Powder for inhalation

Abstract

Provided is a powder for inhalation having an exceptional pulmonary delivery rate while maintaining the pharmacological activity of a medicinal component. This powder for inhalation is characterized by containing carrier particles (a), and fine particles (b) that are present on the surface of the carrier particles and contain a medicinal component and an excipient, the excipient being trehalose.

Description

Inhalable powder

[0001] The present invention relates to powders for inhalation.

[0002] Pulmonary administration of pharmaceuticals is considered promising because it can avoid the hepatic first-pass effect, reducing the dosage and the associated side effects. Pulmonary administration formulations include dry powder inhalers (DPIs) and liquid inhalants. Of these, dry powder inhalers are superior to liquid inhalants in that they have higher storage stability and do not require devices such as a nebulizer for inhalation.

[0003] Known powders for inhalation include carrier particles with a diameter of about 50 to 125 μm, on the surface of which adhere fine particles with a diameter of about 1 to 5 μm, which are a mixture of a medicinal ingredient and an auxiliary substance (excipient). It is known that lactose can be used as this excipient (Patent Document 1).

[0004] Japanese Patent Application Laid-Open No. 2001-072586

[0005] Since lactose, which has been used as an excipient until now, is a reducing sugar, it may react with the active ingredients in formulations containing peptides or proteins, potentially resulting in a loss of stability as a formulation. The objective of the present invention is to provide a powder for inhalation that has an excellent pulmonary delivery rate while maintaining the pharmacological activity of the active ingredients.

[0006] The inventors discovered that the above-mentioned problems can be solved by using trehalose, a non-reducing sugar with excellent crystallinity, as an excipient in an inhalable powder containing carrier particles and fine particles present on the surface of the carrier particles, which contain an active ingredient and an excipient, and thus completed the present invention.

[0007] The present disclosure includes the following aspects: (Item 1) A powder for inhalation, comprising: carrier particles (a); and fine particles (b) present on the surface of the carrier particles and comprising a medicinal ingredient and an excipient, wherein the excipient is trehalose.

[0008] (Item 2) The powder for inhalation according to Item 1, wherein the fine particles (b) have an average particle size of 0.8 μm or more and 5.0 μm or less.

[0009] (Item 3) The powder for inhalation according to Item 1 or 2, wherein the carrier particles (a) contain lactose and / or trehalose.

[0010] (Item 4) The powder for inhalation according to Item 1 or 2, wherein the carrier particles (a) have an average particle size of 30 μm or more and 300 μm or less.

[0011] (Item 5) The powder for inhalation according to Item 1 or 2, wherein the medicinal ingredient is selected from the group consisting of low molecular weight compounds, peptides, and proteins.

[0012] (Item 6) The powder for inhalation according to Item 5, wherein the low molecular weight compound is selected from the group consisting of leukotriene receptor antagonists and xanthine derivatives.

[0013] (Item 7) The powder for inhalation according to Item 6, wherein the leukotriene receptor antagonist is pranlukast or the xanthine derivative is theophylline.

[0014] (Item 8) The powder for inhalation according to Item 5, wherein the peptide or protein is glucagon or an antibody.

[0015] (Item 9) The powder for inhalation according to Item 1 or 2, wherein the total deposition rate of stages #4 to #7 is 10% or more in an inhalation characteristic evaluation using an Andersen cascade impactor.

[0016] (Item 10) The powder for inhalation according to Item 1 or 2, wherein the fine particles (b) are prepared by drying a mixture of a medicinal ingredient and an excipient.

[0017] (Item 11) The powder for inhalation according to Item 1 or 2, wherein the weight ratio of the medicinal ingredient to the excipient is 1:1999 to 19:1.

[0018] (Item 12) The powder for inhalation according to Item 1 or 2, wherein the weight ratio of the carrier particles (a) to the fine particles (b) is 1:1 to 99:1.

[0019] The powder for inhalation of the present invention has low reactivity between the excipient and the medicinal ingredient, and is excellent in pulmonary delivery rate.

[0020] 1 shows a scanning electron microscope image of fine trehalose. 1 shows a scanning electron microscope image of an inhalable powder. 1 shows an evaluation of the inhalable powders of Example 1 and Comparative Example 1 using an Andersen cascade impactor. 1 shows an evaluation of the inhalable powders of Examples 1 and 2 using an Andersen cascade impactor. 1 shows the particle size distribution of fine particles (b) containing a medicinal ingredient and excipients of Examples 1 and 2 and Comparative Example 1. 1 shows an evaluation of the inhalable powders of Example 1 using an Andersen cascade impactor after a storage stability test. 1 shows lung tissue after administration of the formulations of Example 1 and Comparative Example 2. 1 shows the number of infiltrating cells in bronchoalveolar lavage fluid after administration of the formulations of Example 1 and Comparative Example 2. 1 shows the amount of transferred medicinal ingredient into the blood after administration of the formulations of Example 1 and Comparative Example 2. 1 shows an evaluation of the inhalable powders of Example 3 and Comparative Example 3 using an Andersen cascade impactor. 1 shows the inhalation characteristics of the powders for inhalation of Example 4 and Comparative Example 4 evaluated using an Andersen cascade impactor.

[0021] The powder for inhalation of the present invention comprises carrier particles (a) and fine particles (b) present on the surface of the carrier particles and containing a medicinal ingredient and an excipient, wherein the excipient is trehalose.

[0022] <Carrier particles (a)> Carrier particles (a) have the function of improving the inhalation efficiency of the inhalable powder. Furthermore, by adhering fine particles (b) containing medicinal ingredients and excipients to their surfaces, carrier particles (a) have the function of preventing aggregation of the medicinal ingredients and stably dispersing them. In order to increase the absorption efficiency of the medicinal ingredients in the lungs and bronchi, it is preferable that when the inhalable powder is inhaled, the carrier particles (a) and the fine particles (b) containing the medicinal ingredients and excipients are efficiently separated. After separation from the fine particles (b) containing the medicinal ingredients and excipients, the carrier particles (a) are preferably deposited in the upper respiratory tract and excreted from the body.

[0023] The average particle size of the carrier particles (a) is preferably 30 μm or more and 300 μm or less, more preferably 30 μm or more and 100 μm or less, and even more preferably 40 μm or more and 80 μm or less. When the average particle size is 30 μm or more, the deposition of the carrier particles (a) in the upper respiratory tract and their excretion from the body tend to be promoted. When the average particle size is 300 μm or less, the inhalation powder tends to be easily inhaled. In this specification, the average particle size is the particle size (Dv50) corresponding to the cumulative value of 50% in the particle size distribution based on the volume of the particles. The average particle size can be measured using a light scattering particle size analyzer (e.g., Mastersizer 3000, manufactured by Malvern Panalytical).

[0024] The material constituting the carrier particles (a) is not particularly limited as long as it is a substance conventionally used as a carrier for inhalable powders. For example, sugars, sugar alcohols, and common excipients can be used. Examples of sugars include lactose, trehalose, glucose, fructose, sucrose, maltose, cellobiose, and maltotriose. Examples of sugar alcohols include erythritol, sorbitol, mannitol, maltitol, xylitol, arabitol, dulcitol, palatinose, lactitol, inositol, and xylose. Examples of common excipients include calcium sulfate, calcium carbonate, calcium phosphate, talc, titanium oxide, crystalline cellulose, starches, and dextran. Among these, sugars are preferred, and lactose and trehalose are more preferred. The above-mentioned materials may be used alone or in combination of two or more. For example, a mixture of lactose and trehalose can be used as the carrier particles (a).

[0025] In the powder for inhalation, the content of carrier particles (a) is preferably 50 to 99% by weight, more preferably 80 to 95% by weight, and even more preferably 85 to 90% by weight. Within this range, the fine particles (b) tend to adhere uniformly to the surface of the carrier particles (a) while maintaining their pharmacological activity.

[0026] <Medicinal Ingredients> The medicinal ingredients contained in the fine particles (b) are not particularly limited as long as they are APIs (Active Pharmaceutical Ingredients) that can be used in powders for inhalation, and examples thereof include low molecular weight compounds, peptides, proteins, nucleic acids, sugars, lipids (lipid nanoparticles), etc. Examples of low molecular weight compounds include leukotriene receptor antagonists such as pranlukast and montelukast; xanthine derivatives such as caffeine, theophylline, and theobromine; β2 agonists such as salmeterol, formoterol, and indacaterol; anticholinergics such as tiotropium, aclidinium, and umeclidinium; and steroids such as fluticasone, budesonide, and mometasone.

[0027] The peptide or protein is not particularly limited as long as it is a compound in which multiple amino acids are bound by peptide bonds, and examples include antibodies, hormones, cytokines, chemokines, enzymes, enzyme inhibitors, etc. Examples of peptides or proteins are listed below, but these may be modified by intramolecular disulfide bond formation or cyclization, or may have added polyethylene glycol groups, fatty acid groups, phosphate groups, etc., or may be viral constituent proteins or inactivated or attenuated viruses.

[0028] The antibody is not particularly limited as long as it can specifically bind to an antigen, and may be any of IgG, IgA, IgM, IgD, and IgE. Examples of IgG include IgG1, IgG2, IgG3, and IgG4. Examples of IgA include IgA1 and IgA2. The animal from which the antibody is derived is not particularly limited, and examples include humans as well as non-human animals such as mice, rats, rabbits, sheep, goats, and chickens. The antibody may be a chimeric antibody or a humanized antibody that combines a sequence derived from a non-human animal with a sequence derived from a human, or may be a fully human antibody. In addition to antibodies containing a complete constant region and a complete variable region, examples of the antibody include minibodies, Fabs, diabodies, Fab's, triabodies, scFv-Fc, scFvs, and F(ab's). ２, Fv, etc. The antibody may be conjugated with a compound other than an antibody, such as a nucleic acid, a labeled compound, or a low-molecular-weight drug. The antigen to which the antibody specifically binds is not particularly limited, and examples include nucleic acids, proteins, and sugars. Specific examples of antigens include IFNγ, TNFα, IL-1, IL-4, IL-5, IL-6, IL-7, IL-13, IL-18, and leukocyte surface antigen proteins.

[0029] Examples of hormones include glucagon, insulin, parathyroid hormone (PTH), gonadotropin, growth hormone, adrenal medullary hormone, adrenal cortical hormone, calcitonin, melatonin, prolactin, oxytocin, inhibin, amine / amino acid derivative hormone, steroid hormone, and somatostatin.

[0030] Examples of cytokines include IFNs such as IFNα, IFNβ, IFNγ, IFNδ, IFNω, IFNλ, IFNε, and IFNκ; TNFs such as TNFα and TNFβ; interleukins (ILs) such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, and IL-18; CSF, EPO, EGF, FGF, and PDGF.

[0031] Examples of chemokines include CC chemokines such as TCA3, MCP1, MCP2, MCP3, MCP4, MCP5, MIP4, MDC, and MEC; and CXC chemokines such as IL-8, MIG, IP10, PBSF, BLC, NAP3, MIP2, and PF4.

[0032] The nucleic acid is not particularly limited as long as it is a compound in which a plurality of nucleotides and / or nucleosides are bound by phosphodiester bonds, and examples thereof include DNA, RNA, mRNA, siRNA, etc. The nucleic acid may contain artificially modified nucleotides and / or nucleosides, such as LNA.

[0033] Among these medicinal ingredients, low molecular weight compounds, peptides, or proteins are preferred, leukotriene receptor antagonists, xanthine derivatives, peptides, or proteins are more preferred, and pranlukast, theophylline, glucagon, and antibodies are even more preferred.

[0034] The molecular weight of the medicinal ingredient is not particularly limited, but in the case of low molecular weight compounds, it is preferably 100 to 1,000, more preferably 150 to 600. In the case of compounds other than low molecular weight compounds, it is preferably 1,000 to 1,000,000, more preferably 2,000 to 200,000. The powder for inhalation of the present invention can efficiently deliver medicinal ingredients with large molecular weights to the bronchi and lungs.

[0035] <Excipient> Trehalose is used as the excipient contained in the microparticles (b). Trehalose may be a derivative in which a substituent has been introduced into the hydrogen atoms of some of the hydroxyl groups. Examples of the substituent include carboxylic acid esters such as acetate ester and benzoic acid; sulfate ester; fatty acid esters such as laurate ester, myristate ester, palmitate ester, stearate ester, oleate ester, linoleate ester, and linolenate ester; and ethers such as methyl ether, benzyl ether, trityl ether, methylsilyl ether, and dodecyl ether.

[0036] Ordinarily available commercially available trehalose (average particle size: approximately 300 μm) may be used as an excipient for the powder for inhalation as is. The average particle size of unmicronized trehalose is preferably 30 μm or more and 300 μm or less. Trehalose may also be micronized, with the average particle size of fine trehalose preferably being 0.5 μm or more and 8.0 μm or less, and more preferably being 0.8 μm or more and 3.0 μm or less. The method of micronization is not particularly limited, and examples include chemical treatments (dissolution, reprecipitation, etc.) and physical treatments (ultrasonication, pulverization, granulation, etc.).

[0037] In addition to trehalose, a second excipient consisting of a substance other than trehalose may be used as the excipient. Examples of the second excipient include sugars such as lactose, glucose, and sucrose; sugar alcohols such as erythritol, mannitol, and sorbitol; starches; high molecular weight polymers such as cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carmellose sodium, pullulan, dextrin, gum arabic, agar, gelatin, tragacanth, sodium alginate, polyvinylpyrrolidone, and polyvinyl alcohol; fatty acids or salts thereof; waxes; calcium sulfate, calcium carbonate, talc, titanium oxide, and light anhydrous silicic acid. When the excipient contains a second excipient other than trehalose, the trehalose content in the excipient is preferably 1.0% by weight or more and 99.9% by weight or less, and more preferably 50% by weight or more and 95% by weight or less.

[0038] <Microparticles (b)> In the microparticles (b), it is preferable that both the medicinal ingredient and the excipient are present in the form of microparticles, and that they are uniformly mixed. Such microparticles (b) can be obtained by mixing and / or pulverizing the medicinal ingredient and the excipient. Mixing and pulverizing the medicinal ingredient and the excipient can be carried out using a general dry pulverizer. Examples of dry pulverizers include jet mills, media agitation mills, high-speed rotary grinding mills, high-speed rotary impact mills, impact mills, tumbling ball mills, centrifugal ball mills, vibration ball mills, and planetary ball mills, and among these, jet mills are preferred. When using a jet mill, the indentation pressure should be 4.0 kg / cm. ２ G or more 9.0kg / cm ２ G or less is preferable, and 6.0 kg / cm ２ G or more 7.0kg / cm ２ The grinding pressure is preferably 3.5 kg / cm or less. ２ G or more 8.5kg / cm ２ G or less is preferable, and 5.5 kg / cm ２ G or more 6.5kg / cm ２ More preferably, it is equal to or less than G. Methods for mixing the medicinal ingredient and excipient include freeze-drying and spray-drying, in which a mixture of the two is dried to prepare fine particles (b).

[0039] Alternatively, the medicinal ingredient and excipient may be freeze-dried before being processed in a dry grinder. Freeze-drying allows the preparation of a dry powder in which the medicinal ingredient and excipient are uniformly mixed at the molecular level. When freeze-drying, it is preferable to mix the medicinal ingredient and excipient uniformly in a solvent, freeze the mixture preferably at a temperature between -80°C and 0°C, more preferably between -80°C and -20°C, and then dry the mixture under vacuum. Examples of solvents that can be used include water, buffer solutions, physiological saline, Ringer's solution, organic solvents, and mixtures thereof.

[0040] In the microparticles (b), the weight ratio of the medicinal ingredient to the excipient is preferably 1:1999 to 19:1, more preferably 1:199 to 19:1, even more preferably 1:19 to 3:1, and even more preferably 1:2 to 2:1. If the medicinal ingredient and the excipient exceed this range, uniform mixing becomes difficult, making it difficult to exert the medicinal effect, or making freeze-drying difficult.

[0041] The average particle size of the fine particles (b) is preferably 0.8 μm or more and 5.0 μm or less, more preferably 1.0 μm or more and 4.0 μm or less, and even more preferably 2.0 μm or more and 3.5 μm or less. Within this range, the fine particles (b) are easily separated from the carrier after administration of the powder for inhalation, and easily reach the bronchi and alveoli.

[0042] The fine particles (b) are preferably present on the surface of the carrier particles (a) due to the adhesive ability based on the intermolecular interaction with the carrier particles (a). Such powder for inhalation can be obtained by mixing the carrier particles (a) with the fine particles (b). The mixing of the two can be carried out using a general mixer. Examples of the mixer include a horizontal cylindrical mixer, a V-type mixer, a horizontal conical mixer, a double conical mixer, a cube mixer, a screw mixer, a rotating screw mixer, a ribbon mixer, a rotating disk mixer, a medium stirring mill, a high-speed rotary grinding mill, a high-speed rotary impact mill, an impact mill, and a jet mill.

[0043] In the powder for inhalation, the weight ratio of carrier particles (a) to fine particles (b) is preferably 1:1 to 99:1, more preferably 4:1 to 19:1, and even more preferably 5:1 to 9:1. If the carrier particles (a) exceed this range, there is a risk of loss of pharmacological activity. If the fine particles (b) exceed this range, the fluidity of the formulation tends to decrease.

[0044] In the powder for inhalation, the content of the fine particles (b) is preferably 1% by weight to 50% by weight, more preferably 5% by weight to 20% by weight, and even more preferably 9% by weight to 12.5% ​​by weight. Within this range, the fine particles (b) tend to adhere uniformly to the surface of the carrier particles (a) while maintaining their pharmacological activity.

[0045] The ratio of the average particle size of the fine particles (b) to the average particle size of the carrier particles (a) (average particle size of the fine particles (b):average particle size of the carrier particles (a)) is preferably 1:6 to 1:50, and more preferably 1:10 to 1:20.

[0046] <Target Diseases> The powder for inhalation of the present invention can be used as a therapeutic agent for diseases corresponding to the medicinal ingredients, such as asthma (bronchial asthma), asthmatic bronchitis, chronic bronchitis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, intractable chronic cough, diabetes, hypoglycemia, autoimmune diseases, and cancer.

[0047] <Rate of Reaching Bronchi and Lungs> The reach of a powder for inhalation to the bronchi and lungs can be evaluated using an Andersen Cascade Impactor (ACI). Evaluation of inhalation characteristics using an Andersen Cascade Impactor can be performed in accordance with the United States Pharmacopeia (USP29 <601> Aerosols, NASAL Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers). A specific example of a measuring device is the AN-200 model manufactured by Shibata Scientific Co., Ltd.

[0048] In the Andersen Cascade Impactor, the powder for inhalation is separated from top to bottom through eight stages, from Stage No. 0 to Stage No. 7, and the lowest filter, so that smaller particles can be aerodynamically separated and captured as they move downward. The amount of powder for inhalation captured at each stage can be measured by known methods, such as weight measurement or measurement of the active ingredient by liquid chromatography. The particle diameters of the powder for inhalation captured at each stage are as follows: Stage No. #0: 11.0 μm to Stage No. #1: 7.0 μm to 11.0 μm Stage No. #2: 4.7 μm to 7.0 μm Stage No. #3: 3.3 μm to 4.7 μm Stage No. #4: 2.1 μm to 3.3 μm Stage No. Stage No. #5: 1.1 μm to 2.1 μm Stage No. #6: 0.65 μm to 1.1 μm Stage No. #7: 0.43 μm to 0.65 μm Filter: up to 0.43 μm

[0049] In an inhalation characteristic evaluation using an Andersen cascade impactor, the powder for inhalation of the present invention preferably has a total deposition rate of 10% or more in stages #4 to #7, more preferably 20% or more, even more preferably 38% or more, even more preferably 41% or more, and particularly preferably 44% or more. Deposition in stages #4 to #7 indicates the powder for inhalation reaching the bronchi and alveoli. The total deposition rate of stages #4 to #7 can be calculated using the following formula (Formula 1): Total deposition rate (%) of stages #4 to #7 = Total amount (g) of powder for inhalation captured in stages #4 to #7 / Total amount (g) of powder for inhalation captured in stages #0 to #7 × 100 ... Formula 1

[0050] The powder for inhalation of the present invention preferably has an ED (Emitted dose) of 50% or more, more preferably 60% or more, and even more preferably 70% or more, when evaluated for inhalation characteristics using an Andersen cascade impactor. ED can be calculated using the following formula (2): ED (%) = amount of powder for inhalation emitted from capsule (g) / amount of powder for inhalation filled in capsule (g) × 100 ... formula 2

[0051] The powder for inhalation of the present invention preferably has an FPF (Fine Particle Fraction) of 10% or more, more preferably 30% or more, and even more preferably 50% or more, in an inhalation characteristic evaluation using an Andersen Cascade Impactor. The FPF can be calculated using the following formula (3): FPF (%) = Total amount (g) of powder for inhalation captured in stages #2 to #7 / Total amount (g) of powder for inhalation captured in stages #0 to #7 × 100 (Formula 3)

[0052] The powders for inhalation of the present invention contain trehalose as an excipient, and therefore have excellent storage stability and exhibit excellent depth penetration even after storage under high humidity conditions. In an evaluation of the inhalation characteristics of the powders for inhalation of the present invention using an Andersen cascade impactor after storage for two weeks under conditions of 75% relative humidity and 40° C., the total deposition rate of stages #4 to #7 is preferably 10% or more, more preferably 20% or more, and even more preferably 40% or more.

[0053] The present invention will be described below with reference to examples, but is not limited to the following examples. Hereinafter, "parts" and "%" mean "parts by weight" and "% by weight", respectively, unless otherwise specified.

[0054] (1) Pulverization of Trehalose Approximately 17 kg of pharmaceutical-grade trehalose (Trehalose 100PH, manufactured and sold by Hayashibara Co., Ltd.) was pulverized using a jet mill (Nano Jetmizer®: NJ-100 C type, manufactured by Aisin Nano Technologies Co., Ltd.) to prepare approximately 13 kg of fine trehalose with an average particle size of 1.05 μm. The pulverization conditions were a throughput of 7.9 kg / hr, and both the indentation pressure and pulverization pressure were 1.4 MPa. A scanning electron microscope (SEM: SU3500 type, manufactured by Hitachi) was used to observe the fine trehalose. A small amount of sample was placed on the specimen stage, excess particles were removed with air, and observation at an accelerating voltage of 15.0 kV revealed particles with a diameter of approximately 1 μm. The results are shown in Figure 1.

[0055] (2) Preparation of inhalable powders 1 Inhalable powders (PL-RP: Pranlukast Respirable powder) containing pranlukast (PL, Compound ID: AG008R1P, manufactured by Angene International Limited) as the API were prepared with the compositions shown in Table 1, and their inhalation properties were compared.

[0056] Composition of inhalable powder

[0057] Specifically, PL was milled and mixed with pharmaceutically acceptable excipients such as lactose (CAS RN (registered trademark): 64044-51-5) or fine trehalose in a jet mill (A-O-Jet Mill, manufactured by Seishin Enterprise Co., Ltd.) to obtain uniformly mixed microparticles (Dv50 = approximately 3-4 μm). An autofeeder was used to supply raw materials during milling, and a pressure of 6.5 kg / cm was applied. ２ G, crushing pressure 6.5kg / cm ２ The mixture was pulverized under the conditions of G. PL-RP was prepared by mixing the mixture with 9 times the amount of carrier lactose (Dv50 = 60 μm).

[0058] SEM images of mT / PL-RP (Example 1) and L / PL-RP (Comparative Example 1) are shown in Figure 2. In Figure 2, it was observed that fine particles of excipient and PL adhered to the carrier lactose in both Example 1 and Comparative Example 1. Particles of 5.0 μm to 10.0 μm were observed in L / PL-RP (Comparative Example 1), whereas only finer particles adhered to mT / PL-RP (Example 1), which used fine trehalose.

[0059] Next, the inhalation characteristics were evaluated using a cascade impactor. The results are shown in Figure 3, and the achievement rates for each stage are shown in Table 2. A Japanese Pharmacopoeia No. 2 capsule of hydroxypropyl methylcellulose filled with approximately 30 mg was attached to an inhaler (JetHaler®, manufactured by Tokico System Solutions, Inc.). The inhaler was attached to the mouthpiece of the cascade impactor, and after inhalation at a flow rate of 28.3 L / min, the amount of drug at each stage was measured by liquid chromatography.

[0060] Achievement rate for each stage

[0061] The total percentage of API delivered to stages #4 to #7 was 49.7% for mT / PL-RP (Example 1) and 37.5% for L / PL-RP (Comparative Example 1). The improvement in deep delivery rate (proportion of stages #4 to #7) suggested that the use of trehalose is effective in delivering API to the deep lung.

[0062] (3) Preparation of Inhalable Powders 2 To clarify the relationship between the improved deep delivery rate observed in (2) above and the particle size of fine trehalose, PL-RP was prepared using unground trehalose (untreated trehalose, manufactured by Hayashibara Co., Ltd.) as an excipient (T / PL-RP, Example 2), and its inhalation characteristics were evaluated. First, fine trehalose or untreated trehalose and PL were ground and mixed in a jet mill to obtain uniformly mixed fine particles (Dv50 = 3-4 μm). This was mixed with 9 times the amount of carrier lactose to prepare mT / PL-RP (Example 1) and T / PL-RP (Example 2). Examples 1 and 2 were prepared with the compositions listed in Table 3. The inhalation characteristics were then evaluated using a cascade impactor.

[0063] Composition of powder inhalants

[0064] As a result of evaluating the inhalation characteristics, as shown in Figure 4, an improvement in the deep delivery rate was observed with T / PL-RP (Example 2) as with mT / PL-RP (Example 1). The rate of delivery to each stage is shown in Table 4.

[0065] Achievement rate for each stage

[0066] (4) Particle size distribution of inhalable powders For the PL-RP described in (2) to (3) above, the particle size distribution of the mixed fine particles of PL and excipient (fine particles before mixing with the carrier lactose) was measured using a light scattering particle size analyzer (Mastersizer 3000, manufactured by Malvern Panalytical). The results are shown in Table 5 and Figure 5, respectively. The values ​​in Table 5 and Figure 5 represent the average values ​​of Dv10, Dv50, and Dv90 on a volume basis when measurements were taken three times under the same conditions. The particle size distribution curve also shows the average value of three measurements.

[0067] Mixed particle size of each excipient and PL

[0068] The mean particle size (Dv50) of T / PL was 3.29 μm, 0.69 μm larger than that of mT / PL and similar to that of L / PL. Despite the similar mean particle size (Dv50), there was a significant difference in deep delivery rate between Example 2 (T / PL-RP) and Comparative Example 1 (L / PL-RP) (see Figures 3 and 4), indicating that not only the particle sizes of the API and excipients but also the type of carbohydrate used as the excipient affect the inhalation characteristics.

[0069] (5) Storage Stability of Inhalable Powders mT / PL-RP (Example 1), which exhibits a high deep delivery rate, was subjected to a storage stability test under high humidity conditions. After storing mT / PL-RP for 2 weeks under conditions of 75% relative humidity and 40°C temperature, the inhalation characteristics were evaluated using a cascade impactor. The results are shown in Figure 6. As shown in Figure 6, although the total deposition rate in stages #4 to #7 decreased compared to immediately after preparation, it remained relatively high for an inhalable powder.

[0070] (6) Animal Test 1 To evaluate the efficacy of intratracheal administration of mT / PL-RP (Example 1), chronic obstructive pulmonary disease (COPD) was induced in rats, and the effect was compared with that of oral administration. Ovalbumin (OVA, Sigma-Aldrich) was administered intraperitoneally three times at 7-day intervals, and the following day, mT / PL-RP (Example 1) (5 mg PL / kg) was administered intratracheally, or PL (Comparative Example 2) (60 mg / kg) was administered orally. One hour after administration, inflammation was induced by intratracheal administration of OVA micronized powder, and COPD was induced. Twenty-four hours after the induction of inflammation by OVA administration, the lungs were removed and bronchoalveolar lavage fluid (BALF) was collected. Observation of the lung tissue using peroxidase staining using standard methods revealed that induction of COPD induced infiltration of granulocytic or monocytic cells into the lung tissue, but infiltration was suppressed in the intratracheal administration group. The results are shown in Figure 7. Infiltration was also suppressed in the oral administration group, but a more pronounced infiltration suppression effect was observed in the intratracheal administration group.

[0071] Furthermore, when the numbers of infiltrating macrophages, neutrophils, and eosinophils in the BALF were counted using a Birker-Türck hemocytometer (Elma Sales Co., Ltd.), the number of cells in the intratracheal administration group was statistically significantly lower than that in the oral administration group. The results are shown in Figure 8 and Table 6.

[0072] Number of infiltrating cells in BALF

[0073] In asthma, eosinophil infiltration is primarily increased, while in COPD and severe asthma, neutrophil infiltration is increased. In this study, neutrophil infiltration was predominant, indicating a pathological condition similar to COPD. Based on these results, pulmonary administration of PL is expected to reduce the dosage and achieve greater efficacy compared to oral administration.

[0074] (7) Animal Test 2 The amount of PL transferred into the blood was evaluated following oral and intratracheal administration. The blood PL concentration was measured over time up to 12 hours after administration in a group of rats that received intratracheal administration of mT / PL-RP (Example 1) (5 mg PL / kg) and a group that received oral administration of PL (Comparative Example 2) (60 mg / kg). The results are shown in Figure 9 and Table 7. The intratracheal administration group (mT / PL-RP (Example 1)) showed faster absorption than the oral administration group (PL (Comparative Example 2)), and the area under the curve (AUC) 12 hours after administration was approximately 1.4 times higher.

[0075] Pharmacokinetics of PL

[0076] (8) Preparation of Inhalable Powders 3 Theophylline (THE: product code T0179, Tokyo Chemical Industry Co., Ltd.), a therapeutic agent for bronchial asthma, similar to PL, was dissolved with excipients and freeze-dried (FD) to prepare an inhalable powder (FD / THE-RP). The inhalation characteristics were evaluated. Specifically, THE and each excipient (trehalose or lactose) were dissolved in Milli-Q water at a weight ratio of 1:1, frozen at -20°C, and then freeze-dried using an FDU-1200 (Tokyo Rikakikai Co., Ltd.). Fine particles were then prepared using a jet mill and mixed with 9 times the amount of carrier lactose to prepare FD-T / THE-RP (Example 3) and FD-L / THE-RP (Comparative Example 3). The compositions were as shown in Table 8.

[0077] Composition of inhalable powder

[0078] A comparison of inhalation characteristics using a cascade impactor revealed that the percentages of delivery from stage #4 onward for FD-T / THE-RP (Example 3) and FD-L / THE-RP (Comparative Example 3) were 18.6% and 9.5%, respectively, with FD-T / THE-RP (Example 3) demonstrating a deep delivery rate that was approximately two times higher. The results are shown in Figure 10 and Table 9.

[0079] Achievement rate for each stage

[0080] Inhalation powders prepared by freeze-drying are generally highly adhesive and prone to problems with inhalation properties. Trehalose has been shown to be effective in maintaining the inhalation properties of inhalation powders prepared through freeze-drying.

[0081] (9) Preparation of Inhalable Powder 4 An antibody solution containing 21.44 mg of mouse anti-human IL-18 monoclonal antibody, 387 mg of sodium phosphate, and 263 mg of glycine hydrochloride per 26 mL was prepared. This antibody solution was lyophilized and mixed with an excipient (trehalose or lactose) in the ratio shown in Table 10. The mixture was pulverized and mixed using a jet mill to prepare fine particles. This was mixed with the carrier lactose (Dv50 = 60 μm) in the amount shown in Table 10 to prepare T / Ab-RP (Example 4) and L / Ab-RP (Comparative Example 4), each containing an antibody as the active ingredient.

[0082]

[0083] The powdered inhalation formulation was inhaled using a cascade impactor, and the weight of the powdered inhalation formulation that reached each stage was measured. As a result, the percentages of powdered inhalation from stage No. 4 onwards for T / Ab-RP (Example 4) and L / Ab-RP (Comparative Example 4) were 11.1% and 6.8%, respectively, and T / Ab-RP (Example 4) showed a deep delivery rate that was approximately 1.6 times higher than that of Comparative Example 4. The results are shown in Figure 11 and Table 11.

[0084] Trehalose also increased the deep delivery rate of powdered inhalants containing antibodies as active ingredients.

[0085] The present disclosure may include the following aspects.

[0086] (Item 1) A powder for inhalation comprising: carrier particles (a); and fine particles (b) present on the surface of the carrier particles and containing a medicinal ingredient and an excipient, wherein the excipient is trehalose.

[0087] (Item 2) The powder for inhalation according to Item 1, wherein the fine particles (b) have an average particle size of 0.8 μm or more and 5.0 μm or less.

[0088] (Item 3) The powder for inhalation according to Item 1 or 2, wherein the carrier particles (a) contain lactose and / or trehalose.

[0089] (Item 4) The powder for inhalation according to any one of Items 1 to 3, wherein the carrier particles (a) have an average particle size of 30 μm or more and 300 μm or less.

[0090] (Item 5) The powder for inhalation according to any one of Items 1 to 4, wherein the medicinal ingredient is selected from the group consisting of low molecular weight compounds, peptides, and proteins.

[0091] (Item 6) The powder for inhalation according to Item 5, wherein the low molecular weight compound is selected from the group consisting of leukotriene receptor antagonists and xanthine derivatives.

[0092] (Item 7) The powder for inhalation according to Item 6, wherein the leukotriene receptor antagonist is pranlukast or the xanthine derivative is theophylline.

[0093] (Item 8) The powder for inhalation according to Item 5, wherein the peptide or protein is glucagon or an antibody.

[0094] (Item 9) The powder for inhalation according to any one of Items 1 to 8, wherein the total deposition rate of stages #4 to #7 is 10% or more in an inhalation characteristic evaluation using an Andersen cascade impactor.

[0095] (Item 10) The powder for inhalation according to any one of Items 1 to 9, wherein the fine particles (b) are prepared by drying a mixture of a medicinal ingredient and an excipient.

[0096] (Item 11) The powder for inhalation according to any one of Items 1 to 10, wherein the weight ratio of the medicinal ingredient to the excipient is 1:1999 to 19:1.

[0097] (Item 12) The powder for inhalation according to any one of Items 1 to 11, wherein the weight ratio of the carrier particles (a) to the fine particles (b) is 1:1 to 99:1.

Claims

1. A powder for inhalation comprising: carrier particles (a); and fine particles (b) containing an active ingredient and an excipient, the fine particles being present on the surface of the carrier particles, wherein the excipient is trehalose.

2. The powder for inhalation according to claim 1, wherein the average particle size of the fine particles (b) is 0.8 μm or more and 5.0 μm or less.

3. The powder for inhalation according to claim 1 or 2, wherein the carrier particles (a) contain lactose and / or trehalose.

4. The powder for inhalation according to claim 1 or 2, wherein the average particle size of the carrier particles (a) is 30 μm or more and 300 μm or less.

5. The powder for inhalation according to claim 1 or 2, wherein the medicinal ingredient is selected from the group consisting of low molecular weight compounds, peptides, and proteins.

6. The inhalable powder according to claim 5, wherein the low molecular weight compound is selected from the group consisting of leukotriene receptor antagonists and xanthine derivatives.

7. The powder for inhalation according to claim 6, wherein the leukotriene receptor antagonist is pranlukast or the xanthine derivative is theophylline.

8. The inhalable powder according to claim 5, wherein the peptide or protein is glucagon or an antibody.

9. The powder for inhalation according to claim 1 or 2, wherein the total deposition rate of stages No. 4 to No. 7 is 10% or more in an inhalation characteristic evaluation using an Andersen cascade impactor.

10. The powder for inhalation according to claim 1 or 2, wherein the fine particles (b) are prepared by drying a mixture of an active ingredient and an excipient.

11. The powder for inhalation according to claim 1 or 2, wherein the weight ratio of the medicinal ingredient to the excipient is 1:1999 to 19:

1.

12. The powder for inhalation according to claim 1 or 2, wherein the weight ratio of the carrier particles (a) to the fine particles (b) is 1:1 to 99:1.

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