Powdered formulation for nasal administration and method for manufacturing the same

Abstract

The present invention addresses the problem of providing a powder preparation for transnasal administration, the preparation efficiently demonstrating drug efficacy. The problem can be solved by a powder preparation for transnasal administration, containing composite particles in which an effective component and a water-insoluble polysaccharide adhere to each other.

Description

[Technical Field]

[0001] The present invention relates to a powder formulation for intranasal administration and a method for producing the same. [Background technology]

[0002] Traditionally, intranasal administration has been primarily used for local treatments such as rhinitis. However, recently, attempts have been made to utilize intranasal administration to prevent or treat systemic diseases, central nervous system disorders, and infections, and various intranasal administration formulations have been reported. For example, Patent Document 1 discloses "a powdered intranasal administration composition comprising a non-peptide / protein drug and a crystalline cellulose aggregate as a carrier thereof." [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] International Publication No. 2006 / 016530 [Overview of the project] [Problems that the invention aims to solve]

[0004] Patent Document 1 discloses a method for producing a powdered nasal administration composition, which involves mixing a drug with crystalline cellulose in a mortar. However, in this method, when the resulting composition is sprayed from an administration device, the drug and crystalline cellulose may separate, potentially preventing the full utilization of the mucosal adhesion effect of crystalline cellulose. As a result, the expected therapeutic effect may not be achieved.

[0005] The object of this invention is to provide a powder formulation for nasal administration that efficiently exerts its medicinal effects, and a method for producing the same. [Means for solving the problem]

[0006] The inventors have discovered that composite particles that efficiently exert their medicinal effects can be obtained by stirring granulation, fluid bed granulation, or freeze-drying a mixture containing an active ingredient and a water-insoluble polysaccharide.

[0007] The present invention includes the following embodiments. [1] A powder formulation for intranasal administration containing composite particles in which the active ingredient and water-insoluble polysaccharides are adhered to each other. [2] The powder formulation according to [1], wherein the average primary particle size of the composite particles is 20 to 350 μm. [3] The specific surface area of ​​the composite particles is 0.20 to 2.3 m². 2 A powder formulation as described in [1] or [2], which is / g. [4] The powder formulation according to any one of [1] to [3], wherein the Hausner ratio of the composite particles is 1.8 or less. [5] The powder formulation according to any one of [1] to [4], wherein the water-insoluble polysaccharide comprises crystalline cellulose. [6] The powder formulation according to any one of [1] to [5], wherein the composite particles further comprise a binder. [7] The powder formulation according to any one of [1] to [6], wherein the composite particles further comprise an absorption enhancer. [8] The powder formulation according to [7], wherein the absorption enhancer is hydroxypropyl β-cyclodextrin, sodium lauryl sulfate, or n-dodecyl-β-D-maltoside. [9] The process includes stirring and granulating a mixture containing an active ingredient and a water-insoluble polysaccharide to form composite particles in which the active ingredient and the water-insoluble polysaccharide are attached to each other. A method for manufacturing a powder formulation for nasal administration.

[10] The process includes a step of granulating a mixture containing an active ingredient and a water-insoluble polysaccharide in a fluid bed to form composite particles in which the active ingredient and the water-insoluble polysaccharide are attached to each other. A method for manufacturing a powder formulation for nasal administration.

[11] A process of freeze-drying a mixture containing an active ingredient and a water-insoluble polysaccharide to form composite particles in which the active ingredient and the water-insoluble polysaccharide adhere to each other is included, A method for producing a powder formulation for nasal administration.

[12] The production method according to any one of [9] to

[11] , wherein the water-insoluble polysaccharide contains crystalline cellulose.

[13] The production method according to any one of [9] to

[12] , wherein the mixture further contains a binder.

[14] The production method according to any one of [9] to

[13] , wherein the mixture further contains an absorption promoter.

[15] The production method according to

[14] , wherein the absorption promoter is hydroxypropyl β-cyclodextrin, sodium lauryl sulfate or n-dodecyl-β-D-maltoside.

Advantages of the Invention

[0008] According to the present invention, it is possible to provide a powder formulation for nasal administration that efficiently exhibits a medicinal effect and a method for producing the same.

Brief Description of the Drawings

[0009] [Figure 1] An electron micrograph of the test formulation of Example 7 is shown. [Figure 2] An electron micrograph of the test formulation of Example 10 is shown. [Figure 3] An electron micrograph of the test formulation of Example 15 is shown. [Figure 4] An electron micrograph of the test formulation of Example 16 is shown. [Figure 5] An electron micrograph of the test formulation of Comparative Example 1 is shown. [Figure 6] An electron micrograph of the test formulation of Comparative Example 2 is shown.

Modes for Carrying Out the Invention

[0010] <Powdered preparation> One embodiment of the present invention relates to a powder formulation for intranasal administration, comprising composite particles in which an active ingredient and a water-insoluble polysaccharide are attached to each other.

[0011] In this specification, "composite particles" refer to particles (aggregates) formed by the adhesion of an active ingredient and a water-insoluble polysaccharide to each other. Therefore, "composite particles" in this specification are clearly distinguished from a mere mixture of a drug and crystalline cellulose, such as those disclosed in Patent Document 1.

[0012] In this embodiment, since the active ingredient and water-insoluble polysaccharides form a composite particle, when the powder formulation is administered into the nasal cavity, the active ingredient and water-insoluble polysaccharides adhere together to the nasal mucosa. Because water-insoluble polysaccharides have a mucosal adhesion effect, the active ingredient adheres to the nasal mucosa through this effect, and the medicinal effects of the active ingredient are efficiently exerted.

[0013] Simply mixing the active ingredient with water-insoluble polysaccharides can result in uneven mixing of the active ingredient, potentially leading to variations in the amount of active ingredient between different powder formulations. However, in this embodiment, the active ingredient and water-insoluble polysaccharides form composite particles, thus suppressing such variations.

[0014] In this embodiment, the active ingredient and water-insoluble polysaccharides form a composite particle, which improves the fluidity of the powder formulation. This allows the powder formulation to be filled uniformly and easily into a container, and also improves the ejection rate of the powder formulation from the dispensing device.

[0015] When a powder formulation containing small particles is administered into the nasal cavity, there is a possibility that it may pass through the nasal cavity and reach the lungs. On the other hand, in this embodiment, the active ingredient and water-insoluble polysaccharides form a complex particle with a larger particle size, which can suppress passage through the nasal cavity.

[0016] The composite particles of this embodiment have a particle diameter larger than that of each individual component, because the constituent components of the composite particles are formed by adhering to each other.

[0017] As the lower limit of the average primary particle diameter of the composite particles of the present embodiment, for example, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, etc. can be mentioned, and as the upper limit, for example, 350 μm, 300 μm, 250 μm, 200 μm, 150 μm, 100 μm, etc. can be mentioned. By appropriately combining the lower limit and the upper limit, a specific range can be defined. For example, it can be in the range of 20 to 350 μm, 25 to 300 μm, 30 to 250 μm, 35 to 200 μm, 40 to 150 μm. The average primary particle diameter is measured according to the method described in the following examples. Note that since the average primary particle diameter is measured under a dispersion pressure of 2 bar, if the constituent components of the composite particles are not adhered to each other, the composite particles will decompose into each constituent component by the dispersion pressure. For example, in the case of a mere mixture of a drug and crystalline cellulose as disclosed in Patent Document 1, even if some of the constituent components gather to form large particles, under the measurement conditions of the average primary particle diameter, the particles will decompose, which is significantly different from the average primary particle diameter of the composite particles of the present embodiment.

[0018] As the lower limit of the specific surface area of the composite particles of the present embodiment, for example, 0.10 m 2 / g, 0.15 m 2 / g, 0.20 m 2 / g, 0.25 m 2 / g, 0.30 m 2 / g, etc. can be mentioned, and as the upper limit, for example, 2.3 m 2 / g, 2.0 m 2 / g, 1.8 m 2 / g, 1.6 m 2 / g, 1.4 m 2 / g, etc. can be mentioned. By appropriately combining the lower limit and the upper limit, a specific range can be defined. For example, it can be in the range of 0.10 to 2.3 m 2 / g, 0.15 to 2.0 m 2 / g, 0.20 to 1.8 m 2 / g, 0.25 to 1.6 m 2 / g, 0.30 to 1.4 m 2 / g. The specific surface area is measured according to the method described in the following examples.

[0019] Examples of upper limits for the Hausner ratio of the composite particles in this embodiment include 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, and 1.2, and there is no particular lower limit. The Hausner ratio is measured according to the method described in the following examples.

[0020] The seventeenth revised Japanese Pharmacopoeia describes the relationship between the Hausner ratio and fluidity as follows: Hausner ratio: degree of fluidity 1.00~1.11: Excellent 1.12~1.18: Good 1.19~1.25: Fairly good 1.26~1.34: Normal 1.35~1.45: Slightly poor 1.46~1.59: Bad >1.60: Extremely poor

[0021] Diseases that the powder formulation of this embodiment can diagnose, prevent, or treat include, for example, cerebral hemorrhage, cerebral infarction, central nervous system infections, brain tumors, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Lewy body dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, multiple sclerosis, schizophrenia, depression, bipolar disorder, dysthymia, adjustment disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder, autism spectrum disorder, attention deficit hyperactivity disorder, sleep disorders, insomnia, traumatic brain injury, pain, migraines, headaches, fever, inflammation, rheumatism, epilepsy, cerebral circulatory metabolic disorders, muscle relaxation, and autonomic nervous system disorders. This includes conditions such as dizziness, hypertension, angina pectoris, arrhythmia, allergies, bronchiectasis / asthma, other respiratory diseases (cough suppressants, expectorants, etc.), peptic ulcers, other digestive diseases (antidiarrheals, bowel regulation, stomachic, digestive aids, laxatives, etc.), gout / hyperuricemia, dyslipidemia, diabetes, hormone-related disorders (diseases related to pituitary hormones, adrenocortical hormones, sex hormones, and other hormones), uterine-related diseases, osteoporosis / bone metabolic diseases, vitamin deficiencies, nutritional deficiencies, poisoning (including detoxification), cancer, hyperimmune disorders, otolaryngological diseases, oral-related diseases, urinary and reproductive diseases, hemorrhoids, skin diseases, hematopoietic / blood coagulation-related disorders, drug addiction, anesthesia, and lifestyle-related diseases.

[0022] The active ingredients in this embodiment may be used individually or in combination of multiple active ingredients. Examples of active ingredients include small molecule compounds, medium molecule drugs (e.g., peptide drugs), protein drugs (e.g., antibody drugs), nucleic acid drugs, cell drugs, regenerative medicine, vaccine antigens (e.g., peptide antigens), and the like.

[0023] More specific active ingredients include, for example, tissue plasminogen activator, edaravone, ozagrel sodium, selective thrombin inhibitor, vidarabine, acyclovir, ganciclovir, valganciclovir, zidovudine, didanosine, zalcitabine, nevirapine, delavirdin, saquinavir, ritonavir, indinavir, nelfinavir, vancomycin, ceftazidime, ampicillin, panipenem / betamipron, dexamethasone, cisplatin, carboplatin, vincristine, cyclophosphamide, ifosfamide, temozolomide, eto Poside, L-dopa, carbidopa, benserazide, entacapone, adrenaline, amphetamine, apomorphine, amantadine, cabergoline, zonisamide, droxidopa, piperidene, phenobarbital, phenytoin, primidone, ethosuximide, zonisamide, clonazepam, midazolam, remimazolam, flumazenil, sodium valproate, carbamazepine, gabapentin, topiramate, cannabidi, donepezil, rivastigmine, galantamine, memantine, dimethyl fumarate, natalizumab, haloperidol, spiperone, fluf Enazine, chlorpromazine, risperidone, blonanserin, quetiapine, olanzapine, aripiprazole, brexpiprazole, triazolam, zopiclone, zolpidem, etizolam, lormetazepam, bromovalerylurea, chloral hydrate, pentobarbital, rilmazafone, oxytocin, vasopressin, desmopressin, granisetron, ondansetron, tropisetron, palonosetron, indisetron, triazolam, melatonin, levetiracetam, cannabinoids, clonazepam, diazepam, nitrazepam, zolpidem, Donepezil, memantine, tiapride, cefaclor, enoxacin, acyclovir, zidovudine, didanosine, nevirabine, indinavir, dantrolene, digoxin, trihexyphenidyl, piperidene, dextromethorphan, naloxone, betahistine, naphazoline, diltiazem, tranilast, loperamide, beclomethasone, chlorpheniramine, sildenafil, tadalafil, vardenafil, cyanocobalamin, finasteride, epinephrine, oxybutynin, propiverine, solifenacin, tolterodine, imidafenacin,Fesoterodine, mirabegron, tamsulosin, silodosin, 5-FU, telaprevir, ribavirin, simeprevir, guanfacine, metylphenidate, atomoxetine, progesterone, sumatriptan, zolmitriptan, dihydroergotamine, rizatriptan, camostat, famostat, erenumab, galcanezumab, fremanezumab, homivirsen, mipomasen, nusinersen, cyclosporine, tacrolimus, fluorodeoxyglucose, fluorothymidine, iopamidol, thallium, manganese, technetium, insulin, growth hormone, growth hormone-releasing peptide, ghrelin, glucagon, calcitonin, interferon, erythropoietin, interleukin, PTH(1-84), PTH(1-34), PTH-related peptide, GLP-1, Sopressin, leuprorelin, granulocyte colony-stimulating factor, prolactin, pituitary gonadotropin, placental gonadotropin Snbl2600 hormone, follicle-stimulating hormone, luteinizing hormone, leptin, nerve growth factor (NGF), stem cell growth factor (SCGF), keratinocyte growth factor (KGF), low molecular weight heparin, tacrolimus, allergen extract powder, human antibodies (e.g., adalimumab, paniton). Examples of antibodies include mumab, golimumab, canakinumab, ofatumumab, denosumab, ipilimumab, belimumab, laxibakumab, ramucirumab, nivolumab, secukinumab, evolocumab, alirocumab, necitumumab, nivolumab, pembrolizumab, etc.), chimeric antibodies (e.g., absiximab), humanized antibodies (e.g., bevacizumab), and mouse antibodies (e.g., blinatumomab).

[0024] More specific examples of active ingredients include vaccine antigens against the following viruses or pathogens. Adenovirus, AIDS virus, baculovirus, HCMV (human cytomegalovirus), hemorrhagic fever virus, hepatitis virus, herpes B virus, immunodeficiency virus, human immunodeficiency virus, human T-cell leukemia virus, neonatal gastroenteritis virus, infectious hematopoietic necrosis virus, infectious pancreatic necrosis virus, influenza virus, Japanese encephalitis virus, leukemia virus, mumps virus, orthomyxovirus, pneumonia virus, poliovirus, polidonnavirus, ro Taenivirus, SARS virus, vaccinia virus, RSV, Shigella species, Salmonella typhi, Mycobacterium tuberculosis, Neisseria tetanus, Neisseria diphtheriae, Neisseria meningitidis, Bordetella pertussis, Streptococcus pneumoniae, Bacillus anthrax, Clostridium difficile, Clostridium perfringens, Enterococcus faecalis, Enterococcus facium, Haemophilus influenzae, Helicobacter pylori, Mycobacterium leprae, Neisseria gonorrhoeae, Neisseria meningitidis, Salmonella typhi, Staphylococcus aureus, Treponema pallidum, Vibrio cholerae, Plasmodium falciparum.

[0025] In this specification, "water-insoluble polysaccharides" means polysaccharides that dissolve in 1000 ml of water (20°C) at a concentration of 0.001 g or less. Water-insoluble polysaccharides may be used individually or in combination of multiple types.

[0026] Examples of water-insoluble polysaccharides include cellulose, hemicellulose, chitosan, and chitin, with cellulose or hemicellulose being preferred, cellulose more preferably, and crystalline cellulose particularly preferred. Using crystalline cellulose can further improve the fluidity of the powder formulation. Examples of commercially available crystalline cellulose include CEOLUS® PH grade and AVICEL® PH grade, and more specifically, CEOLUS® PH-F20JP, AVICEL® PH-105, CEOLUS® PH-UF702, etc.

[0027] The composite particles of this embodiment may further contain a binder. The inclusion of a binder in the composite particles can increase the adhesion strength between the active ingredient and the water-insoluble polysaccharide, and adjust the primary particle size and disintegration properties of the composite particles. The binder may be used alone or in combination of multiple types.

[0028] Examples of binders include purified water, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, carboxymethylcellulose, pregelatinized starch, partially pregelatinized starch, and salts thereof, with hydroxypropyl methylcellulose or pregelatinized starch being preferred.

[0029] The composite particles of this embodiment may further contain additives. Examples of additives include absorption enhancers, solubilizers, stabilizers, fluidizers, disintegrants, masking agents, flavoring agents, preservatives, and immunostimulants.

[0030] Absorption enhancers include, for example, surfactants, chelating agents, cyclodextrins, and membrane-permeable peptides. Examples of surfactants include anionic surfactants such as sodium lauryl sulfate and sodium caprate, nonionic surfactants such as n-dodecyl-β-D-maltoside and tetradodecyl-β-D-maltoside, and amphoteric surfactants such as dipalmitoylphosphatidylcholine and sodium taurocholate. Examples of chelating agents include EDTA, citrate, and pyrophosphate. Examples of cyclodextrins include β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and methyl-β-cyclodextrin. Examples of membrane-permeable peptides include penetratin, HIV-1 Tat, HIV-1 Rev, arginine octamer, arginine dodecamer, pVEC, Ems, RRL helix, and PRL4.

[0031] Examples of solubilizing and dissolving agents include cyclodextrin, capric acid, lecithin, dipalmitoylglycerophosphatidylcholine, dodecyl maltoside, dodecylphosphocholine, and polyethylene glycol.

[0032] Examples of stabilizers include disaccharides (e.g., sucrose, lactulose, maltose, trehalose, cellobiose, xylobiose, maltulose, galactosucrose, and their derivatives), vitamins (e.g., ascorbic acid, tocopherol), amino acids (e.g., glycine), citrates, pyrophosphates, and the like.

[0033] Examples of fluidizing agents include crystalline cellulose and tricalcium phosphate.

[0034] Examples of disintegrants include cellulose, starch, and crospovidone.

[0035] Examples of masking agents include mannitol.

[0036] Examples of flavoring agents include aspartame and menthol.

[0037] Examples of preservatives include thimerosal.

[0038] Examples of immunostimulants include cyclodextrins, aluminum salts, and CpG oligonucleotides.

[0039] <Manufacturing of powdered formulations> One embodiment of the present invention relates to a method for producing a powder formulation for intranasal administration, comprising the steps of stirring and granulating a mixture containing an active ingredient and a water-insoluble polysaccharide, fluid bed granulation, or freeze-drying to form composite particles in which the active ingredient and the water-insoluble polysaccharide are attached to each other. Hereinafter, the stirring and granulation method, the fluid bed granulation method, and the freeze-drying method will be referred to as "stirring and granulation method," "fluid bed granulation method," and "freeze-drying method," respectively. The components of the composite particles are as described in the <Powder Formulation> section above.

[0040] In the stirring granulation method, the amount of binder added is preferably 5 mL to 150 mL, more preferably 15 mL to 100 mL, and even more preferably 20 mL to 75 mL per 100 g of total powder weight in the granulation tank. By stirring granulation with this amount of binder added, composite particles with desirable properties can be obtained.

[0041] In the fluidized bed granulation method, the spray rate of the binder is preferably 0.001 g / min to 0.4 g / min, more preferably 0.005 g / min to 0.3 g / min, and even more preferably 0.01 g / min to 0.25 g / min per 50 g of total powder weight in the granulation tank. The total amount of binder added in the fluidized bed granulation method is preferably 0.01 g to 4.0 g, more preferably 0.05 g to 3.0 g, and even more preferably 0.1 g to 2.5 g per 50 g of total powder weight in the granulation tank. By performing fluidized bed granulation under these conditions, composite particles with desirable properties can be obtained.

[0042] The freezing temperature in the freeze-drying method is preferably -100°C to -10°C, more preferably -80°C to -15°C, and even more preferably -60°C to -20°C. By freezing at such temperatures, composite particles with desirable properties can be obtained. [Examples]

[0043] The present invention will be described in more detail below using examples and comparative examples, but the technical scope of the present invention is not limited thereto.

[0044] <Material> (Active ingredients) • Levodopa (Cayman Chemical Company) • Indomethacin (Wako Pure Chemical Industries, Ltd.) • Testosterone (Wako Pure Chemical Industries, Ltd.) • Zolmitriptan (Tokyo Chemical Industries Co., Ltd.) Ibuprofen (Wako Pure Chemical Industries, Ltd.)

[0045] (Water-insoluble polysaccharides) • Crystalline cellulose (Ceolus® PH-F20JP, Asahi Kasei Chemicals Corporation)

[0046] (Binder) • Hydroxypropylcellulose (HPC-H, Nippon Soda Co., Ltd.) • Hydroxypropyl methylcellulose (HPMC TC-5E, Shin-Etsu Chemical Co., Ltd.) • Pregelatinized starch (Asahi Kasei Chemicals Corporation)

[0047] (Additives) • Hydroxypropyl β-cyclodextrin (Wako Pure Chemical Industries, Ltd.) • Ascorbic acid (Wako Pure Chemical Industries, Ltd.) • Trehalose (Hayashibara Co., Ltd.) • Crystalline cellulose (Ceolus® PH-301, Asahi Kasei Chemicals Corporation) • Tricalcium phosphate (ICL Performance Products LP) • Sodium lauryl sulfate (Wako Pure Chemical Industries, Ltd.) n-dodecyl-β-D-maltoside (Wako Pure Chemical Industries, Ltd.)

[0048] <Manufacturing method> (Agitating granulation method) The active ingredient, water-insoluble polysaccharides, and additives were placed in the granulation tank of a high-speed mixer (FS-GS-5, Fukae Pawtech Co., Ltd.), and the powder in the granulation tank was stirred and mixed under stirring conditions of an agitator rotation speed of 400 rpm and a chopper rotation speed of 1500 rpm. Then, the binder was added dropwise to the granulation tank while stirring and mixing was carried out under the same stirring conditions for about 6 to 8 minutes. The mixture removed from the granulation tank was dried in a shelf-type dryer (NO607C, Iwakuro Seisakusho) at 50°C for more than 2 hours. The resulting dried mixture was passed through 32 μm and 180 μm sieves (JIS Z 8801, Iida Seisakusho), and the dried mixture remaining on the 32 μm sieve was used as the test formulation.

[0049] (Fluidized bed granulation method) The active ingredient, water-insoluble polysaccharides, and additives were placed in the chamber of a fluid bed granulator (FL-LABO, Freund Industrial Co., Ltd.), and the powders in the chamber were fluid-mixed with 70°C air. Subsequently, a binder dissolved in purified water was sprayed into the chamber at a spray rate of 3.6 g (as the amount of binder solution) / min for 10 minutes while fluid mixing was performed. The dried mixture removed from the chamber was passed through 32 μm and 180 μm sieves (JIS Z 8801, Iida Seisakusho), and the dried mixture remaining on the 32 μm sieve was used as the test formulation.

[0050] (lyophilization method) First, 200 mL of ultrapure water was placed in an aluminum tray, and the bottom of the tray was frozen at -20°C. Then, the active ingredient, water-insoluble polysaccharide, binder, and additives were mixed with phosphate buffer, placed in the aluminum tray, and pre-frozen at -20°C for 2 hours. The mixture was then placed in a shelf-type freeze-dryer (FreeZone Triad Freeze Dry System, Labconco Corp.) and freeze-dried under the following conditions: Primary drying was performed at -25°C for 30 hours under reduced pressure of 105 mTorr, followed by secondary drying at 30°C for 37 hours. The prepared freeze-dried product was ground in a glass mortar and pestle to obtain the test formulation.

[0051] (Mortar and pestle mixing method) Crystalline cellulose was added to a glass mortar and pestle, and the excess crystalline cellulose was removed. The active ingredient, water-insoluble polysaccharides, and additives were then added to this glass mortar and mixed with a glass pestle for 10 minutes to obtain the test formulation.

[0052] Details of each example and comparative example are shown in Table 1. [Table 1-1] [Table 1-2]

[0053] <Observation using an electron microscope> The test formulations were placed in an electron microscope (Miniscope TM3000, Hitachi High-Technologies Corporation) and observed after depressurization using a vacuum pump. Figures 1-6 show electron microscope images of the test formulations for Examples 7, 10, 15, and 16, and Comparative Examples 1 and 2, respectively. In the example formulations, unlike the comparative example formulations, it was observed that the various components had aggregated to form composite particles.

[0054] <Measurement of average primary particle diameter> The average primary particle size of the test formulation was measured using a laser diffraction-based particle size distribution analyzer (Mastersizer 2000, Malvern) connected to a dry automatic dispersion unit (Scirocco 2000, Malvern) under a dispersion pressure of 2 bar. The results of the average primary particle size calculated based on particle size distribution analysis using the volume conversion method are shown in Table 2. The average primary particle size of the test formulation in the example was significantly larger than that of the test formulation in the comparative example, indicating that the various components formed composite particles.

[0055] <Average content and content uniformity> (Levodopa-containing test formulation) The levodopa content was measured by reverse-phase chromatography. Specifically, a pH 2.8 acetonitrile / 0.05% trifluoroacetic acid (5 / 95) mobile phase was used, and the test formulation was diluted to an appropriate concentration in the mobile phase. The filtrate, filtered through a 0.45 μm syringe filter, was measured using high-performance liquid chromatography (LC-2010 or LC-2030C 3D plus, Shimadzu Corporation) to calculate the levodopa content in the test formulation. This procedure was performed three times for each test formulation, and the mean and relative standard deviation of the measured levodopa content relative to the theoretical levodopa content in the amount of test formulation used for measurement were calculated, and these were expressed as content (%) and content uniformity (%), respectively.

[0056] (Indomethacin-containing test formulation) The measurement was performed using reverse-phase chromatography. Specifically, methanol / 0.1% phosphoric acid (28 / 12) was used as the mobile phase, and the test formulation was diluted to the appropriate concentration in the mobile phase. The filtrate, filtered through a 0.45 μm syringe filter, was measured using high-performance liquid chromatography (LC-2030C 3D plus, Shimadzu Corporation) to calculate the indomethacin content in the test formulation. This procedure was performed three times for each test formulation, and the mean and relative standard deviation of the measured indomethacin content relative to the theoretical indomethacin content in the amount of test formulation used for measurement were calculated, and these were expressed as content (%) and content uniformity (%), respectively.

[0057] The results are shown in Table 2. These results indicate that the various components are uniformly contained in the composite particles of the example. [Table 2]

[0058] <Measurement of specific surface area> The test formulations were dried under reduced suction pressure at 100°C for 1 hour, and then the specific surface area was measured using the BET method with a specific surface area analyzer (Autosorb-iQ-MP, CANTAchrome) based on gas adsorption using nitrogen gas. The results are shown in Table 3. The specific surface area of ​​the test formulation in the example was significantly smaller than that of the test formulation in the comparative example, indicating that the various components formed composite particles.

Table 3

[0059] <Measurement of Hausner Ratio> Based on the powder physical property measurement method of the Japanese Pharmacopoeia general test method, the volume when a test preparation of known mass was placed in a graduated cylinder was measured, and the bulk density was calculated by dividing the mass by the volume. Based on the powder physical property measurement method of the Japanese Pharmacopoeia general test method, after a test preparation of known mass was placed in a graduated cylinder, the graduated cylinder was tapped, the volume at which no change in the volume of the test preparation was observed was measured, and the tapped density was calculated by dividing the mass by the volume. The Hausner ratio was calculated by dividing the bulk density by the tapped density. The results are shown in Table 4. The Hausner ratio of the test preparation of the example was significantly smaller than that of the test preparation of the comparative example, indicating that the fluidity of the test preparation of the example is excellent.

Table 4

[0060] <Measurement of Injection Rate> A 20 mg test preparation was filled into capsules (HPMC capsules, Size 2, Qualicaps). After setting it on a nebulizer (Forte Grow Medical Co., Ltd.), the weight of the nebulizer was measured. After pressing the pump of the nebulizer only once to inject the test preparation, the weight of the nebulizer was measured again, and the weight difference before and after injection was taken as the injection amount. The injection rate (injection amount as a percentage of the weight of the filled test preparation) was calculated. The results are shown in Table 5. It is shown that the test preparation of the example was injected at a significantly higher rate than the test preparation of the comparative example.

Table 5

Claims

1. The process includes the steps of adding an active ingredient, a water-insoluble polysaccharide, and optionally an additive to the granulation tank of a stirring granulator, stirring and mixing the powder in the granulation tank, and then adding purified water or purified water and one selected from HPMC, HPC, and pregelatinized starch as a binder dropwise into the granulation tank while stirring and mixing to form composite particles in which the active ingredient and the water-insoluble polysaccharide adhere to each other. The above water-insoluble polysaccharide is crystalline cellulose (Ceolus® PH-F20JP, Asahi Kasei Chemicals Corporation), The composite particles are aggregates formed by the adhesion of the active ingredient and the water-insoluble polysaccharide to each other, and have an average primary particle diameter of 20 to 350 μm under a dispersion pressure of 2 bar, and have a particle diameter larger than that of each component of the composite particles. A method for manufacturing a powder formulation for nasal administration.

2. The process includes the steps of: first, freezing ultrapure water in a tray; then, mixing the active ingredient, water-insoluble polysaccharide, and binder or additive with phosphate buffer; placing the mixture in a tray; pre-freezing the mixture; and freeze-drying the mixture in a freeze-dryer to form composite particles in which the active ingredient and the water-insoluble polysaccharide are attached to each other. The above water-insoluble polysaccharide is crystalline cellulose (Ceolus® PH-F20JP, Asahi Kasei Chemicals Corporation), The composite particles are aggregates formed by the adhesion of the active ingredient and the water-insoluble polysaccharide to each other, and have an average primary particle diameter of 20 to 350 μm under a dispersion pressure of 2 bar, and have a particle diameter larger than that of each component of the composite particles. A method for manufacturing a powder formulation for nasal administration.

3. The manufacturing method according to claim 1 or 2, further comprising mixing an absorption enhancer.

4. The production method according to claim 3, wherein the absorption enhancer is hydroxypropyl β-cyclodextrin, sodium lauryl sulfate, or n-dodecyl-β-D-maltoside.

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