KR20090022908A - A pharmaceutical composition for inhalation comprising fibroblast growth factor-2 as an effective ingredient for treatment or prevention of asthma and chronic obstructive pulmonary disease - Google Patents

Abstract

A pharmaceutical composition for an inhalable medicine using fibroblast growth factor-2 as an active ingredient is provided to ensure an excellent treatment effect with a little amount of the inhalable medicine without a side effect. A pharmaceutical composition for a chronic obstructive pulmonary disease comprises fibroblast growth factor-2 as an active ingredient. The fibroblast growth factor-2 is administered to patients who suffer from asthmas or chronic obstructive lung diseases with the amount of 0.015-600ng per day. The liquid composition is transferred to a lung by a nebulizer. The suspension composition is transferred to the lung through a metered dose inhaler. The powder composition is transferred to the lung through a dried powder inhaler.

Description

A PHARMACEUTICAL COMPOSITION FOR INHALATION COMPRISING FIBROBLAST GROWTH FACTOR-2 AS AN EFFECTIVE INGREDIENT FOR TREATMENT OR PREVENTION OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE}

The present invention is effective for one day fibroblast growth factor-2 (or basic Fibroblast Growth Factor, bFGF) in patients in need of treatment or prevention of asthma and chronic obstructive pulmonary disease (COPD) It relates to a pharmaceutical composition for inhalation that can be administered or administered at a dose of 0.015 to 600 ng to treat or prevent asthma and chronic obstructive pulmonary disease.

In the past two decades, the incidence of asthma has doubled and affects 8-10% of the world's population today. Asthma, a chronic inflammatory disease of the airways, is characterized by Airway HyperResponsiveness (AHR) and airway remodeling to non-specific stimuli, the latter being related to the structure and structure of related components such as A change in function is involved. Asthma types include bronchial asthma and cardiac asthma, simply asthma means bronchial asthma.

Along with asthma, Chronic Obstructive Pulmonary Disease (COPD), which is one of the representative lung diseases, differs from asthma in that it is accompanied by irreversible airway obstruction, and currently ranks fourth in the world's mortality rate. It is an important disease that increases the incidence. COPD is a disease caused by pathological changes in bronchioles and pulmonary parenchyma by airway and lung parenchymal inflammation, characterized by obstructive bronchiolitis and emphysema (pulmonary parenchymal destruction). Types of COPD include chronic obstructive bronchitis, chronic bronchiolitis and emphysema.

Conventional methods of treating such asthma and COPD are to use a therapeutic agent having an anti-inflammatory action or a bronchodilator effect. Representative therapeutic agents having the anti-inflammatory action include glucocorticoids, leukotriene modifiers, theophylline, and the like.

However, the glucocorticoid (glucocorticoid) is powerful in terms of effectiveness, but the therapeutic effect does not act selectively, but because it suppresses all immune and anti-inflammatory responses, there is a problem of suppressing the necessary immune response in some cases, Drug side effects are great. The leukotriene modifiers (leukotriene modifiers) has a small side effect but limited in terms of effectiveness, and when used alone, there is a problem that most of them can not be used to control asthma. Theophylline (theophylline) is not excellent in terms of effectiveness and there is a problem that there is a concern of side effects are urgently required to develop a therapeutic agent with excellent effects and fewer side effects, and this requires an accurate understanding of the mechanism of disease occurrence.

In this regard, the present inventors have shown that airway hypersensitivity is suppressed by inhibiting airway hyperresponsiveness by interleukin-13 and its vascular endothelial growth factor, which are thought to be important mediators of the development of asthma and COPD. By lowering the level of phosphate, and confirming that it inhibits airway hypersensitivity by interferon-gamma, inflammation of the airways and lung parenchyma, and that FGF-2 can be usefully used for the treatment or prevention of asthma and COPD. It has been filed in the application 2005-39405 and international patent application PCT / KR05 / 001390.

Fibroblast growth factor 2 was obtained by single and repeated dose toxicity test results (Ann NY Acad Sci 638: 329-340, 1991; IYAKUHIN KENKYU 27 (7): 351-355, 1996; IYAKUHIN KENKYU 27 (7): 379-). 408, 1996; IYAKUHIN KENKYU 27 (7): 309-318, 1996; IYAKUHIN KENKYU 27 (7): 297-308, 1996; Cancer Letters 105: 195-202, 1996). Results (Makoto Okumura et al, Drug Res 46 (II) (7): 727-739, 1996) indicate that the somatic nervous system, autonomic nervous system, muscle and blood system It has been reported to affect the circulatory system, central nervous system and renal function. In other words, blood pressure, heart rate, respiratory rate and femoral blood flow rate were decreased in anesthetized dogs when administered intravenously at 0.01 ~ 0.1mg / kg dose, Na + and Cl- at 1mg / kg dose. Significantly reduces urinary excretion, so side effects can be predicted in humans.

Asthma and COPD are chronic chronic diseases that require long-term treatment without cure from children to old age. Therefore, the treatment or prevention of asthma and COPD should be easy and inexpensive, with low toxicity and side effects.

The present inventors have shown that fibroblast growth factor 2 is effective at high doses of 0.01 to 1 mg / kg for intravenous or subcutaneous administration, which is a common route of administration of biologics in animal models, while at low doses of 0.003 to 10 ng / kg for inhalation. The present invention has been completed by confirming that the same or better efficacy as in intravenous administration or subcutaneous administration can be minimized and toxicity or side effects can be minimized.

In the present invention, fibroblast growth factor 2 is administered to a patient in need of the treatment or prevention of asthma and chronic obstructive pulmonary disease, even when administered at a lower dose than the effective dose in intravenous or subcutaneous administration. At the same time to provide a pharmaceutical composition for inhalation that can minimize toxicity or side effects.

The present invention is effective for one day fibroblast growth factor-2 (or basic Fibroblast Growth Factor, bFGF) in patients in need of treatment or prevention of asthma and chronic obstructive pulmonary disease (COPD) It provides a pharmaceutical composition for inhalation that can be administered or dosed at 0.015 to 600ng to treat or prevent asthma and chronic obstructive pulmonary disease.

Hereinafter, the present invention will be described in detail.

Fibroblast growth factor 2 in the present invention may be FGF-2 or bFGF produced by natural or genetic recombination.

Fibroblast growth factor 2 is a known strain (W. Knoerzer et al., Gene. 75: 21-30, 1989, Thompson et al., Methods Enzymol. 198: 96-116, 1991, Iwane et al., Biochem Biophys.Res.Comm. 146: 470-477, 1987, Abrahm, J. et al., Science 233: 545-548, 1986), and the purification process (Judith A. Abraham et al., The EMBO Journal 5: 2523-2528, 1986, Burgess et al., Annu. Rev. Biochem. 58: 575-606, 1988, Shing et al., Biol. Chem. 263: 9059-9062, 1988, Gunnar Garke et al , Journal of Chromatography B 737: 25-38, 2000, A. Seeger et al., Journal of Chromatography A 746: 17-24, 1996).

It is known that fibroblast growth factor 2 has a therapeutic effect on asthma and COPD in the range of 0.01-1 mg / kg for intravenous administration and 0.01-1 mg / kg for subcutaneous administration.

Surprisingly, when inhaled according to the present invention, the effective dose shows a therapeutic effect at a dose of 0.003 to 10 ng / kg, which is 1000 times different from the effective dose of the usual route of administration. This inhalation effective dose was attempted by the inventors for the first time as a result that is 1000 times better than predictable results in terms of pharmacokinetics.

In general, inhalants are administered in the range of 10 to 1/10 of the effective dosage of other routes of administration (oral, intravenous, subcutaneous, etc.). However, the present invention shows a therapeutic effect at an inhalation dose of about 1/1000, which is much lower than the effective dose seen in the change of general dosage form.

As a specific example, the insulin inhaler Exubera ^® is known to have a similar or slightly better effect at the same dose of inhalation and subcutaneous administration (Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with ype 2 diabetes.Priscilla A. Hollander.Diabetes care 2004.27 (10); 2356-2362), according to Pfizer's study (Table 1), Exuvera's inhalation dose 3 mg and subcutaneous At a dose of 0.364 mg (8 IU), the effect is similar (approximately 10-fold difference), and AstraZeneca's budesonide is 3 mg or 6 mg per day for Entocort, an oral dosage form. In the case of Pulmicort, which is an inhalation drug, the daily dose is 1 or 2 mg, and budesonide also has a difference of about 1 / 1.5 to 1/6 times the dose between oral administration and inhalation for the same inflammatory disease. Produce another (http://www.astrazenecaclinicaltrials.com/article/514051.aspx).

Therefore, the present invention is generally characterized in that the same drug is effective at a dose that is significantly lower than the dose when the same drug is used simultaneously as a preparation using inhalation and other routes.

Inhaled pharmaceutical compositions of the present invention may be in the form of solutions, suspensions or dry powders suitable for administration by inhalation, and are delivered to the lungs, preferably the lower airways or alveoli, using one of a variety of suitable inhalation devices known in the art. Can be.

There are several desirable properties for inhalation devices for the administration of the pharmaceutical compositions for inhalation of the present invention. For example, delivery by an inhalation device is advantageously reliable, reproductive and accurate. These devices include inhalers, nebulizers, dry powder inhalers (DPIs), and the like. Some specific examples of commercially available inhalation devices, or those in later stages of development, suitable for the practice of the present invention are Turbohaler ^TM (Astra), Rotahaler ^® (Glaxo), Discus ^® (Glaxo), Spiros ^TM Inhaler (Dura), devices developed by Nectar, AER _X ^TM (Aradaim), UltraBent ^® Nebulizer (Marinecrot), ACOON II ^® Nebulizer (Market Medical Products), Spinhaler ^® Powder In Haller (Pisons).

Specifically, the inhaled pharmaceutical composition of the present invention may be delivered through a dry powder inhaler. When fibroblast growth factor 2 is administered via a dry powder inhaler, fibroblast growth factor 2 is prepared in particulate form and preferably has a mass mean aerodynamic diameter (MMAD) of less than about 10 μm, more preferably an MMAD of less than about 5 μm. And most preferably with a particle size of MMAD of 1-5 μm. Dry powder is usually composed of particles produced such that most of the particles have a size in the desired range. Conveniently, at least 50% of the dry powder is made of particles having an MMAD diameter of less than about 10 μm. Such particle size in the dry powder can be obtained by spray drying, milling or supercritical fluid methods and the like. Other methods also suitable for producing dry powder particles useful in the present invention are known in the art.

In addition, when fibroblast growth factor 2 is administered through a dry powder inhaler, the fibroblast growth factor 2 particles have a moisture content that can readily disperse in the inhalation device to form an aerosol. The moisture content is generally less than about 10% by weight of water, preferably less than about 5% by weight.

Fibroblast growth factor 2 inhaled pharmaceutical compositions for administration from a dry powder inhaler include finely distributed dry powders containing fibroblast growth factor 2, but the composition also includes swelling agents, carriers, excipients, and other additives. And the like. The additive may be used to facilitate dispersion of the powder from the inhalation device, for example, to dilute the powder required for delivery from a particular powder inhaler, to facilitate the formulation process, to provide beneficial powder properties to the formulation. To stabilize the formulation (eg, antioxidants or buffers), and to use it to flavor the formulation, and the like, in a dry powder composition of fibroblast growth factor 2. Advantageously, the additive does not adversely affect the patient's airways. These additives may simply act as diluents to reduce the concentration of fibroblast growth factor 2 in the powder to be delivered to the patient, but increase the stability of the fibroblast growth factor 2 composition and improve the dispersibility of the powder in the powder dispersing device to Delivers blast growth factor 2 more efficiently and reproducibly, and may improve the handling properties of fibroblast growth factor 2 such as fluidity and consistency to facilitate manufacturing and powder filling. Fibroblast growth factor 2 may be mixed with additives at the molecular level or the solid preparation may comprise protein particles mixed with or coated on the particles of the additive. Typical additives are sugar alcohols such as mono-, di-, and polysaccharides such as lactose, glucose, raffinose, elegitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch or combinations thereof. And other surfactants such as polyol sorbitol, sorbitol such as diphosphatidyl choline or lecithin, and the like. In general, additives such as swelling agents are present in amounts effective for the purposes described above, often from about 5 to 95 weight percent of the formulation. Additional agents known in the art for protein formulation can also be included in the formulations.

In addition, specifically, the inhalation pharmaceutical composition containing fibroblast growth factor 2 as an active ingredient may be administered by a nebulizer, such as a jet nebulizer or an ultrasonic nebulizer. Fibroblast growth factor 2 delivered by the nebulizer has a particle size of less than about 10 μm MMAD, preferably less than about 5 μm MMAD, and most preferably about 1 to about 5 μm MMAD.

Pharmaceutical compositions for inhalation of fibroblast growth factor 2 for use with jet or ultrasonic nebulizers generally comprise an aqueous protein solution at a concentration of about 0.001 to about 100 ng per ml of solution. This formulation may include agents such as excipients, buffers, isotonic agents, preservatives, surfactants, stabilizers and divalent metal cations. The buffer adjusts the final pH of the formulation and may be selected from the group consisting of sodium acetate, citrate, maleate, phosphate. Fibroblast growth factor 2 formulations may also include surfactants, which may reduce or prevent surface induced aggregation of peptides caused by atomization of the solution in forming aerosols. The amount will generally be from 0.001 to 4% by weight of the formulation. Particularly preferred surfactants for the purposes of the present invention consist of polysorbate 20, polysorbate 80, polyoxyethylene sorbitan monollivate, diphosphatidyl choline or lecithin It can be selected from the group. Stabilizers are derived from proteins consisting of carbohydrates consisting of mannitol, sorbitol, sucrose, lactose, trehalose, glucose, and albumin, protamine, etc. Can be selected. In addition, additional agents known in the art for formulating proteins may also be included in the formulations.

More specifically, in order to provide pharmaceutically stable fibroblast growth factor 2 for successful inhalation administration through nebulizer, the concentration of fibroblast growth factor 2 is 0.001-100 ng / ml, the buffer concentration is 5-100 mM, and the stabilizer concentration. 5 to 100 mg / ml, the concentration of the surfactant is included as 0.001 to 1% by weight, a liquid formulation of pH 5.0 to 6.0 may be provided.

In particular, inhaled pharmaceutical compositions of the present invention may be administered via a metered dose inhaler (MDI). In this embodiment, the propellant, excipient or other additives may be contained in the Canister as a mixture comprising liquefied compressed gas. The operation of the metering valve is a mixture as an aerosol, preferably containing inhaled particles of MMAD size of less than about 10 μm, preferably less than about 5 μm, and most preferably of MMAD size of about 1 to about 5 μm. Release. Preferred aerosol particle sizes can be obtained by using the preparation of fibroblast growth factor 2 produced by various methods known to those skilled in the art, including jet milling, stray drying, and the like.

Fibroblast growth factor 2 inhalation formulations for use with a metered dose inhaler device are generally finely divided powders containing the protein as a suspension in a non-aqueous medium suspended in a propellant, for example, with the aid of a surfactant. It includes. Propellants include chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, or trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluorofluoroethanol and 1,1,1,2-tetrafluoroethane Conventional materials used for this purpose, such as hydrocarbons, including hydrofluoroalkyl-134a (HFA-134a), hydrofluoroalkane-227 (HFA-227), and the like. Preferably the propellant is hydrofluorocarbon. Surfactants can be selected to stabilize the fibroblast growth factor 2 as a suspension in propellant, to protect the active agent against chemical degradation and the like. Suitable surfactants include trioleate, soya lecithin, oleic acid and the like. In some cases, the solution aerosol is preferably to use a solvent such as ethanol. Other surfactants can also be used, such as diphosphatidyl choline or lecithin. Additional agents known in the art for protein formulation can also be included in the formulations.

The amount of fibroblast growth factor 2 delivered once and the number of administrations of the daily dose by the pharmaceutical composition for inhalation of the present invention depend on the type of inhalation device used. For example, shorter doses may be used at higher concentrations of fibroblast growth factor 2 in the nebulizer solution. Devices such as metered dose inhalers (MDIs) can produce higher aerosol concentrations and can be operated for shorter periods of time to deliver the desired amount of fibroblast growth factor 2. Devices such as dry powder inhalers deliver the active agent until a given amount of agent is released from the device. In this type of inhaler, the amount of fibroblast growth factor 2 in a given amount of powder determines the dose delivered in a single dose.

The pharmaceutical composition for inhalation containing low dose fibroblast growth factor 2 according to the present invention as an active ingredient can be inhaled in a range of very safe dosages, so that serious side effects and high costs that may result from intravenous or subcutaneous administration It can be usefully used as a prophylactic or therapeutic agent for asthma and COPD by solving problems in drug development, such as biological drug prices.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Examples and Experimental Examples.

Example 1 Preparation of Pharmaceutical Composition for Inhalation

Inhalation pharmaceutical compositions were prepared in the configuration shown in Table 1 for inhalation administration using a nebulizer.

Example 2 Preparation of Dry Powder Inhalation Composition

For inhalation administration using a dry powder inhaler, a dry powder inhalation composition having a MMAD having a moisture content of less than 5% by weight and a particle size of less than 5 μm was prepared as follows.

FGF-2 was dissolved in 10 mM sodium citrate buffer containing 1 mM ethylenediaminetetraacetic acid (EDTA) and 5% mannitol to prepare an aqueous mixture at a final solid concentration of 5.0 mg / ml and pH 5.0 ± 0.2. This aqueous mixture was filtered through a 0.22 μm filter and spray dried in a Buchi Spray Dryer with inlet temperature 100-120 ° C., liquid feed rate 5 ml / min, outlet temperature 70-80 ° C. The water content of the spray-dried FGF-2 was measured by the Coulombic Karl Fischer method and showed a water content of less than 3%. The particle size was measured using an Andersen Cascade Impactor. The measurement resulted in MMAD of less than approximately 5 μm.

Experimental Example 1 Measurement of FGF-2 Concentration in Alveolar Lavage Solution According to Inhalation Concentration of FGF-2

Balb / c mice (female, 6 weeks old, 18-20 g, 8 mice) were inhaled with FGF-2 as follows. FGF-2 was prepared in 100ml PBS buffer solution by volume and placed in nebulizer (OMRON, NE-U17) and saturated for 5 minutes under nebulization rate of 1.93ml / L and nebulization air flow of 15 L / min. Afterwards, mice were placed in a hemispherical chamber of 3,435 cm ³ , and FGF-2 was inhaled for 3 minutes by dose. Mice were sacrificed 5 minutes after removal from the chamber and immediately necropsied to extract alveolar lavage fluid. The extracted alveolar lavage fluid was centrifuged at 1000 rpm for 10 minutes and the supernatant was measured for FGF-2 concentration using FGF-2 ELISA kits (R & D system, cat.SFB50).

Inhalation dose of FGF-2 was calculated as follows.

D = mean dose level (ug / kg)

C = mean aerosol concentration of the active ingredient (ug / L)

The average spray concentration was based on the FGF-2 concentration of 10 µg / mL, spray rate of 1.93 mL / min, and spray stream of 15 L / min.

t = duration of daily exposure (min)

m = average mouse weight (approximately 20 g)

MV = average minute volume (mL / min) = m ^0.75 x 2.1 (Guyton * formula)

(* Guyton AC: Measurement of the respiratory volumes of laboratory animals.Am. J. Physiol. 150 , 70-77, 1947)

After administration by the above inhalation administration method, the concentration of FGF-2 in the alveolar lavage fluid was increased in a dose-dependent manner as shown in Table 1 when measured.

Experimental Example 2 Measurement of Anti-asthma Effect Using Inhalation Composition

Allergens were sensitized by intraperitoneal administration of 75 ug OVA and 2 mg alum on days 0 and 7 in Balb / c mice (female, 6 weeks old, 18-20 g, 8). Again, on day 14, 15, 21, 22, 50ul OVA 30ul was administered nasal to induce asthma.

The inhalation composition prepared in Example 2 was administered once a day in the same manner as in Experimental Example 1. The mice were removed from the chamber 5 minutes later and sacrificed immediately for necropsy to extract alveolar lavage fluid. As a control drug, 3 mg / kg dexamethasone was administered intravenously.

As a result, FGF-2 lowers the number of BALF cells (especially eosinophils) at the 0.003--10 ng / kg inhalation dose as shown in FIGS. 1 and 2A to 2D, and etaxin, an asthma-associated cytokine of BALF ( eotaxin), Interleukin-13, Tumor Necrosis Factor-α (TNF-α), and Vascular Endothelial Growth Factor (VEGF) were lowered.

Experimental Example 3 Measurement of Anti-COPD Effect Using Inhalation Composition

Balb / c mice (female, 6 weeks old, 18-20 g, 8 mice) were sensitized to allergens by nasal administration of 75 ug OVA and 10 ug LPS 30 ul on 0 and 7 days. Again, COPD was induced by nasal administration of 50 ug OV 30ul at 14, 15, 21, and 22 days, and the inhalation composition prepared in Example 2 was administered once a day in the same manner as in Experimental Example 1. Mice were sacrificed 5 minutes after removal from the chamber and immediately necropsied to extract alveolar lavage fluid. As a control drug, 3 mg / kg dexamethasone was administered intravenously.

As a result, FGF-2 lowers the number of BALF cells (particularly the number of eosinophils) at the 0.003--10 ng / kg inhalation dose as shown in FIGS. 3 and 4A-4C, and TNF-α, a COPD-related cytokine of BALF. , Inducible Protein-10 (IP-10) and VEGF levels were lowered.

< Experimental Example  4> Egg albumin  Depending on the route of administration in the induced asthma model FGF -2 Anti Asthma Effect Comparison

Asthma was induced in Balb / c mice in the same manner as in Experimental Example 2, followed by intravenous administration of FGF-2 at 0.01, 0.1, and 1 mg / kg doses, at 0.01, 0.2, and 1 mg / kg doses. Subcutaneous administration, nasal administration at doses of 1, 10, 100 ng / kg, inhalation at doses of 0.01, 0.1, 1 ng / kg, and nasal administration of 1, 3 mg / kg dexamethasone (dexamethasone) as a control drug.

As shown in FIGS. 5 and 6A to 6D, the effective dose of FGF-2 was significantly different according to the administration route, and the effect was in the order of subcutaneous administration <venous administration <nasal administration <inhalation administration. In particular, inhalation administration showed a 1000-fold difference in effective dose compared to intravenous administration. In all administration routes, FGF-2 lowered the number of BALF cells (especially eosinophils) and lowered the levels of BALF's asthma-related cytokines eotaxin, IL-13, TNF-α and VEGF.

< Experimental Example  5> COPD  In animal models FGF -2 according to the route of administration COPD Compare Effect

After inducing COPD in Balb / c mice in the same manner as in Experiment 3, FGF-2 was administered intravenously at 0.01, 0.2, 1 mg / kg doses during asthma induction, at 0.01, 0.2, 1 mg / kg doses. Subcutaneous administration, nasal administration at doses of 1, 10 and 100 ng / kg, inhalation at doses of 0.01, 0.1 and 1 ng / kg, and 3 mg / kg dexamethasone (dexamethasone) as a control drug were administered intravenously.

As shown in FIG. 7 and FIGS. 8A to 8C, the effective dose of FGF-2 was significantly different according to the administration route, and the effect was in the order of subcutaneous administration <venous administration <nasal administration <inhalation administration. In particular, inhalation administration showed a 1000-fold difference in effective dose compared to intravenous administration. In all routes of administration, the number of BALF cells (particularly the number of neutrophils) was lowered dose-dependently, and the levels of BALF's COPD-related cytokines, TNF-α, IP-10, and VEGF.

< Experimental Example  6> Conversion of clinical effective doses to humans from animal model effective doses

As a result of the pharmacological effect of 0.003 ~ 10 ng / kg dose in FGF-2 mouse asthma and COPD disease model, human equivalence using body surface area for setting the starting dose Pharmacological initial clinical dose was calculated as following formula.

From the above calculation, the initial clinical effective dose of FGF-2 for humans using body surface area is converted to about 0.014634 ~ 48.78049 ng, and the clinical effective dose using body weight is 0.18 ~ 600 ng for 60kg adult weight. The range of effective clinical doses of FGF-2, including both effective dose ranges, is approximately 0.015-600 ng.

In particular, fibroblast growth factor 2 was measured by blood pressure in dogs anesthetized when administered intravenously at 0.01 to 0.1 mg / kg dose (Makoto Okumura et al, Drug Res 46 (II) (7): 727-739, 1996). , Heart rate, increased respiratory rate and decreased femoral blood flow, and significantly reduced Na + and Cl- urinary excretion at 1 mg / kg. However, the present invention has a very safe dosage range when fibroblast growth factor 2 is administered at 0.015 to 600 ng per day effective dose to patients in need of treatment or prevention of asthma.

Figure 1 shows the dose-dependent inhibitory effect of FGF-2 inhalation administration to inflammatory cells in alveolar lavage fluid of an eosinophilic asthma mouse model.

2A to 2D are dose-dependent inhibitory effects of FGF-2 inhalation administration on asthma related cytokines in alveolar lavage fluid of an eosinophilic asthma mouse model.

Figure 2a shows the inhibitory effect on Eotaxin,

2b shows the inhibitory effect on IL-13,

Figure 2c shows the inhibitory effect on TNF-α,

2d shows the inhibitory effect on VEGF,

Figure 3 shows the dose-dependent inhibitory effect on FGF-2 inhalation administration to inflammatory cells in alveolar lavage fluid of the COPD mouse model,

4A to 4C show dose-dependent inhibitory effects of FGF-2 inhalation on cytokines in alveolar lavage fluid of a COPD mouse model.

4A shows the inhibitory effect on TNF-α,

4b shows the inhibitory effect on VEGF,

4c shows the inhibitory effect on IP-10,

5 shows the inhibitory effect of FGF-2 on inflammatory cells in alveolar lavage fluid of an eosinophilic asthma mouse model.

6a to 6d are related to the inhibitory effect of FGF-2 on the asthma related cytokines in alveolar lavage fluid of the eosinophilic asthma mouse model.

Figure 6a shows the inhibitory effect on Eotaxin,

Figure 6b shows the inhibitory effect on IL-13,

Figure 6c shows the inhibitory effect on VEGF,

Figure 6d shows the inhibitory effect on TNF-α,

Figure 7 shows the inhibitory effect of each administration route of FGF-2 on inflammatory cells in alveolar lavage fluid of the COPD mouse model,

8A to 8C show the inhibitory effects of FGF-2 on the cytokines in the alveolar lavage fluid of the COPD mouse model.

8a shows the inhibitory effect on TNF-α,

8b shows the inhibitory effect on IP-10,

8c shows the inhibitory effect on VEGF.

Claims (10)

An inhaled pharmaceutical composition capable of treating and preventing asthma or chronic obstructive pulmonary disease by administering fibroblast growth factor 2 to a patient in need of treatment and prevention of asthma or chronic obstructive pulmonary disease (COPD). The pharmaceutical composition for inhalation according to claim 1, wherein fibroblast growth factor 2 is administered in an effective daily dose of 0.015 to 600 ng to treat and prevent asthma. The pharmaceutical composition for inhalation according to claim 1, wherein fibroblast growth factor 2 is administered at an effective daily dose of 0.015 to 600ng to treat and prevent chronic obstructive pulmonary disease. 2. A pharmaceutical composition for inhalation according to claim 1, wherein the composition is in solution. The pharmaceutical composition for inhalation according to claim 4, wherein the composition is delivered to the lungs through a nebulizer. 2. A pharmaceutical composition for inhalation according to claim 1, wherein the composition is in suspension. 7. A pharmaceutical composition for inhalation according to claim 6, wherein the composition is delivered to the lungs via a metered dose inhaler. The inhalation pharmaceutical composition according to claim 1, wherein the composition is in a dry powder state. 9. A pharmaceutical composition for inhalation according to claim 8, wherein the composition is delivered to the lungs through a dry powder inhaler. The inhalation pharmaceutical composition of claim 1, wherein the composition has a particle size of a mass average aerodynamic diameter of less than 5 μm.

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