable salt thereof, a solvate or a physiological function thereof are provided. Derivative combinations are provided.
[0007]
It will be appreciated that the compounds of the above combinations may be administered simultaneously or sequentially as the same or separate pharmaceutical preparations. When administered sequentially, a delay in the administration of the second compound should not impair the therapeutically beneficial effect of the combination.
[0008]
According to a further aspect of the present invention, there is provided (R, R) -formoterol or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, rofleponide or a pharmaceutically acceptable salt, solvate or physiological function thereof. There is provided a medical formulation comprising certain derivatives and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients. According to a preferred embodiment of the present invention, a medicament comprising (R, R) -formoterol fumarate and rofleponide palmitate, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients. Formulations are provided. In a most preferred embodiment, the pharmaceutical formulation described above is suitable for administration by inhalation.
[0009]
It will be understood that the scope of the present invention includes all combinations that are particular preferred embodiments of the invention described herein.
[0010]
As will be appreciated by those skilled in the art, rofleponide has several asymmetric centers. The present invention includes each isomer of rofleponide, particularly the (22R) and (22S) isomers in substantially pure form or mixed in any proportion. Isomers of rofleponide have already been described in WO 92/13872.
[0011]
The term "physiologically functional derivative" means a chemical derivative of (R, R) -formoterol or rofleponide which has the same physiological function as the free compound, for example by being converted into the free compound in the body. . According to the invention, examples of derivatives having a physiological function include esters.
[0012]
Suitable salts of the present invention include those formed with both organic and inorganic acids. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid Naphthalenecarboxylic acids such as oxalic acid, fumaric acid, maleic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, isethionic acid, and 1-hydroxy-2-naphthalenecarboxylic acid Includes acid addition salts derived from acids.
[0013]
Pharmaceutically acceptable esters of (R, R) -formoterol or rofleponide may have a hydroxyl group converted to a C _1-6 alkyl, aryl, aryl C _1-6 alkyl, or amino acid ester.
[0014]
As noted above, both (R, R) -formoterol and rofleponide and their pharmaceutically acceptable salts, solvates and physiologically functional derivatives have been described for use in the treatment of respiratory diseases. Accordingly, (R, R) - formoterol and rofleponide and pharmaceutically acceptable salts, preparation of derivatives have solvates and physiological functions, selective beta ₂ - adrenergic receptor agonist and / or anti-inflammatory Koruchiko It has application in the prevention or treatment of clinical conditions requiring steroids. Such conditions include diseases associated with reversible airway obstruction such as asthma, chronic obstructive pulmonary disease (COPD) (chronic and asthmatic bronchitis, emphysema, etc.), respiratory tract infections or upper respiratory tract disease. It is.
[0015]
Accordingly, the present invention provides (R, R) -formoterol or a pharmaceutically acceptable salt, solvate or derivative having a physiological function thereof, and rofleponide or a pharmaceutically acceptable salt, a solvate or a physiological function thereof. For the prevention or treatment of a clinical condition requiring a β ₂ -adrenergic receptor agonist and / or an anti-inflammatory corticosteroid in a mammal such as a human, comprising administering a therapeutically effective amount of the derivative combination. To provide a way. The present invention further provides (R, R) -formoterol or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and rofleponide or a pharmaceutically acceptable salt, solvate or physiological function thereof. A selective β ₂ -adrenoreceptor agonist and / or in a mammal such as a human, comprising administering a therapeutically effective amount of a derivative, and a pharmaceutical formulation comprising a pharmaceutically acceptable carrier or excipient. Alternatively, a method for preventing or treating a clinical condition requiring an anti-inflammatory corticosteroid is provided. In a preferred embodiment, there is provided a method comprising administering a therapeutically effective amount of a pharmaceutical formulation comprising (R, R) -formoterol fumarate, rofleponide palmitate, and a pharmaceutically acceptable carrier or excipient. You. In particular, the present invention provides methods for preventing or treating a disease associated with reversible airway obstruction, such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
[0016]
In another embodiment, (R, R) is used for the treatment, particularly for the prevention or treatment of a clinical condition requiring a selective β ₂ -adrenoreceptor agonist and / or an anti-inflammatory corticosteroid. Combinations of R) -formoterol or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and rofleponide or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof are provided. In particular, (R, R)-, for use in therapy, especially for use in the prevention or treatment of clinical conditions requiring a selective β ₂ -adrenergic receptor agonist and / or anti-inflammatory corticosteroid. Formoterol or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof (preferably (R, R) -formoterol fumarate), and rofleponide or a pharmaceutically acceptable salt, solvate or physiological salt thereof Pharmaceutical formulations are provided that include a functional derivative (preferably rofleponide palmitate), and a pharmaceutically acceptable carrier or excipient. In a preferred aspect, the present invention relates to the prevention or treatment of a disease associated with reversible airway obstruction, such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
[0017]
The amount of (R, R) -formoterol and rofleponide or their pharmaceutically acceptable salts, solvates or physiologically functional derivatives required to achieve a therapeutic effect will, of course, depend on the particular compound, Will vary with the route of treatment, the subject being treated, and the disorder or disease being treated. As a sole therapeutic agent, (R, R) -formoterol fumarate is generally administered to adults by aerosol inhalation twice daily at a dose of 12 mcg (μg) to 24 mcg. As a sole therapeutic agent, rofleponide is described in WO 92/13872 when administered to adults by aerosol inhalation at doses of 10 mcg to 1000 mcg, preferably 20 mcg to 250 mcg.
[0018]
While it is possible for the active ingredient of the combination to be administered as is, it is preferable to present it as a pharmaceutical formulation. If each compound of the combination is to be administered separately, it will generally be provided, respectively, as a pharmaceutical formulation as previously described in the art.
[0019]
Pharmaceutical formulations are often prescribed to patients in the form of “patient packs” which contain all of the therapeutic agents in a single package. Note that patient packs are included in patient packs (usually lost in traditional prescriptions) versus traditional prescriptions where pharmacists divide large doses of medication into patient doses There is an advantage in that you can always see. It has been shown that the integration of the precautionary statement increases the patient's compliance with the physician's instructions, and therefore generally leads to more successful treatment. Administering the combination of the present invention in a single patient pack or a patient pack for each component compound, and including precautionary statements that direct patients to the appropriate use of the present invention, are other desirable features of the present invention It will be understood that
[0020]
Hereinafter, the term "active ingredient" refers to (R, R) -formoterol or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, preferably (R, R) -formoterol fumarate, and rofleponide Or a pharmaceutically acceptable salt, solvate or derivative having a physiological function (preferably rofleponide palmitate).
[0021]
Suitably, the pharmaceutical formulation of the present invention that is suitable for inhalation has a therapeutically effective dose, for example a dose of 10 mcg to 150 mcg, preferably 24 mcg of (R, R) -formoterol, and 10 mcg to 1.6 mg, preferably Contains the active ingredient in such an amount that a dose of 20 mcg to 250 mcg of rofleponide is supplied in a single actuation.
[0022]
Pharmaceutical formulations of the present invention may include other therapeutic agents, such as other corticosteroids (eg, fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide) or NSAIDs (eg, cromoglyce Anti-inflammatory agents such as sodium acetate, nedocromil sodium, PDE-4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists) or other β ₂ − It may further comprise an adrenergic receptor agonist (such as salbutamol, salmeterol, fenoterol, terbutaline, salts thereof) or an anticholinergic (such as ipratropium, tiotropium).
[0023]
The most suitable route will depend, for example, on the condition and disorder of the recipient, but the formulation includes oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular administration) ), Intranasal administration, inhalation administration (including various metered dose pressurized aerosols, fine powder or fine mist that can be generated by a nebulizer or inhaler), rectal administration and topical administration (administration to the skin, buccal , Sublingual administration and intraocular administration). The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the resulting product into the desired formulation.
[0024]
Formulations for inhalation include powder compositions, preferably containing lactose, and suitable propellants, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2,3,3 , 3-heptafluoropropane, 1,1,1,2-tetrafluoroethane, carbon dioxide or other suitable gas), for example, as an aqueous solution or suspension, or as an aerosol delivered from a pressurized container. Spray compositions that can be formulated are included. Suitable aerosol formulations include those described in EP 0372777 and WO 93/11743. For a suspension aerosol, the active ingredient should be micronised so that substantially all of the active ingredient can be inhaled into the lungs when the aerosol formulation is administered. Thus, the active ingredient will have a particle size of less than 100 microns, preferably less than 20 microns, more preferably in the range of 1-10 microns, for example in the range of 1-5 microns.
[0025]
Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with agents such as thickening agents, buffer salts or acids or alkalis to control pH, osmotic agents or antioxidants.
[0026]
Capsules or cartridges, for example made of gelatin, enclosing a powder mixture of the active ingredient and a suitable powder base such as lactose or starch, or for example made of laminated aluminum foil, for use in an inhaler or insufflator May be prepared. In this embodiment, the active ingredient is preferably finely divided so that substantially all of the active ingredient can be inhaled into the lung when the dry powder formulation is administered. Thus, the active ingredient will have a particle size of less than 100 microns, preferably less than 20 microns, more preferably in the range of 1-10 microns.
[0027]
Solutions for inhalation by nebulization may be formulated with an aqueous vehicle to which an agent such as an acid or alkali, a buffer salt, an osmotic agent or an antibacterial substance has been added. They may be sterilized by filtration or heating in an autoclave, or may be provided as a non-sterile product.
[0028]
Preferred unit dosage formulations are those containing an active ingredient, as described above, in a pharmaceutically effective dose, or an appropriate fraction of that dose. Thus, for formulations designed to deliver a metered dose pressurized aerosol, a single actuation of the aerosol will deliver half the therapeutically effective amount, thereby delivering a therapeutically effective dose Two operations may be required to do so.
[0029]
It is to be understood that the formulations of the present invention may include, in addition to the components specifically mentioned above, other agents conventional in the art, given the type of formulation of interest. Furthermore, the claimed formulations also include bioequivalents as defined by the U.S. Food and Drug Administration.
[0030]
The following examples are illustrated for a better understanding of the present invention.
[0031]
Example
A: metered dose inhaler
Example 1
[Table 1]

The finely divided active ingredient was weighed and placed in an aluminum can, and then 1,1,1,2-tetrafluoroethane was added from a vacuum flask, and a measuring valve was attached in a predetermined position.
[0032]
The same method can be used for the formulation of Example 2:
Example 2
[Table 2]

[0033]
B: Dry powder inhaler
Example 3
[Table 3]

The active ingredient was miniaturized and mixed with lactose on a large scale in the above proportions. The mixture is filled into hard gelatin capsules or cartridges or double foil blister packs specially made for administration by inhaler, such as a Rotahaler, Diskhaler or Discus inhaler (each of which is a trademark of Glaxo Group Limited). did.
[0034]
A similar method can be used for the formulation of Example 4:
Example 4
[Table 4]

Claims (10)

(R, R) -formoterol or a pharmaceutically acceptable salt thereof, a solvate or a derivative having a physiological function, and rofleponide or a pharmaceutically acceptable salt thereof, a solvate or a derivative having a physiological function, and a pharmaceutically acceptable salt thereof. A pharmaceutical formulation comprising an acceptable carrier or excipient, and optionally one or more other therapeutic ingredients. Pharmaceutical formulation comprising (R, R) -formoterol fumaric acid, rofleponide palmitate, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients. Other corticosteroids, other beta ₂ - containing adrenergic receptor agonists or anticholinergic agents, pharmaceutical formulation of claim 1 or 2. beta ₂ - adrenoceptor agonist salbutamol, salmeterol, fenoterol, terbutaline or their salts, pharmaceutical formulation of claim 3. The pharmaceutical preparation according to claim 3, wherein the anticholinergic agent is ipratropium or tiotropium. The pharmaceutical preparation according to any one of claims 1 to 5, which is suitable for administration by inhalation. The pharmaceutical preparation according to any one of claims 1 to 6, which is suitable for intranasal administration. (R, R) -formoterol or a pharmaceutically acceptable salt thereof, a solvate or a derivative having a physiological function, and rofleponide or a pharmaceutically acceptable salt thereof, a solvate or a derivative having a physiological function, and optionally, Pharmaceutical formulations comprising one or more other therapeutic ingredients and 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or a mixture thereof as propellant . A selective β ₂ -adrenoreceptor agonist and / or anti-inflammatory corticosteroid comprising administering a therapeutically effective amount of a pharmaceutical formulation according to any one of claims 1 to 8. For preventing or treating clinical symptoms in mammals such as humans. 10. The method of claim 9, wherein the clinical condition is a disease associated with reversible airway obstruction, such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory disease.