Powder preparation for nasal administration and method for producing same
阅读说明：本技术 经鼻施予用粉末制剂及其制造方法 (Powder preparation for nasal administration and method for producing same ) 是由 治田俊志 园田阳 于 2020-05-01 设计创作，主要内容包括：本发明的课题为提供高效地发挥药效的经鼻施予用粉末制剂等。前述课题可通过含有有效成分与水不溶性多糖类附着于彼此而成的复合粒子的经鼻施予用粉末制剂来解决。(The present invention addresses the problem of providing a powder preparation for nasal administration which exhibits a drug effect efficiently. The above object can be achieved by a powder preparation for nasal administration containing composite particles in which an active ingredient and a water-insoluble polysaccharide are adhered to each other.)
1. A powder preparation for nasal administration, which comprises composite particles having an active ingredient and a water-insoluble polysaccharide adhered to each other.
2. The powder formulation according to claim 1, wherein the composite particles have an average primary particle diameter of 20 to 350 μm.
3. The powder formulation according to claim 1 or 2, wherein the specific surface area of the composite particles is 0.20 to 2.3m2/g。
4. The powder formulation as claimed in any one of claims 1 to 3, wherein the composite particles have a Hausner ratio of 1.8 or less.
5. The powder preparation according to any one of claims 1 to 4, wherein the water-insoluble polysaccharide comprises crystalline cellulose.
6. The powder formulation of any one of claims 1 to 5, wherein the composite particles further comprise a binder.
7. The powder formulation according to any one of claims 1 to 6, wherein the composite particles further contain an absorption enhancer.
8. The powder formulation of claim 7, wherein the absorption enhancer is hydroxypropyl beta cyclodextrin, sodium lauryl sulfate, or n-dodecyl-beta-D-maltoside.
9. A method for producing a powder preparation for nasal administration, which comprises the steps of:
a mixture containing an active ingredient and a water-insoluble polysaccharide is granulated by stirring to form composite particles in which the active ingredient and the water-insoluble polysaccharide are adhered to each other.
10. A method for producing a powder preparation for nasal administration, which comprises the steps of:
a mixture containing an active ingredient and a water-insoluble polysaccharide is granulated in a fluidized bed to form composite particles in which the active ingredient and the water-insoluble polysaccharide are adhered to each other.
11. A method for producing a powder preparation for nasal administration, which comprises the steps of:
a mixture containing an active ingredient and a water-insoluble polysaccharide is freeze-dried to form composite particles in which the active ingredient and the water-insoluble polysaccharide are attached to each other.
12. The production method according to any one of claims 9 to 11, wherein the water-insoluble polysaccharide comprises crystalline cellulose.
13. The production method according to any one of claims 9 to 12, wherein the mixture further contains a binder.
14. The production process according to any one of claims 9 to 13, wherein the mixture further contains an absorption accelerator.
15. The method according to claim 14, wherein the absorption enhancer is hydroxypropyl β cyclodextrin, sodium lauryl sulfate, or n-dodecyl- β -D-maltoside.
Technical Field
The present invention relates to a powder preparation for nasal administration and a method for producing the same.
Background
Conventionally, nasal administration is mainly intended for topical treatment such as rhinitis treatment. However, recently, nasal administration has been attempted for the purpose of preventing or treating systemic diseases, central nervous system diseases, infectious diseases, and the like, and various preparations for nasal administration have been reported. For example, patent document 1 discloses "a powdery composition for nasal administration containing a non-peptide/proteinaceous drug and crystalline cellulose aggregates as carriers thereof".
Documents of the prior art
Patent document
Patent document 1: international publication No. 2006/016530
Disclosure of Invention
Problems to be solved by the invention
Patent document 1 discloses a method of mixing a drug and crystalline cellulose using a mortar as a method of producing a powdery nasal composition. However, this production method has the following problems: when the obtained composition is ejected from the administration device, the drug and the crystalline cellulose are separated, and the mucoadhesive effect of the crystalline cellulose may not be sufficiently utilized, and as a result, the expected drug effect may not be exhibited.
The present invention addresses the problem of providing a powder preparation for nasal administration that exhibits drug efficacy efficiently, and a method for producing the same.
Means for solving the problems
The present inventors have found that composite particles exhibiting an effective drug effect efficiently can be obtained by subjecting a mixture containing an active ingredient and a water-insoluble polysaccharide to agitation granulation, fluidized bed granulation, or freeze drying.
The present invention includes the following embodiments.
[1]
A powder preparation for nasal administration, which comprises composite particles having an active ingredient and a water-insoluble polysaccharide adhered to each other.
[2]
The powder preparation according to [1], wherein the composite particles have an average primary particle diameter of 20 to 350 μm.
[3]
Such as [1]]Or [ 2]]The powder preparation, wherein the specific surface area of the composite particles is 0.20 to 2.3m2/g。
[4]
The powder preparation according to any one of [1] to [3], wherein the composite particles have a Hausner ratio of 1.8 or less.
[5]
The powder preparation according to any one of [1] to [4], wherein the water-insoluble polysaccharide comprises crystalline cellulose.
[6]
The powder preparation according to any one of [1] to [5], wherein the composite particles further contain a binder.
[7]
The powder preparation according to any one of [1] to [6], wherein the composite particle further contains an absorption enhancer.
[8]
The powder preparation according to [7], wherein the absorption enhancer is hydroxypropyl β cyclodextrin, sodium lauryl sulfate or n-dodecyl- β -D-maltoside.
[9]
A method for producing a powder preparation for nasal administration, which comprises the steps of:
a mixture containing an active ingredient and a water-insoluble polysaccharide is granulated by stirring to form composite particles in which the active ingredient and the water-insoluble polysaccharide are adhered to each other.
[10]
A method for producing a powder preparation for nasal administration, which comprises the steps of:
a mixture containing an active ingredient and a water-insoluble polysaccharide is granulated in a fluidized bed to form composite particles in which the active ingredient and the water-insoluble polysaccharide are adhered to each other.
[11]
A method for producing a powder preparation for nasal administration, which comprises the steps of:
a mixture containing an active ingredient and a water-insoluble polysaccharide is freeze-dried to form composite particles in which the active ingredient and the water-insoluble polysaccharide are attached to each other.
[12]
The production method according to any one of [9] to [11], wherein the water-insoluble polysaccharide comprises 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 accelerator.
[15]
The production method according to [14], wherein the absorption enhancer is hydroxypropyl β cyclodextrin, sodium lauryl sulfate or n-dodecyl- β -D-maltoside.
Effects of the invention
The present invention provides a powder preparation for nasal administration which exhibits a drug effect efficiently, and a method for producing the same.
Drawings
FIG. 1 shows an electron micrograph of the test formulation of example 7.
FIG. 2 shows an electron micrograph of the test formulation of example 10.
FIG. 3 shows an electron micrograph of the test formulation of example 15.
FIG. 4 shows an electron micrograph of the test formulation of example 16.
FIG. 5 shows an electron micrograph of the test preparation of comparative example 1.
FIG. 6 shows an electron micrograph of the test preparation of comparative example 2.
Detailed Description
< powder preparation >
One embodiment of the present invention relates to a powder preparation for nasal administration containing composite particles in which an active ingredient and a water-insoluble polysaccharide are attached to each other.
The "composite particles" in the present specification are particles (aggregates) in which the active ingredient and the water-insoluble polysaccharide are attached to each other. Therefore, "composite particles" in the present specification can be clearly distinguished from a simple mixture of a drug and crystalline cellulose, as disclosed in patent document 1, for example.
In the present embodiment, the active ingredient and the water-insoluble polysaccharide form composite particles, and therefore, when the powder preparation is administered into the nasal cavity, the active ingredient and the water-insoluble polysaccharide are integrated and adhere to the nasal mucosa. Since the water-insoluble polysaccharides have a mucosa-adhering effect, the active ingredient adheres to the nasal mucosa by the effect, and the drug effect of the active ingredient can be exhibited efficiently.
When only the active ingredient and the water-insoluble polysaccharide are simply mixed, the active ingredients may not be uniformly mixed, and the amount of the active ingredient may vary between powder preparations. On the other hand, in the present embodiment, since the active ingredient and the water-insoluble polysaccharide form composite particles, such a difference can be suppressed.
In the present embodiment, the active ingredient and the water-insoluble polysaccharide form composite particles, and therefore the flowability of the powder preparation is improved. Thereby, the powder preparation can be uniformly and easily filled into the container, and the ejection rate of the powder preparation from the administration device is improved.
When a powder preparation containing particles having a small particle size is administered into the nasal cavity, the powder preparation may pass through the nasal cavity and reach the lung. On the other hand, in the present embodiment, since the effective component and the water-insoluble polysaccharide form composite particles and the particle diameter increases, passage through the nasal cavity can be suppressed.
The composite particles of the present embodiment are formed by adhering the constituent components of the composite particles to each other, and therefore have a larger particle diameter than each constituent component.
The lower limit of the average primary particle diameter of the composite particles of the present embodiment is, for example, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, etc., and the upper limit is, for example, 350 μm, 300 μm, 250 μm, 200 μm, 150 μm, 100 μm, etc. The specific range can be defined by appropriately combining the above lower limit and the above upper limit. For example, the particle size can be set to 20 to 350 μm, 25 to 300 μm, 30 to 250 μm, 35 to 200 μm, 40 to 150 μm. The average primary particle size was measured by the method described in the following examples.
Since the average primary particle diameter is measured under a dispersion pressure of 2bar, if the components of the composite particles are not adhered to each other, the composite particles are decomposed into the respective components by the dispersion pressure. For example, in the case of a simple mixture of a drug and crystalline cellulose as disclosed in patent document 1, even if some of the constituent components aggregate to form large particles, the particles are decomposed under the measurement conditions of the average primary particle diameter, and therefore, the average primary particle diameter is greatly different from that of the composite particles of the present embodiment.
The lower limit of the specific surface area of the composite particle of the present embodiment is, for example, 0.10m2/g、0.15m2/g、0.20m2/g、0.25m2/g、0.30m2The upper limit is, for example, 2.3m2/g、2.0m2/g、1.8m2/g、1.6m2/g、1.4m2And/g, etc. The specific range can be defined by appropriately combining the above lower limit and the above upper limit. For example, it can be set to 0.10 to 2.3m2/g、0.15～2.0m2/g、0.20～1.8m2/g、0.25～1.6m2/g、0.30～1.4m2(ii) a range of/g. The specific surface area was measured by the method described in the following examples.
Examples of the upper limit of the Hausner ratio of the composite particles of the present embodiment include 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, and 1.2, and the lower limit is not particularly limited. The Hausner ratio was measured according to the method described in the following examples.
The seventeenth japanese pharmacopoeia describes the following in relation to the Hausner ratio and flowability.
Hausner ratio: degree of fluidity
1.00-1.11: is extremely good
1.12-1.18: good effect
1.19-1.25: slightly good
1.26-1.34: general purpose
1.35-1.45: slight defect
1.46-1.59: failure of the product
More than 1.60: is extremely poor
Examples of the diseases diagnosed, prevented, or treated by the powder preparation of the present embodiment include cerebral hemorrhage, cerebral infarction, central nervous system infection, brain tumor, 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, mood disorder (dynamic disorder), adaptation disorder, social anxiety disorder, panic disorder, obsessive compulsive disorder, autism spectrum disorder, attention deficit/hyperactivity disorder, sleep disorder, insomnia, traumatic brain injury, pain, migraine, headache, fever, inflammation, rheumatism, epilepsy, cerebral circulatory metabolism disorder, muscle relaxation, autonomic neuropathy, dizziness, hypertension, cerebral infarction, cerebral hemorrhage, cerebral infarction, cerebral hemorrhage, and the like, Angina pectoris, arrhythmia, allergy, bronchiectasis and asthma, other respiratory diseases (cough relieving and phlegm removing), peptic ulcer, other digestive diseases (diarrhea relieving, intestinal function regulating, stomach strengthening, digestion promoting, and constipation relieving), gout, hyperuricemia, dyslipidemia, diabetes, hormone-related diseases (diseases related to pituitary hormone, adrenocortical hormone, sex hormone, and other hormones), uterine-related diseases, osteoporosis, bone metabolism diseases, vitamin deficiency, nutritional deficiency, poisoning (including detoxification), cancer, hyperimmunity, otorhinolaryngological diseases, oral cavity-related diseases, urinary and reproductive organ diseases, hemorrhoid, skin diseases, hematopoietic and blood coagulation-related diseases, narcotic dependence, anesthesia, and lifestyle-related diseases.
The active ingredient of the present embodiment may be used alone in 1 kind, or a plurality of active ingredients may be used in combination. Examples of the active ingredient include low-molecular compounds, intermediate-molecular 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.
More specific examples of the active ingredient include tissue plasminogen activator, edaravone, ozagrel sodium, selective thrombin inhibitor, vidarabine, acyclovir, ganciclovir, valganciclovir, zidovudine, didanosine, zalcitabine, nevirapine, delavirdine, saquinavir, ritonavir, indinavir, nelfinavir, vancomycin, ceftazidime, ampicillin, panipenem-betamipron, dexamethasone, cisplatin, carboplatin, vincristine, cyclophosphamide, ifosfamide, temozolomide, etoposide, L-dopa, carbidopa, benserazide, entacapone, epinephrine, amphetamine, apomorphine, adamantane, cabergoline, zonisamide, droxidopa, biperiden, phenobarbital, phenytoin, paminone, ethosuximide, zonisamide, and indoxamine, Clonazepam, midazolam, remidazolam, flumazenil, sodium valproate, carbamazepine, gabapentin, topiramate, cannabinoid, donepezil, rivastigmine, galantamine, memantine, dimethyl fumarate, natalizumab, haloperidol, spiroperidine, fluphenazine, chlorpromazine, risperidone, blonanserin, quetiapine, olanzapine, aripiprazole, epipiprazole, triazolam, zopiclone, zolpidem, etizoledron, chlordiazepam, bromoisoylurea, chloral hydrate, pentobarbital, limazapine, oxytocin, vasopressin, desmopressin, granisetron, ondansetron, tropisetron, palonosetron, dolasetron, amistropheron, granisetron, triadimefon, melanine, levetiracetam, cloracetam, clonazepam, diazepam, mepiquat, a, mepiquat chloride, mepiquat chloride, mepiquat chloride, mepiquat chloride, an, mepiquat, Cefaclor, enoxacin, acyclovir, zidovudine, didanosine, nevirapine, indinavir, dantrolene, digoxin, diphenoxylate, biperiden, dextromethorphan, naloxone, betahistine, naphazoline, diltiazem, tranilast, loperamide, beclomethasone, chlorpheniramine, sildenafil, tadalafil, vardenafil, cyanocobalamin, finasteride, epinephrine, oxybutynin, propiverine, solifenacin, tolterodine, imidafenacin, frothidine, mirabegron, tamsulosin, silodosin, 5-FU, telaprevir, ribavirin, cimetivir (simevir), guanfacia, methylphenidate, tomomumab, sumatriptan, zolmitriptan, dihydroergotamine, ritriptan, ritatriptan, nafarex, temozolone, tamsulindac, rimonavir, ritin, temozolomide, ritonavir, rituximab, temeprinozide, temab, temeprinozide, temb, temozin, temozolol, and other, temozolol, and other, etc, Riemanlizumab, fomivirsen, propofol, norcinolone, cyclosporine, tacrolimus, fluorodeoxyglucose, fluorothymidine, iopamidol (iopamidol), thallium, manganese, technetium, insulin, growth hormone releasing peptide, ghrelin, glucagon, calcitonin, interferon, erythropoietin, interleukin, PTH (1-84), PTH (1-34), PTH-related peptide, GLP-1, vasopressin, leuprolide, granulocyte colony stimulating factor, prolactin, pituitary gonadotropin, placental gonadotropin Snbl2600, follicle stimulating hormone, luteinizing hormone, leptin, Nerve Growth Factor (NGF), Stem Cell Growth Factor (SCGF), Keratinocyte Growth Factor (KGF), oligoheparin, tacrolimus, allergen extract powder, human antibodies (e.g., adalimumab, and/or amanitol), and pharmaceutically acceptable salts thereof, Panitumumab, golimumab, canakinumab, ofatumumab, denomumab, ipilimumab (ipilimumab), belimumab, resilinumab (rapibakumab), ramucirumab, nivolumab (nivolumab), secukinumab, eloitumumab (evolumab), aliskirumab, nixituzumab, nivolumab, pambolizumab (pembrolizumab), etc., chimeric antibody (e.g., abciximab)), humanized antibody (e.g., bevacizumab), mouse antibody (e.g., bornautuzumab), etc.
More specific examples of the active ingredient include vaccine antigens against the following viruses or pathogens.
Adenovirus, AIDS virus, baculovirus, HCMV (human cytomegalovirus), hemorrhagic fever virus, hepatitis virus, B herpes virus, immunodeficiency virus, human T cell leukemia virus, infantile gastroenteritis virus, infectious hematopoietic necrosis virus, infectious pancreatic necrosis virus, influenza virus, Japanese encephalitis virus, leukemia virus, mumps virus, orthomyxovirus, pneumonia virus, polio virus, multi-component DNA virus, rotavirus, SARS virus, vaccinia virus, RS virus, Shigella species, Salmonella Typhi (Salmonella enterica serovar Typhi), Mycobacterium tuberculosis, tetanus, diphtheria, meningococcus (meggonnococcus), Bordetella pertussis, Streptococcus pneumoniae, anthrax, botulinum, Clostridium difficile, Clostridium perfringens, enterococcus faecalis, enterococcus faecium, Haemophilus influenzae, helicobacter pylori, mycobacterium leprae, neisseria gonorrhoeae, meningococcus, salmonella typhi, staphylococcus aureus, treponema pallidum, vibrio cholerae, Plasmodium falciparum (Plasmodium falciparum).
The term "water-insoluble polysaccharide" as used herein means a polysaccharide having 0.001g or less dissolved in 1000ml of water (20 ℃ C.). The water-insoluble polysaccharide may be used alone in 1 kind, or may be used in combination of a plurality of kinds.
Examples of the water-insoluble polysaccharide include cellulose, hemicellulose, chitosan, chitin, and the like, and cellulose or hemicellulose is preferable, cellulose is more preferable, and crystalline cellulose is particularly preferable. By using crystalline cellulose, the flowability of the powder formulation can be further improved. Examples of commercially available crystalline cellulose include the pH series of CEOLUS (registered trademark) and the pH series of AVICEL (registered trademark), and more specifically, CEOLUS (registered trademark) pH-F20JP, AVICEL (registered trademark) pH-105, and CEOLUS (registered trademark) pH-UF 702.
The composite particle of the present embodiment may further contain a binder. By containing the binder in the composite particles, the adhesion strength between the active ingredient and the water-insoluble polysaccharide can be improved, and the primary particle diameter and disintegration property of the composite particles can be adjusted. The binder may be used alone in 1 kind, or a plurality of binders may be used in combination.
Examples of the binder include purified water, Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), methylcellulose, carboxymethylcellulose, gelatinized starch, partially gelatinized starch, and salts thereof, and preferably hydroxypropylmethylcellulose or gelatinized starch.
The composite particle of the present embodiment may further contain an additive. Examples of the additives include absorption promoters, solubilizing and solubilizing agents, stabilizers, fluidizing agents, disintegrating agents, masking agents, flavoring agents, preservatives, and immune activators.
Examples of the absorption enhancer include surfactants, chelating agents, cyclodextrins, and permeant peptides. Examples of the surfactant 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 zwitterionic surfactants such as dipalmitoylphosphatidylcholine and sodium taurocholate. Examples of the chelating agent include EDTA, citrate, pyrophosphate, and the like. Examples of the cyclodextrin include β -cyclodextrin, 2-hydroxypropyl- β -cyclodextrin, and methyl- β -cyclodextrin. Examples of the membrane-permeable peptide include penetratin (penetratin), HIV-1Tat, HIV-1Rev, arginine octamer (arginine octamer), arginine dodecamer (arginine dodecamer), pVEC, Ems, RRL helix, and PRL 4.
Examples of the solubilizing and solubilizing agent include cyclodextrin, capric acid, lecithin, dipalmitoyl glycerophosphatidylcholine, dodecyl maltoside, dodecyl phosphorylcholine, and polyethylene glycol.
Examples of the stabilizer include disaccharides (e.g., sucrose, lactulose, lactose, maltose, trehalose, cellobiose, xylobiose, maltulose, galactosucrose, and derivatives thereof), vitamins (e.g., ascorbic acid and tocopherol), amino acids (e.g., glycine), citrate, pyrophosphate, and the like.
Examples of the fluidizing agent include crystalline cellulose and tricalcium phosphate.
Examples of the disintegrant include cellulose, starch, and crospovidone.
Examples of the masking agent include mannitol.
Examples of the taste-improving agent include aspartame and menthol.
Examples of the preservative include thimerosal and the like.
Examples of the immune activator include cyclodextrin, aluminum salt, and CpG oligonucleotide.
< production of powdery preparation >
One embodiment of the present invention relates to a method for producing a powder preparation for nasal administration, which includes the steps of: a mixture containing an active ingredient and a water-insoluble polysaccharide is subjected to stirring granulation, fluidized bed granulation or freeze drying to form composite particles in which the active ingredient and the water-insoluble polysaccharide are adhered to each other. Hereinafter, the method by stirring granulation, the method by fluidized bed granulation, and the method by freeze-drying are referred to as "stirring granulation method", "fluidized bed granulation method", and "freeze-drying method", respectively. The constituent components of the composite particles are the same as those described in the item < powder preparation >.
The amount of the binder to be added in the stirring granulation method is preferably 5 to 150mL, more preferably 15 to 100mL, and still more preferably 20 to 75mL, per 100g of the total weight of the powder in the granulation tank. By stirring and granulating in such an amount of the binder added, composite particles having desirable properties can be obtained.
The spraying rate of the binder in the fluidized bed granulation method is preferably 0.001 g/min to 0.4 g/min, more preferably 0.005 g/min to 0.3 g/min, and still more preferably 0.01 g/min to 0.25 g/min, based on 50g of the total weight of the powder in the granulation tank. The total amount of the binder to be added in the fluidized bed granulation method is preferably 0.01g to 4.0g, more preferably 0.05g to 3.0g, and still more preferably 0.1g to 2.5g, based on 50g of the total weight of the powder in the granulation tank. By performing fluidized bed granulation under such conditions, composite particles having desirable properties can be obtained.
The freezing temperature in the freeze-drying method is preferably from-100 ℃ to-10 ℃, more preferably from-80 ℃ to-15 ℃, and still more preferably from-60 ℃ to-20 ℃. By freezing at such a temperature, composite particles having desirable properties can be obtained.
Examples
The present invention will be described in more detail below with reference to examples and comparative examples, but the technical scope of the present invention is not limited thereto.
< Material >
(active ingredient)
L-dopa (Cayman Chemical Company)
Indometacin (Heguang pure drug industry Co., Ltd.)
Testosterone (Heguang pure chemical industry Co., Ltd.)
Zolmitriptan (Tokyo chemical industry Co., Ltd.)
Ibuprofen (Heguang pure drug industry Co., Ltd.)
(Water-insoluble polysaccharides)
Crystalline cellulose (Ceolus (registered trademark) PH-F20JP, Asahi Kasei Chemicals Corporation)
(Binder)
Hydroxypropyl cellulose (HPC-H, Nippon Caoda corporation)
Hydroxypropyl methylcellulose (HPMC TC-5E, shin-Etsu chemical Co., Ltd.)
Alphanized starch (Asahi Kasei Chemicals Corporation)
(additives)
Hydroxypropyl beta cyclodextrin (Heguang pure drug industries, Ltd.)
Ascorbic acid (Heguang pure chemical industry Co., Ltd.)
Trehalose (Kyowa forest land)
Crystalline cellulose (Ceolus (registered trademark) PH-301, Asahi Kasei Chemicals Corporation)
Tricalcium phosphate (ICL Performance Products LP)
Sodium dodecyl sulfate (Heguang pure chemical industry Co., Ltd.)
N-dodecyl-. beta. -D-maltoside (Heguang Chunyi Kaisha)
< manufacturing method >
(stirring granulation method)
The active ingredient, the water-insoluble polysaccharide and the additive were charged into a granulation tank of a high-speed mixer FS-GS-5 (Fukae Powtec Kk), and the powder in the granulation tank was stirred and mixed under stirring conditions in which the rotation speed of a stirrer (agitator) was 400rpm and the rotation speed of a chopper (chopper) was 1500 rpm. Then, the binder is dropped into the granulation tank, and the mixture is stirred and mixed for about 6 to 8 minutes under the same stirring condition. The mixture taken out of the granulation tank was dried in a shelf dryer (NO607C, manufactured by rock black) at 50 ℃ for 2 hours or more. The resulting dry mixture was passed through 32 μm and 180 μm sieves (JIS Z8801, manufactured by Hotan Co., Ltd.), and the dry mixture remaining on the 32 μm sieves was used as a test preparation.
(fluidized bed granulation method)
The active ingredient, water-insoluble polysaccharides, and additives were charged into a chamber of a fluidized bed granulator (FL-LABO, Freund Corporation), and the powder in the chamber was fluidized and mixed in air at 70 ℃. Then, the binder dissolved in purified water was fluidized and mixed while spraying the binder into the chamber at a spray rate of 3.6g (as an amount of the binder solution) per minute for 10 minutes. The dried mixture taken out of the chamber was passed through sieves of 32 μm and 180 μm (JIS Z8801, manufactured by Hotan Co., Ltd.), and the dried mixture remaining on the sieves of 32 μm was used as a test preparation.
(Freeze-drying method)
200mL of ultrapure water was put in an aluminum pan in advance, the bottom of the aluminum pan was frozen at-20 ℃, the active ingredient, water-insoluble polysaccharides, a binder, and additives were mixed with a phosphate buffer, the mixture was put in an aluminum pan, the mixture was frozen at-20 ℃ for 2 hours, and the frozen product was placed in a shelf freezer dryer (Freezone Triad Freeze Dry System, Labconco Corp.) under the following conditions. As the freeze-drying conditions, primary drying was carried out at-25 ℃ for 30 hours under a reduced pressure of 105mTorr, and secondary drying was carried out at 30 ℃ for 37 hours. The freeze-dried product thus obtained was pulverized in a glass mortar to prepare a test preparation.
(mortar mixing method)
Crystalline cellulose was added to the glass mortar for caulking (Japanese: kogaku し), and excess crystalline cellulose was removed. The active ingredient, water-insoluble polysaccharide, and additive were put into the glass mortar, and mixed with a glass pestle for 10 minutes to prepare a test preparation.
The detailed information of each example and comparative example is shown in table 1.
[ tables 1-1]
TABLE 1 compositions of the test preparations and methods of preparation
[ tables 1-2]
TABLE 1 compositions of the test preparations and methods of preparation
HPMC: hydroxypropyl methylcellulose
HPC: hydroxypropyl cellulose
And (3) Ca phosphate: tricalcium phosphate
< Observation with an Electron microscope >
The test preparations were placed in an electron microscope (Miniscope TM3000, Hitachi High-Technologies Corporation), and observed after reduced pressure was applied using a vacuum pump. FIGS. 1 to 6 show electron micrographs of the test formulations of examples 7, 10, 15 and 16 and comparative examples 1 and 2, respectively. In the test preparations of examples, different from the test preparations of comparative examples, a state was observed in which various components aggregated to form composite particles.
< measurement of average Primary particle diameter >
The dry autodispersing unit (Scirocco 2000, Malvern) was connected to a particle size distribution measuring device (Mastersizer 2000, Malvern) based on laser diffraction, and the average primary particle size of the test formulation was measured at a dispersing pressure of 2 bar. The average primary particle size was calculated based on particle size distribution analysis using a volume conversion algorithm, and the results are shown in table 2. The average primary particle size of the test formulations of the examples was superior to that of the test formulations of the comparative examples, indicating that the various components formed composite particles.
< average content and content uniformity >
(test preparation containing L-dopa)
The measurement was carried out by reverse phase chromatography. Specifically, the test preparation was diluted to an appropriate concentration using mobile phase of ph2.8 acetonitrile/0.05% trifluoroacetic acid (5/95), filtered using a 0.45 μm syringe filter, and the filtrate was measured using a high performance liquid chromatograph (LC-2010 or LC-2030C 3D plus, shimadzu corporation) to calculate the L-dopa content in the test preparation. This operation was performed 3 times for 1 test preparation, and the average value and the relative standard deviation of the measured L-dopa content with respect to the theoretical L-dopa content contained in the test preparation amount used for the measurement were calculated as the content (%) and the content uniformity (%).
(test preparation containing Indometacin)
The measurement was carried out by reverse phase chromatography. Specifically, methanol/0.1% phosphoric acid (28/12) was used as a mobile phase, the mobile phase was diluted to an appropriate concentration with respect to the test preparation, the filtrate was filtered through a 0.45 μm syringe filter, and the filtrate was measured by a high performance liquid chromatograph (LC-2030C 3D plus, shimadzu corporation) to calculate the indomethacin content in the test preparation. This operation was performed 3 times for 1 test preparation, and the average value and the relative standard deviation of the measured indomethacin content with respect to the theoretical indomethacin content contained in the test preparation amount used for the measurement were calculated as the content (%) and the content uniformity (%).
The results are shown in Table 2. The results show that the composite particles of the examples uniformly contain various components.
[ Table 2]
TABLE 2 average particle size, content and content uniformity of the test formulations
Average particle diameter (μm)
Content (%)
Content uniformity (%)
Example 1
42.9
100.8
2.6
Example 2
36.0
98.2
5.6
Example 3
42.6
101.6
0.2
Example 4
40.6
102.2
5.2
Example 5
55.6
-
-
Example 6
31.6
90.4
3.5
Example 7
37.7
102.6
5.2
Example 8
31.6
107.1
1.8
Example 9
32.8
96.9
1.5
Example 10
34.2
103.3
3.2
Example 11
124.1
97.8
3.2
Example 12
120.6
96.3
3.3
Example 13
35.4
-
-
Example 14
37.1
-
-
Example 15
45.6
104.6
2.7
Example 16
35.9
92.6
1.0
Example 17
41.6
83.9
0.7
Example 18
37.6
-
-
Example 19
43.2
-
-
Example 20
34.8
96.3
2.0
Practice ofExample 21
35.8
98.7
0.2
Example 22
34.7
110.2
0.7
Example 23
34.1
99.2
0.7
Comparative example 1
16.2
103.3
1.9
Comparative example 2
17.6
102.4
1.1
< measurement of specific surface area >
The test preparations were dried at 100 ℃ for 1 hour under reduced pressure with suction, and then measured for surface area by BET method using a specific surface area meter (Autosorb-iQ-MP, Quantachrome) based on a gas adsorption method using nitrogen gas. The results are shown in Table 3. The specific surface area of the test formulations of the examples was significantly smaller than the test formulations of the comparative examples, indicating that the various ingredients formed composite particles.
[ Table 3]
TABLE 3 specific surface area of the test formulations
Specific surface area (m)2/g)
Example 1
0.453
Example 2
0.521
Example 3
0.582
Example 4
0，302
Example 5
0.483
Example 6
1.218
Example 7
0.753
Example 8
1.069
Example 9
0.668
Example 10
0.550
Example 11
0.213
Example 12
0.335
Example 13
0.956
Example 14
0.809
Example 15
0.772
Example 16
1.221
Example 17
1.019
Example 18
0.971
Example 19
0.718
Example 20
0.674
Example 21
1.368
Example 22
0.946
Example 23
0.853
Comparative example 1
2.391
Comparative example 2
2.388
< measurement of Hausner ratio >
The bulk density was calculated by measuring the volume of a test preparation of known mass when it was loaded into a measuring cylinder and dividing the mass by the volume, based on the method for measuring the physical properties of powder in the general test method of japanese pharmacopoeia.
In the method for measuring the physical properties of a powder according to the general test method of japanese pharmacopoeia, a test preparation having a known mass is put into a measuring cylinder, the measuring cylinder is tapped to measure the volume at which the change in volume of the test preparation is no longer observed, and the tap density is calculated by dividing the mass by the volume.
The Hausner ratio is calculated by dividing the bulk density by the tap density. The results are shown in Table 4. The Hausner ratio of the test formulations of the examples was significantly less than that of the comparative examples, indicating that the flowability of the test formulations of the examples was excellent.
[ Table 4]
TABLE 4 Hausner ratio of the test formulations
Hausner ratio
Example 1
1.44
Example 2
1.40
Example 3
1.31
Example 4
1.38
Example 5
1.35
Example 6
1.65
Example 7
1.35
Example 8
1.57
Example 9
1.48
Example 10
1.33
Example 11
1.08
Example 12
1.14
Example 13
1.33
Example 14
1.26
Example 15
1.41
Example 16
1.65
Example 17
1.25
Example 18
1.59
Example 19
1.62
Example 20
1.79
Example 21
1.56
Example 22
1.39
Example 23
1.39
Comparative example 1
1.89
Comparative example 2
1.86
< measurement of injection Rate >
The weight of the mini-jets was determined after filling 20mg of the test formulation into capsules (HPMC capsules, Size2, Qualicas) and placing them in mini-jets (Publizer, Japan: パブライザ I) (FORTE GROW MEDICAL co., ltd.). The pump of the small injector was pushed only 1 time, the test agent was injected, and then the weight of the small injector was measured again, and the difference in weight between before and after injection was defined as the injection amount. The ejection amount (ejection rate) was calculated with the weight of the filled test formulation as 100%. The results are shown in Table 5. It is shown that the test formulations of the examples were sprayed at a significantly higher ratio than the test formulations of the comparative examples.
[ Table 5]
TABLE 5 injection rate from injector for test formulations
Injection rate from injector (%)
Example 1
68.2
Example 2
59.0
Example 3
76.9
Example 4
91.5
Example 5
70.1
Example 6
57.3
Example 7
68.0
Example 8
52.7
Example 9
78.0
Example 10
70.6
Example 11
66.9
Example 12
69.5
Example 13
60.2
Example 14
72.9
Example 15
69.0
Example 16
64.7
Example 17
57.8
Example 18
72.9
Example 19
76.6
Example 20
64.0
Example 21
57.6
Example 22
82.1
Example 23
79.9
Comparative example 1
12.5
Comparative example 2
17.1
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