Preparation of a pharmaceutical composition comprising olodaterol and budesonide

Abstract

The present invention relates to a liquid pharmaceutical preparation and a method for administering a drug by atomizing the pharmaceutical preparation with an inhaler. The pharmaceutical preparation without a propellant comprises: (a) an active substance selected from budesonide and olodaterol; (b) a solvent; (c) a pharmacologically acceptable solubilizer; (d) a pharmaceutically acceptable preservative, and (e) a pharmaceutically acceptable stabilizer.

Description

[0001] Priority declaration

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 043,094, filed on June 23, 2020, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present application relates to the field of pharmaceutical preparations, and in particular to the preparation of a pharmaceutical composition comprising olodaterol and budesonide. Background Art

[0004] Budesonide, also known as 11b,21-dihydroxy-16a,17a-(butylidenebis(oxy))progesterone-1,4-diene-3,20-dione, is a synthetic pregnane steroid and non-halogenated cyclic ketal corticosteroid with the following chemical structure:

[0005]

[0006] Olodaterol, chemically known as 6-hydroxy-8-[(1R)-1-hydroxy-2-{[1-(4-methoxyphenyl)-2-methylpropan-2-yl]amino}ethyl]-3,4-dihydro-2H-l,4-benzoxazin-3-one, has the following chemical structure:

[0007]

[0008] Budesonide is a glucocorticoid with a highly effective local anti-inflammatory effect, which can enhance the stability of endothelial cells, smooth muscle cells and lysosomal membranes, immunosuppressive reactions and the synthesis of reduced antibodies, thereby releasing active mediators such as histamine. It can also reduce and actively reduce, and can reduce the enzymatic process stimulated by antigen-antibody over time, inhibit the synthesis and release of bronchial contractile substances and reduce the contractile reaction of smooth muscles.

[0009] Olodaterol is a novel long-acting β2-adrenergic agonist (LABA) that exerts its pharmacological effects by binding to and activating β2-adrenergic receptors located primarily in the lungs. β2-adrenergic receptors are membrane-bound receptors that are normally activated by endogenous adrenaline, and their signaling mediates smooth muscle relaxation and bronchial dilation through downstream L-type calcium channel interactions. Activation of the receptor stimulates associated G proteins, which then activate adenylate cyclase, catalyzing the formation of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). Elevations in both of these molecules induce bronchodilation by relaxing airway smooth muscle. It is through this mechanism that olodaterol is used to treat chronic obstructive pulmonary disease (COPD) and the progressive airflow obstruction that characterizes it. Treatment with bronchodilators can reduce associated symptoms, such as shortness of breath, cough, and sputum production.

[0010] Both compounds have valuable pharmacological properties.Budesonide and olodaterol may provide therapeutic benefit in the treatment of asthma or chronic obstructive pulmonary disease, including chronic bronchitis.

[0011] The present invention relates to a propellant-free inhalable formulation of budesonide and olodaterol dissolved in water or a pharmaceutically acceptable salt or solvate thereof in combination with an inactive ingredient, which can be administered using a soft mist or nebulizer inhalation device, and a propellant-free inhalable aerosol produced thereby. The pharmaceutical formulation of the present invention is particularly suitable for administration by nebulizer inhalation, and has better lung deposition (usually up to 55-60%, even up to 85-95%) compared to methods involving administration by dry powder inhalation.

[0012] The pharmaceutical preparation of the present invention is particularly suitable for administering active substances by aerosol inhalation, and is particularly suitable for treating asthma and chronic obstructive pulmonary disease. Summary of the invention

[0013] The present invention relates to a pharmaceutical preparation of budesonide and olodaterol and a pharmaceutically acceptable salt or solvate thereof which can be administered by aerosol inhalation. The pharmaceutical preparation of the present invention meets high quality standards.

[0014] One aspect of the present invention is to provide an aqueous pharmaceutical formulation containing budesonide and olodaterol that meets the high standards required for optimal atomization of the solution using the inhaler mentioned above. The formulation has a shelf life of several years. In one embodiment, the shelf life is at least one year. In one embodiment, the shelf life is at least three years.

[0015] Another aspect is to provide a propellant-free formulation comprising budesonide and olodaterol which is aerosolized under pressure using an inhaler, preferably a nebulizer inhaler device, the composition delivered by the generated aerosol falling reproducibly within the specified range.

[0016] Another aspect of the present invention is to provide a pharmaceutical formulation comprising budesonide and olodaterol and other inactive excipients, which can be administered by aerosol inhalation using an ultrasound-based or air pressure-based nebulizer / inhaler. In one embodiment, the formulation has a shelf life of at least 1 month. In one embodiment, the formulation has a shelf life of at least 6 months. In one embodiment, the formulation has a shelf life of at least one year. In one embodiment, the formulation has a shelf life of at least three years.

[0017] More specifically, another aspect is to provide a stable pharmaceutical formulation containing an aqueous solution of budesonide and olodaterol and other excipients, which can be administered by a nebulizer device. The formulation has substantially long-term stability. In one embodiment, the formulation has a storage time of at least about 6 months at a temperature of about 15°C to about 25°C. In one embodiment, the formulation has a storage time of at least about 1 year at a temperature of about 15°C to about 25°C. Degrees Celsius. In one embodiment, the formulation has a storage time of at least about 2 years at a temperature of about 15°C to about 25°C.

[0018] More specifically, another aspect of the present invention is to provide a stable pharmaceutical formulation containing budesonide and olodaterol and other excipients, which can be administered by aerosol inhalation using an ultrasonic jet or mesh nebulizer. The formulation of the present invention has long-term stability. In one embodiment, the formulation has a storage time of at least about 6 months at a temperature of about 15°C to about 25°C. In one embodiment, the formulation has a storage time of at least about 1 year at a temperature of about 15°C to about 25°C. Degrees Celsius. In one embodiment, the formulation has a storage time of at least about 2 years at a temperature of about 15°C to about 25°C.

[0019] Detailed description of the invention

[0020] It is advantageous to administer liquid formulations of active substances without propellant gas using a suitable inhaler to achieve better distribution of the active substance in the lungs. More importantly, the lung deposition of drugs delivered by inhalation can be maximized.

[0021] Conventional pMDIs (pressurized metered dose inhalers) or DPIs (dry powder inhalers) can only deliver approximately 20-30% of the drug to the lungs, resulting in a large amount of drug being deposited in the mouth and throat, which can then enter the stomach and cause unwanted side effects and / or secondary absorption through the oral digestive system.

[0022] Therefore, it is necessary to improve the delivery of inhaled drugs by increasing lung deposition. The soft mist or inhalation device disclosed in US20190030268 can significantly increase the lung deposition of inhalable drugs.

[0023] Such inhalers can nebulize small amounts of liquid formulations into aerosols suitable for therapeutic inhalation within a few seconds. Such inhalers are particularly suitable for the liquid formulations of the present invention.

[0024] In one embodiment, the atomizing device containing the aqueous pharmaceutical preparation of the present invention is a device in which less than about 70 microliters of the pharmaceutical preparation can be atomized in one spray, so that the inhalable portion of the aerosol corresponds to a therapeutically effective amount. In one embodiment, the atomizing device containing the aqueous pharmaceutical preparation of the present invention is a device in which less than about 30 microliters of the pharmaceutical preparation can be atomized in one spray, so that the inhalable portion of the aerosol corresponds to a therapeutically effective amount. In one embodiment, the atomizing device containing the aqueous pharmaceutical preparation of the present invention is a device in which less than about 15 microliters of the pharmaceutical preparation can be atomized in one spray, so that the inhalable portion of the aerosol corresponds to a therapeutically effective amount. In one embodiment, the average particle size of the aerosol formed by one spray is less than about 15 microns. In one embodiment, the average particle size of the aerosol formed by one spray is less than about 10 microns.

[0025] In one embodiment, the atomizing device containing the pharmaceutical preparation of the present invention is a device in which less than about 8 mL of the pharmaceutical preparation can be atomized in one puff, so that the inhalable portion of the aerosol corresponds to a therapeutically effective amount. In one embodiment, the atomizing device containing the pharmaceutical preparation of the present invention is a device in which less than about 2 mL of the pharmaceutical preparation can be atomized in one puff, so that the inhalable portion of the aerosol corresponds to a therapeutically effective amount. In one embodiment, the atomizing device containing the pharmaceutical preparation of the present invention is a device in which less than about 1 mL of the pharmaceutical preparation can be atomized in one puff, so that the inhalable portion of the aerosol corresponds to a therapeutically effective amount. In one embodiment, the average particle size of the aerosol formed by one puff is less than about 15 microns. In one embodiment, the average particle size of the aerosol formed by one puff is less than about 10 microns.

[0026] Such devices for metered administration of propellant-free liquid pharmaceutical inhalable formulations have been described in detail, for example in US20190030268.

[0027] The drug formulation, which can be a solution, is converted into an aerosol for delivery to the lungs in a nebulizer, which uses high pressure to spray the drug formulation.

[0028] The drug solution is stored in a reservoir in such an inhaler. The preparation, which can be a solution, must not contain any ingredients that could interact with the inhaler to affect the drug quality of the preparation or the aerosol produced. In addition, the active substance in the drug preparation is very stable when stored and can be administered directly.

[0029] In one embodiment, the formulation of the invention for use with the above inhaler comprises an additive, such as the disodium salt of edetic acid (sodium edetate), to reduce the incidence of nebulization abnormalities and stabilize the formulation. In one embodiment, the formulation has a minimum concentration of sodium edetate.

[0030] One aspect of the present invention is to provide a pharmaceutical formulation comprising budesonide and olodaterol that meets the high standards required for optimal aerosolization of the formulation using a nebulizer inhaler device. In one embodiment, the formulation has a shelf life of several months or years. In one embodiment, the formulation has a shelf life of at least about 1 month. In one embodiment, the formulation has a shelf life of at least about 6 months. In one embodiment, the formulation has a shelf life of at least about one year. In one embodiment, the formulation has a shelf life of at least three years.

[0031] Another aspect of the present invention is to provide a propellant-free formulation, which may be a solution, comprising budesonide and olodaterol, which is aerosolized under pressure using an inhaler. In one embodiment, the inhaler is a nebulizer inhaler. In one embodiment, the aerosol generated by the inhaler can reproducibly fall within a specified particle size range.

[0032] Another aspect of the present invention is to provide an aqueous pharmaceutical formulation, which may be a solution, comprising budesonide and olodaterol and other inactive excipients that can be administered by inhalation.

[0033] Any pharmaceutically acceptable salt or solvate of budesonide and olodaterol may be used in the formulation.As used herein, the terms "budesonide" and "olodaterol" refer to budesonide or its salt or solvate and olodaterol or its salt or solvate, respectively.

[0034] In one embodiment, the active substances are budesonide and olodaterol.

[0035] In the preparations according to the invention, the active substance is preferably selected from a combination of budesonide and olodaterol.

[0036] In one embodiment of the formulation according to the invention, budesonide and olodaterol are dissolved in a solvent. In one embodiment, the solvent comprises water. In one embodiment, the solvent is water.

[0037] In one embodiment, the therapeutically effective dose of budesonide ranges from about 1 μg to about 100 μg. In one embodiment, the therapeutically effective dose of budesonide ranges from about 5 μg to about 50 μg. In one embodiment, the therapeutically effective dose of budesonide ranges from about 10 μg to about 30 μg. In one embodiment, the therapeutically effective dose of olodaterol ranges from about 5 μg to about 500 μg. In one embodiment, the therapeutically effective dose of olodaterol ranges from about 10 μg to about 200 μg. In one embodiment, the therapeutically effective dose of olodaterol ranges from about 10 μg to about 80 μg.

[0038] In one embodiment, the concentration range of budesonide in the preparation for nebulization is about 1mcg / ml to about 100mcg / ml. In one embodiment, the concentration range of budesonide in the preparation for nebulization is about 5mcg / ml to about 100mcg / ml. In one embodiment, the concentration range of budesonide in the preparation for nebulization is about 10mcg / ml to about 50mcg / ml. In one embodiment, the concentration range of olodaterol in the preparation for nebulization is about 2mcg / ml to about 500mcg / ml. In one embodiment, the concentration range of olodaterol in the preparation for nebulization is about 10mcg / ml to about 200mcg / ml. In one embodiment, the concentration range of olodaterol in the preparation for nebulization is about 30mcg / ml to about 100mcg / ml.

[0039] In one embodiment, the formulation includes a pH adjuster to maintain the pH of the formulation. Suitable pH adjusters include acids and bases. In one embodiment, the pH adjuster is selected from hydrochloric acid, citric acid and salts thereof.

[0040] Other suitable pH adjusting agents may also be used. In one embodiment, the pH adjusting agent is sodium hydroxide.

[0041] The pH affects the stability of the active substance and / or other excipients in the formulation. In one embodiment, the pH range of the formulation is from about 2.0 to about 6.0, and in one embodiment, the pH range of the formulation is from about 3.0 to about 5.0. In one embodiment, the pH range of the formulation is from about 3.0 to about 4.0.

[0042] In one embodiment, the formulation includes a stabilizer or complexing agent. In one embodiment, the stabilizer or complexing agent is selected from edetic acid (EDTA) or one of its known salts, edetic acid disodium or edetic acid disodium dihydrate. In one embodiment, the formulation comprises edetic acid and / or its salt.

[0043] Other suitable stabilizers or complexing agents can be used in the formulation.Other suitable stabilizers or complexing agents include, but are not limited to, citric acid, disodium edetate, and disodium edetate dihydrate.

[0044] As used herein, the phrase "complexing agent" refers to a molecule that is capable of entering into a complex bond. Preferably, these compounds should have the effect of complexing cations. In one embodiment, the concentration range of the stabilizer or complexing agent is from about 0.04 mg / 4 ml to about 20 mg / 4 ml. In one embodiment, the concentration range of the stabilizer or complexing agent is from about 0.2 mg / 4 ml to about 8 mg / 4 ml. In one embodiment, the stabilizer or complexing agent is disodium edetate dihydrate at a concentration of about 0.4 mg / 4 ml.

[0045] In one embodiment, all ingredients of the formulation are present in solution.

[0046] As used herein, the term "additive" refers to any pharmacologically acceptable and therapeutically useful substance that is not an active substance but can be formulated with an active substance in a pharmacologically suitable solvent to improve the quality of the drug. Preferably, these substances do not have a pharmacological effect or do not have a significant or at least undesirable pharmacological effect in the context of the desired treatment.

[0047] Suitable additives include, but are not limited to, other stabilizers, complexing agents, antioxidants, surfactants and / or preservatives to extend the shelf life of the final pharmaceutical formulation, vitamins and / or other additives known in the art.

[0048] Suitable preservatives may be added to protect the formulation from contamination by pathogens. Suitable preservatives include, but are not limited to, benzalkonium chloride, benzoic acid, and sodium benzoate. In one embodiment, the formulation comprises benzalkonium chloride as the sole preservative. In one embodiment, the amount of preservative is in the range of about 0.08 mg / 4 ml to about 12 mg / 4 ml. In one embodiment, the preservative is benzalkonium chloride in an amount of about 0.4 mg / 4 ml.

[0049] In one embodiment, the formulation includes a solubilizing agent. In one embodiment, the solubilizing agent is selected from Tween 80 and a cyclodextrin derivative. In one embodiment, the solubilizing agent is a cyclodextrin derivative or one of its known salts. The addition of a solubilizing agent to the formulation helps the solubility of the active ingredient or other excipients. In one embodiment, the formulation comprises sulfobutyl ether beta-cyclodextrin or a salt thereof.

[0050] In one embodiment, the preparation for inhalation by aerosolization includes a surfactant or other solubilizing agent. In one embodiment, the solubilizing agent is selected from Tween 80 and a cyclodextrin derivative. In one embodiment, the solubilizing agent is one of a cyclodextrin derivative or a known salt thereof. In one embodiment, the solubilizing agent is sulfobutyl ether β-cyclodextrin. In one embodiment, the solubilizing agent is sulfobutyl ether β-cyclodextrin, and the content range is about 0.04g / 4ml to about 1.6g / 4ml. In one embodiment, the solubilizing agent is sulfobutyl ether β-cyclodextrin, and the content is about 0.8g / 4ml.

[0051] Another aspect of the present invention is to provide a stable drug aerosol formulation containing budesonide and olodaterol and other excipients, which can be administered by aerosolization using an inhaler. In one embodiment, the formulation has substantially long-term stability. In one embodiment, the formulation has a storage time of at least about 6 months at a temperature of about 15°C to about 25°C. In one embodiment, the formulation has a storage time of at least about 1 year at a temperature of about 15°C to about 25°C. In one embodiment, the formulation has a storage time of at least about 2 years at a temperature of about 15°C to about 25°C.

[0052] Another aspect of the present invention is to provide a pharmaceutical formulation comprising a solution of budesonide and olodaterol and other inactive excipients, which can be administered by atomization inhalation using an ultrasound-based or air pressure-based nebulizer / inhaler. In one embodiment, the preparation has a storage time of several months or several years. In one embodiment, the preparation has a storage time of about 1 month at a temperature of about 15°C to about 25°C. In one embodiment, the preparation has a storage time of about 6 months at a temperature of about 15°C to about 25°C. In one embodiment, the preparation has a storage time of about one year at a temperature of about 15°C to about 25°C. In one embodiment, the preparation has a storage time of about 2 years at a temperature of about 15°C to about 25°C. In one embodiment, the preparation has a storage time of about three years at a temperature of about 15°C to about 25°C. Another aspect of the present invention is to provide a stable pharmaceutical formulation containing budesonide and olodaterol and other excipients, which can be administered by atomization inhalation using an ultrasound-based or air pressure-based nebulizer / inhaler. In one embodiment, the preparation has substantially long-term stability. In one embodiment, the formulation has a shelf life of at least about 6 months at a temperature of about 15° C. to about 25° C. In one embodiment, the formulation has a shelf life of at least about 1 year at a temperature of about 15° C. to about 25° C.

[0053] In one embodiment, the formulation includes sodium chloride. In one embodiment, the concentration of sodium chloride ranges from about 0.1 g / 100 ml to about 0.9 g / 100 ml.

[0054] In one embodiment, the concentration of budesonide in the formulation ranges from about 1mcg / ml to about 100mcg / ml. In one embodiment, the concentration of budesonide in the formulation ranges from about 5mcg / ml to about 100mcg / ml. In one embodiment, the concentration of budesonide in the formulation ranges from about 10mcg / ml to about 50mcg / ml. In one embodiment, the concentration of olodaterol in the formulation ranges from about 2mcg / ml to about 500mcg / ml. In one embodiment, the concentration of olodaterol in the formulation ranges from about 10mcg / ml to about 200mcg / ml. In one embodiment,

[0055] In one embodiment, the formulation includes a surfactant or other solubilizing agent. In one embodiment, the surfactant or other solubilizing agent is selected from Tween 80 and a cyclodextrin derivative. In one embodiment, the surfactant or other solubilizing agent is a cyclodextrin derivative or one of its known salts. In one embodiment, the solubilizing agent is sulfobutyl ether beta-cyclodextrin.

[0056] In one embodiment, the formulation includes a surfactant or other solubilizing agent. In one embodiment, the surfactant or solubilizing agent is selected from Tween 80 and a cyclodextrin derivative. In one embodiment, the surfactant or solubilizing agent is a cyclodextrin derivative or one of its known salts. In one embodiment, the solubilizing agent is sulfobutyl ether beta-cyclodextrin. In one embodiment, the content of sulfobutyl ether beta-cyclodextrin ranges from about 5 mg / ml to about 0.4 g / ml. In one embodiment, the content of sulfobutyl ether b-cyclodextrin is about 0.2 g / ml.

[0057] Surprisingly, it has been found that sulfobutyl ether b-cyclodextrin has not only a solubility-enhancing effect but also an effect of improving the stability of the active ingredient.

[0058] Another aspect of the present invention is to provide a stable pharmaceutical formulation containing budesonide and olodaterol and other excipients that can be administered by a nebulizer. In one embodiment, the formulation of the present invention has substantially long-term stability. In one embodiment, the formulation has a storage time of at least about 6 months at a temperature of about 15°C to about 25°C. In one embodiment, the formulation has a storage time of at least about 1 year at a temperature of about 15°C to about 25°C.

[0059] In one embodiment, the pH of the formulation ranges from about 3 to about 6. In one embodiment, the pH of the formulation ranges from about 3 to about 5. In one embodiment, the pH of the formulation ranges from about 3 to about 4.

[0060] The preparation according to the present invention can be filled into a tank to form a highly stable preparation for an atomizing device. In one embodiment, the preparation is substantially free of particle growth, morphological changes or precipitation. There is also no or substantially no problem of suspended particles being deposited on the surface of the tank or valve, so the preparation can be discharged from a suitable atomizing device with high dose uniformity. Suitable atomizers include, but are not limited to, ultrasonic atomizers; jet atomizers; and mesh atomizers, such as ParieFlow atomizing inhalers, or other commercially available ultrasonic atomizers, jet atomizers or mesh atomizers.

[0061] The drug formulation in the nebulizer is converted into an aerosol for use in the lungs. The nebulizer uses high pressure to spray the drug formulation.

[0062] A nebulizer is an instrument that produces very fine liquid particles in a gas. As is well known, the maximum size of particles used to treat the lower airways, i.e., the bronchial tree or the lungs, is usually less than about 10 microns to prevent undesirable deposition on the oral and pharyngeal surfaces. In one embodiment, the particle size of the aerosol is less than about 10 microns in maximum size to achieve the desired pharmacological effect. In one embodiment, the particle size of the aerosol is less than about 5 μm in maximum size to achieve the desired pharmacological effect. In addition, particles with a maximum size much smaller than about 0.5 μm are generally not easy to deposit in the desired position, and a large part of them are just exhaled by the patient. For these reasons, it is advantageous to produce particles with a maximum size average particle size between about 1 μm and about 5 μm, while minimizing particles with a size less than about 0.5 μm and greater than about 10 μm. The average particle size range of the aerosol is from about 0.5 μm to about 5 μm.

[0063] Nebulization, while less frequently used than other drug delivery techniques, has certain advantages for special patient populations, such as young children and the infirm. Although some bulky equipment is required and there may be more stringent cleaning requirements than with other popular delivery techniques, no special patient skills or coordination are required: the patient simply breathes normally to introduce the drug into the airway. Thus, even unconscious patients or infants can be treated. Another advantage of the nebulizer is that a large amount of moisture is delivered to the airway, which may help to fluidify secretions and improve patient comfort.

[0064] In one embodiment, the atomizing device for administering the pharmaceutical preparation of the present invention is a device in which less than about 8 mL of the pharmaceutical preparation can be atomized in one puff, so that the inhalable portion of the aerosol corresponds to a therapeutically effective amount. In one embodiment, the atomizing device for administering the pharmaceutical preparation of the present invention is a device in which less than about 2 mL of the pharmaceutical preparation can be atomized in one puff, so that the inhalable portion of the aerosol corresponds to a therapeutically effective amount. In one embodiment, the atomizing device for administering the pharmaceutical preparation of the present invention is a device in which an amount of less than about 1 mL of the pharmaceutical preparation sprayed out at one time can be atomized, so that the inhalable portion of the aerosol corresponds to a therapeutically effective amount. In one embodiment, the average particle size of the aerosol formed by one spray is less than about 15 microns. In one embodiment, the average particle size of the aerosol formed by one spray is less than about 10 microns.

[0065] Such devices for propellant-free administration of metered liquid drug formulations for inhalation are described in detail, for example, in US20190030268 entitled "Inhalation nebulizer including a shut-off function and a counter."

[0066] The drug formulation in the nebulizer is converted into an aerosol for the lungs. The nebulizer uses high pressure to spray the drug formulation.

[0067] The drug preparation is stored in the reservoir of this inhaler. The preparation must not contain any ingredients that could interact with the inhaler and affect the drug quality of the solution or the generated aerosol. In addition, the active substance in the drug preparation is very stable during storage and can be administered directly.

[0068] The ultrasonic nebulizer is large in size and can atomize water-soluble drugs into tiny mist particles of about 1-5 microns at room temperature. The jet nebulizer includes a compressed air source and a nebulizer. The compressed air passes through a narrow opening at high speed and suddenly decompresses, generating negative pressure locally, and sucking the drug-containing solution out of the container by siphoning. When subjected to high-speed airflow, the drug-containing solution is broken into small aerosol particles by collision. The mesh nebulizer includes a stainless steel mesh covered with micropores with a diameter of about 3pm. The number of micropores on the mesh exceeds about 1000, and the mesh is conical with the bottom of the cone facing the liquid surface. Figure 1 a Depicts an ultrasonic nebulizer. Figure 1 b depicts the jet nebulizer. Figure 1 c Depicts the pressure vibration element and micropores of the mesh nebulizer.

[0069] Olodaterol is a selective, fast-acting p2-adrenergic receptor agonist, chemically known as 6-hydroxy-8-[(1R)-1-hydroxy-2-{[1-(4-methoxyphenyl)-2-methylpropane-2-yl]amino}ethyl]-3,4-dihydro-2H-1,4-benzoxazin-3-one. Olodaterol is highly selective for the β2-adrenergic receptor (referred to as β2-receptor), has a rapid onset of action, and a long half-life (more than 12 hours). The bronchodilator activity of Olodaterol can be maintained for 24 hours.

[0070] Budesonide is a glucocorticoid with a highly effective local anti-inflammatory effect, which can enhance the stability of endothelial cells, smooth muscle cells and lysosomal membranes, immunosuppressive reactions and the synthesis of reduced antibodies, thereby releasing active mediators such as histamine. It can also reduce and actively reduce, and can reduce the enzymatic process stimulated by antigen-antibody over time, inhibit the synthesis and release of bronchial contractile substances and reduce the contractile reaction of smooth muscles. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 Various atomizers or components of atomizers are depicted. Figure 1 a depicts an ultrasonic nebulizer, Figure 1 b depicts the jet atomizer, Figure 1 c Depicts the pressure vibration element and micropores of the mesh nebulizer. DETAILED DESCRIPTION

[0072] Materials and Reagents:

[0073] 50% Benzalkonium chloride aqueous solution was purchased from Merck.

[0074] Edetate disodium dihydrate was purchased from Merck.

[0075] Sodium hydroxide was purchased from Titan Reagent.

[0076] Hydrochloric acid was purchased from Titan Reagent.

[0077] Citric acid (CA) was purchased from Merck.

[0078] Sodium chloride was purchased from Merck.

[0079] Sulfonbutyl ether β-cyclodextrin was purchased from Zhiyuan Biotechnology Co., Ltd., China.

[0080] Budesonide, olodaterol, and SBECD were purchased from Zhiyuan Biotechnology Co., Ltd., China.

[0081] Example 1

[0082] The formulation and preparation method of the solution for administration by nebulization inhalation (Samples 1-4) are as follows:

[0083] 1. Weigh the specified amount of SBECD in a beaker and add the specified amount of water to make the weight reach 104.70 g.

[0084] 2. After stirring to dissolve SBECD, adjust the pH to about 4.00 with CA.

[0085] 3. After adjusting the pH, add the specified amount of BD according to Table 1 and stir overnight in a dark place to dissolve it.

[0086] 4. After BD is dissolved, add the specified amount of OH according to Table 1 and filter after dissolution.

[0087] 5. Divide the above sample into four parts, and adjust the pH value of each sample to 5.5, 5.0, 4.5 and 4.0 respectively with CA solution. The samples are designated as sample 1, sample 2, sample 3 and sample 4 respectively.

[0088] Table 1 Composition of samples 1-4

[0089]

[0090]

[0091] Example 2

[0092] The thermal stability of samples 1-4 of Example 1 at 60°C is provided as follows:

[0093] Impurity detection method:

[0094] Mobile phase A: Accurately weigh 3.17 g of sodium dihydrogen phosphate, add 1 L of pure water to dissolve it, and adjust the pH of the solution to 3.20 with phosphoric acid.

[0095] Mobile phase B: acetonitrile.

[0096] Instrument number: HPLC.

[0097] Column ID: YMC-Triart C18250*4.6 5pm.

[0098] Detection wavelength: 230nm.

[0099] Flow rate: 10 mL / min.

[0100] Running time: 35 minutes.

[0101] time Liquidity A% Liquidity B% 0 70 30 7 70 30 8 60 40 32 60 40 33 70 30 35 70 30

[0102] The test results are shown below.

[0103] Table 2 Thermal stability of samples 1-4 at 60°C (conditions: 60°C ± 2°C / RH 75%)

[0104]

[0105]

[0106] CA citric acid solution was used to adjust pH. We found that OH was relatively stable at pH 5.5 and pH 4.0, and BD was relatively stable at pH 4.0 and 4.5. Therefore, the formulation was relatively stable when adjusted to a pH of about 4.0 with citric acid.

[0107] Example 3

[0108] The formulation and preparation of the aerosol inhalation dosing solution (sample 5-8) are as follows:

[0109] 1: Weigh a specified amount of SBECD into an empty beaker, add 93g of pure water to dissolve it, adjust the pH to the target value with hydrochloric acid after dissolution.

[0110] 2: Weigh the specified amount of BD and add it to the above solution. Stir in dark place until dissolved.

[0111] 3: After dissolution, add OH to the above solution until dissolved.

[0112] 4: Adjust the pH value of each sample to 5.0, 4.5, 4.0, and 3.5 with hydrochloric acid. Designate the samples as sample 5, sample 6, sample 7, and sample 8, respectively.

[0113] 5: Add purified water to a final volume of 104.7 g.

[0114] 6: Each sample was divided into several portions and stored at 40°C and 60°C for 5 days and 10 days respectively. Impurities were tested at each time point.

[0115] Table 3 Composition of samples 5-8

[0116]

[0117] Table 4 Thermal stability of samples 5-8 of Example 3 at 40°C (conditions: 40°C ± 2°C / RH 75%)

[0118]

[0119] Table 5 Thermal stability of samples 5-8 of Example 3 at 60°C (conditions: 60°C±2°C / RH 75%)

[0120]

[0121]

[0122] Hydrochloric acid solution was used to adjust the pH, and the total impurities after storage are shown in the table above. At each different pH value, each active ingredient showed different degrees of degradation. When hydrochloric acid was used to adjust the pH, pH 5.0 showed the best stability at 60℃±2℃ / RH 75%.

[0123] Example 4

[0124] Solubility studies were performed to investigate the solubilization effect of SBECD and Tween 80 on BD and to study the solubility of BD at different concentrations.

[0125] Study the solubility of BD at different concentrations of SBECD: weigh 0.1g, 0.3g, 0.5g and 1.0g of BD in a 10ml EP tube, add 10ml of pure water, shake until completely dissolved, add excess BD (about 500mg / 100mL), and wrap the EP tube in tin foil to avoid light. After avoiding light, shake the EP tube on a shaker for 24 hours.

[0126] To investigate the solubility of BD at different concentrations of Tween 80: weigh 0.002g, 0.001g, 0.0005g, 0.1g, 0.3g, 0.5g and 1.0g of BD into a weighing bottle, transfer BD to a 10ml EP tube, rinse the weighing bottle with enough water to make 10ml in the EP tube, add excess BD (about 500mg / 100mL), and wrap the EP tube in tin foil to avoid light. After avoiding light, place the EP tube on an oscillator for 24 hours and centrifuge to take the supernatant.

[0127] Table 6: Solubility of BD in solutions with different SBECD and Tween 80 concentrations

[0128]

[0129] According to the above results, it can be seen that SBECD and Tween 80 have similar solubilization effects on BD. Tween-80 is within the acceptable range. According to the USP requirements, the concentration of Tween-80 in the inhalation suspension should not exceed 20 mg / 100 ml. The solubility of BD in a concentration of 20 mg / 100 ml Tween-80 is only 2.92 μg / ml. It cannot meet the requirements. A BD solubility of about 500 μg / ml is required.

[0130] Example 5

[0131] Aerodynamic particle size distribution:

[0132] The aerodynamic particle size distribution of Sample 2 of Example 1 was measured using a Next Generation Pharmaceutical Impactor (NGI).

[0133] Aerodynamic particle size distribution was determined using a Next Generation Drug Impactor (NGI). A soft mist inhaler was placed close to the NGI inlet until no aerosol was visible. The flow rate of the NGI was set to 15 L / min and operated at ambient temperature and 90% relative humidity (RH).

[0134] The solution of sample 2 was discharged into the NGI. Depending on the particle size of the fraction, the dosed fractions were deposited at different stages of the NGI. Each fraction was washed off the stage and analyzed using HPLC.

[0135] The results are shown in Table 7.

[0136] Table 7 Aerodynamic particle size distribution of sample 2

[0137]

[0138]

[0139] MOC is microporous collector.

[0140] ISM is the impactor dimensional mass.

[0141] FPF is the fine particle fraction.

[0142] FPD is fine particle dose.

[0143] MMAD is the mass median aerodynamic diameter.

[0144] GSD is the geometric standard deviation.

[0145] Class F is a filter which is a DDU tube connected to the end of the NGI.

[0146] Comparative Example 1

[0147] Aerodynamic particle size distribution of budesonide suspension (Comparative sample 1 (Pulmicort): batch number: LOT324439; dose: 0.5 mg; specification: 2 ml / inhalation / time).

[0148] Budesonide suspension samples were purchased from AstraZeneca Pty Ltd.

[0149] The aerodynamic particle size distribution was determined using a Next Generation Pharmaceutical Impactor (NGI). The sample was Pulmicort. The device used to form the aerosol was an LC-Plus purchased from PARI, Germany. The device was close to the NGI inlet until no aerosol was visible. The flow rate of the NGI was set to 30 L / min and operated at ambient temperature and 90% relative humidity (RH).

[0150] The solution of comparative sample 1 was discharged into the NGI. Depending on the particle size of the fraction, the fractions of the dose were deposited at different stages of the NGI. Each fraction was washed from the bench and analyzed using HPLC.

[0151] The results are shown in Table 8.

[0152] Table 8 Comparative Sample 1 Budesonide Suspension Aerodynamic Particle Size Distribution

[0153]

[0154]

[0155] The NGI parameters of the comparative sample 1 (Pulmicort) and the sample 2 of Example 1 of the present invention show that the effective lung deposition of the sample 2 of Example 1 is much higher than that of the comparative sample 1 (Pulmicort), indicating that the bioavailability of the sample 2 of Example 1 sprayed with the E-flow device is higher.

[0156] Because the ISM of sample 2 of Example 1 is much higher than that of comparative sample 1 (Pulmicort), in order to be consistent with the dose of Pulmicort, it is considered that the effective doses of OH and BD can be reduced. Therefore, for the preparation of the present invention, the dose of OH is about 5.56 μg and the dose of BD is about 161.25 μg. Giving a lower dose can reduce the side effects of the drug on the human body.

[0157] Comparative Example 2

[0158] Aerodynamic particle size distribution of budesonide inhalation aerosol

[0159] Comparative Sample 2: Budesonide suspension for inhalation was purchased from AstraZeneca Pty Ltd.

[0160] The budesonide suspension sample purchased from AstraZeneca Pty Ltd. (Comparative Example 2) was administered at 160 ug / tablet press, containing 120 tablet presses / bottle, and administered via 2 tablet presses / time, twice / day.

[0161] The aerodynamic particle size distribution was determined using the Next Generation Pharmaceutical Impactor (NGI). The sample was Comparative Sample 2. The device used to atomize the sample was an electronic stream, purchased from PARI, Germany. The device was close to the NGI inlet until no aerosol was visible. The flow rate of the NGI was set to 30 L / min, and the NGI was operated at ambient temperature and 90% relative humidity (RH).

[0162] The solution of Comparative Sample 2 was discharged into the NGI. Depending on the particle size of the fraction, the fractions of the dose were deposited at different stages of the NGI. Each fraction was washed from the stage and analyzed using HPLC.

[0163] The results are shown in Table 9.

[0164] Table 9 Aerodynamic particle size distribution of comparative sample 2

[0165]

[0166]

[0167] The effective lung deposition of Sample 2 of Example 1 is much higher than that of Comparative Sample 2.

[0168] Example 6

[0169] 1: Weigh the specified amount of SBECD and NaCl into an empty beaker, add 93g of pure water to dissolve, and adjust to the target pH with hydrochloric acid or CA according to Table 10.

[0170] 2: Weigh a specified amount of BD into the above solution and dissolve it.

[0171] 3: After dissolution, add OH to the above solution to dissolve.

[0172] 4: According to Table 10, the pH value of each sample was adjusted to the target pH value with hydrochloric acid or CA, and they were named Sample 9 and Sample 10 respectively.

[0173] 5: Add purified product to a final weight of 104.70 g.

[0174] Table 10 Composition of samples 9-10

[0175]

[0176]

Claims

1. A propellant-free aqueous solution pharmaceutical preparation, comprising the following (a)-(e) raw materials: (a) 53.33 mg of budesonide; (b) 1.842 mg of olodaterol; (c) 10.00 g of sodium sulfobutyl ether β-cyclodextrin; (d) citric acid in an amount sufficient to adjust the pH to 4.0; and (e) water without other solvents, so that the total weight of the pharmaceutical formulation reaches 104.70 g.

2. A propellant-free aqueous solution pharmaceutical preparation, comprising the following (a)-(e) raw materials: (a) 53.33 mg of budesonide; (b) 1.842 mg of olodaterol; (c) 10.00 g of sodium sulfobutyl ether β-cyclodextrin; (d) hydrochloric acid in an amount sufficient to adjust the pH to 5.0; and (e) water without other solvents to make the total weight of the pharmaceutical formulation reach 104.70 g.

3. Use of a pharmaceutical preparation as claimed in claim 1 or 2 in the preparation of a medicament for treating asthma or COPD, comprising atomizing the pharmaceutical preparation to form an inhalable aerosol by forcing a defined amount of the pharmaceutical preparation through a nozzle by applying pressure.

4. The use according to claim 3, wherein the defined amount of the pharmaceutical preparation is less than 8 microliters.

5. The use according to claim 4, wherein the pharmaceutical preparation is administered with a therapeutically effective dose ranging from 1 μg to 100 μg of budesonide and a therapeutically effective dose ranging from 5 μg to 500 μg of olodaterol.

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