CN1370523A - Salmon calcitonin snuff and its prepn - Google Patents
Salmon calcitonin snuff and its prepn Download PDFInfo
- Publication number
- CN1370523A CN1370523A CN 01105431 CN01105431A CN1370523A CN 1370523 A CN1370523 A CN 1370523A CN 01105431 CN01105431 CN 01105431 CN 01105431 A CN01105431 A CN 01105431A CN 1370523 A CN1370523 A CN 1370523A
- Authority
- CN
- China
- Prior art keywords
- salmon calcitonin
- powder
- snuff
- agglomerate
- pastille
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 title claims abstract description 71
- 108010068072 salmon calcitonin Proteins 0.000 title claims abstract description 65
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 title claims abstract description 63
- 239000000843 powder Substances 0.000 claims abstract description 51
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 9
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 9
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 9
- 239000003085 diluting agent Substances 0.000 claims abstract description 7
- 239000004094 surface-active agent Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- 229940098458 powder spray Drugs 0.000 claims description 33
- 238000002360 preparation method Methods 0.000 claims description 24
- 239000000227 bioadhesive Substances 0.000 claims description 14
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 13
- 239000008101 lactose Substances 0.000 claims description 13
- 239000008187 granular material Substances 0.000 claims description 12
- 235000010603 pastilles Nutrition 0.000 claims description 12
- 229920002472 Starch Polymers 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 11
- 239000008107 starch Substances 0.000 claims description 11
- 235000019698 starch Nutrition 0.000 claims description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 10
- 229930195725 Mannitol Natural products 0.000 claims description 10
- 239000000594 mannitol Substances 0.000 claims description 10
- 235000010355 mannitol Nutrition 0.000 claims description 10
- 238000010521 absorption reaction Methods 0.000 claims description 9
- -1 hydroxypropyl Chemical group 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 102000055006 Calcitonin Human genes 0.000 claims description 8
- 108060001064 Calcitonin Proteins 0.000 claims description 8
- 229920000858 Cyclodextrin Polymers 0.000 claims description 8
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 8
- 229960004015 calcitonin Drugs 0.000 claims description 8
- 229960000502 poloxamer Drugs 0.000 claims description 8
- 229920001983 poloxamer Polymers 0.000 claims description 8
- 229920000881 Modified starch Polymers 0.000 claims description 7
- 238000001694 spray drying Methods 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 239000000969 carrier Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000003623 enhancer Substances 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 6
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 6
- 239000007779 soft material Substances 0.000 claims description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical group CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 235000010489 acacia gum Nutrition 0.000 claims description 2
- 239000001785 acacia senegal l. willd gum Substances 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 238000000643 oven drying Methods 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 229950008882 polysorbate Drugs 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- VILMUCRZVVVJCA-UHFFFAOYSA-M sodium glycolate Chemical compound [Na+].OCC([O-])=O VILMUCRZVVVJCA-UHFFFAOYSA-M 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 25
- 239000007787 solid Substances 0.000 abstract description 2
- 239000003364 biologic glue Substances 0.000 abstract 3
- 229940124532 absorption promoter Drugs 0.000 abstract 1
- 210000001331 nose Anatomy 0.000 description 24
- 210000003928 nasal cavity Anatomy 0.000 description 21
- 241001465754 Metazoa Species 0.000 description 18
- 239000011575 calcium Substances 0.000 description 18
- 241000283973 Oryctolagus cuniculus Species 0.000 description 17
- 230000000694 effects Effects 0.000 description 16
- 239000007921 spray Substances 0.000 description 13
- 210000002850 nasal mucosa Anatomy 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 229940079593 drug Drugs 0.000 description 8
- 239000003292 glue Substances 0.000 description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 6
- 208000001132 Osteoporosis Diseases 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 210000000981 epithelium Anatomy 0.000 description 5
- 238000010171 animal model Methods 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 210000004379 membrane Anatomy 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000000877 morphologic effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000002354 daily effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 206010009866 Cold sweat Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 208000003076 Osteolysis Diseases 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- 208000032183 Scleromalacia Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 239000002085 irritant Substances 0.000 description 2
- 231100000021 irritant Toxicity 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 2
- 231100000682 maximum tolerated dose Toxicity 0.000 description 2
- 230000009245 menopause Effects 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 210000001747 pupil Anatomy 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 240000000560 Citrus x paradisi Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- MWKXCSMICWVRGW-UHFFFAOYSA-N calcium;phosphane Chemical compound P.[Ca] MWKXCSMICWVRGW-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000007905 drug manufacturing Methods 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 210000002175 goblet cell Anatomy 0.000 description 1
- 230000037308 hair color Effects 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003035 hyaline cartilage Anatomy 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003780 keratinization Effects 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 210000004409 osteocyte Anatomy 0.000 description 1
- 230000001009 osteoporotic effect Effects 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 229940088440 salmon calcitonin nasal spray Drugs 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000001720 vestibular Effects 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
Abstract
The salmon calcitonin snuff consists of biological adhesive medicine-containing agglomerase in 1-99 % and carrier with excellent flowability and adsorptility in 1-99 %, where the medicine-containing agglomerate consists of active compound salmon calcitonin, biological adhesive, surfactant and diluent and has grain size of 10-200 microns; and the carrier consists of biological adhesive, physiologically acceptable powder, microcrystalline cellulose and absorption promoter. The new form medicine has medicine existing in solid form and has high stability.
Description
The present invention relates to a kind of nose with inhalant and preparation method, be specifically related to a kind of salmon calcitonin snuff and preparation method.
Salmon calcitonin is the main adjusting factor of mineral such as bone metabolism and calcium phosphorus.Thereby reaching by the effect to the balance influence parathyroid hormone of bone and calcium, it keeps the bone density quality.Its possible mechanism is to suppress the generation of osteoclast activity and stimulating osteoblast and improves active.It suppresses osteolysis can make the serum calcium that increases unusually reduce.Thereby clinically, calcitonin is the main medicine of treatment osteoporosis, osteodynia and Paget ＇ s (scleromalacia).
Along with development of biology, polypeptide drug is applied to clinical more and more, seek the non-injection administration approach of polypeptide drug, become a research focus of pharmaceutics, nasal-cavity administration then is to substitute the most frequently used approach of drug administration by injection, Salmon Calcitonin Nasal Spray (trade name: Rem, Italian Lisapharma) has entered the domestic market, and said preparation has satisfied the needs of being reluctant to inject the patient that maybe can't inject, easy to use, patient's compliance is good, but said preparation is a liquid multiple dose form, and medicine stability is lower, portably use inconvenience, and need spray in advance before using, residual liquor in addition installing is so that cause the waste of expensive medication.
Japan Patent JP5032560 is for the stability that improves salmon calcitonin discloses a kind of nose Sprinkle Caps type spray.Salmon calcitonin capsule-type powder nose inhalant with the fill of medicated powder end in capsule, because principal agent is to thermally labile, so need stored refrigerated, the glue shell is easy embrittlement under low temperature environment, so that when medication, cause the expensive medication loss, cause the dosage deficiency, and broken glue shell might enter nasal cavity, nasal mucosa is caused damage.
The objective of the invention is to disclose a kind of medicine stability height, use easy to carry, the salmon calcitonin powder inhalation that cooperates nose can initiatively suck with powder inhalation device.
Salmon calcitonin nose disclosed by the invention is made up of the carrier that the pastille agglomerate and the 99-1% of 1-99% tool bioadhesive has good fluidity and adsorptivity with powder inhalation.Wherein the pastille agglomerate is made up of 0.1-90.0% reactive compound salmon calcitonin, 9-50% bioadhesive material, 0-1% surfactant and 0-90% diluent, and pastille agglomerate particle diameter is 10-200 μ m, and the best is that 80% grain diameter is at 30-100 μ m; Carrier can be accepted powder body, 0-20% microcrystalline Cellulose, 0-2% absorption enhancer by 0-10% bioadhesive material, 70-100% physiology and form.Salmon calcitonin is tired in every mg and is that it is 10 μ g that 5000IU, 50IU are equivalent to weight.
The bioadhesive material of composition pastille agglomerate of the present invention is: sodium alginate, arabic gum, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, starch, carboxymethyl starch sodium, pregelatinized Starch, cyclodextrin etc.
The used surfactant of the present invention can reduce vessel surface being adsorbed as reactive compound: Polysorbate, poloxamer, Brij (Mjri) etc.
The used diluent of the present invention is the forming agent of agglomerate, and the effect of tool caffolding agent and dispersant comprises: starch, lactose, mannitol, sorbitol, pregelatinized Starch, cyclodextrin etc.
Carrier of the present invention can be accepted powder body by the better mobile physiology of tool and form, good Emptying Rate with the accuracy that guarantees powder body dosage when machine is filled automatically and when sucking, selectable powder body has: starch, lactose, mannitol, sorbitol, pregelatinized Starch, cyclodextrin etc.Should be recommended as less than 40 ° the angle of repose of carrier less than 45 °.
Absorption enhancer of the present invention is poloxamer, glycolate sodium or natrii tauroglycocholas.
Another object of the present invention is to disclose the preparation method of above-mentioned nose with powder inhalation.
Nose disclosed by the invention comprises the following steps: with the preparation method of powder inhalation
(1) agglomerate preparation
Salmon calcitonin, 9-50% bioadhesive material, 0-1% surfactant and the 0-9% diluent of percentage by weight 0.1-90.0% are dissolved in the 10-100 times of water, placed the freeze dryer lyophilizing 10-20 hour or spray drying, promptly get the agglomerate powder.
(2) powder spray preparing carriers
Get after 0-10% bioadhesive material, 70-100% physiology can accept powder body and 0-20% microcrystalline Cellulose, 0-2% absorption enhancer mixing, make soft material with suitable amount of adhesive, crossing 30 mesh sieves granulates, put 50-70 ℃ of oven drying 20 minutes to 1 hour, take out, cross 40 mesh sieve granulate, put 50-70 ℃ of oven for drying, cross 80 mesh sieves promptly.
(3) powder inhalation preparation
Getting percentage by weight is the pastille agglomerate that 1-99% crosses 100 mesh sieves, adds 99-1% powder spray carrier, makes in every gram powder spray to contain salmon calcitonin 1500-8000IU, presses the required dosage fill in vesicle, promptly gets nose calcitonin powder spray.
Salmon calcitonin powder inhalation of the present invention cooperates the up-to-date dose double vesicle type nose of German Pfeiffer company to use with powder inhalation device, initiatively suck by the patient, make the medicated powder in the vesicle directly enter nasal cavity, adhere on the nasal mucosa, medicine is brought into play curative effect through Nasal Mucosa Absorption.From human physiology and aerodynamics angle, this suction makes air be turbulence state and enters nasal cavity, the easier position deposition in tool treatment meaning of medicine; And spray and capsule-type powder nose inhalant commonly used, medicine is by the passive nasal cavity that sprays into of doser, and air draught is a laminar condition, and medicine affects the treatment easily in the anterior deposition of nasal cavity.
The present invention adopts spray drying or Freeze Drying Technique, makes the material of calcitonin and tool bioadhesive etc. form agglomerate, and with the carrier mix homogeneously of Grapefruit Essential Oil, make medicine more stable.
Because the activity of salmon calcitonin and temperature, humidity are relevant, so stability of drug will directly affect the treatment.Product of the present invention is the vesicle type, can select blister materails such as PVC or PET and aluminium foil or composite membrane for use, and moisture-proof characteristic obviously is better than gelatine capsule type powder spray.Product of the present invention was placed 10 days under placement 5 days, super-humid conditions under 60 ℃ of conditions, and outward appearance has no significant change.The concrete variation of capsule-type powder spray is as follows:
| Condition | Time | Outward appearance | Moisture (%) | Operating position |
| Original | 0 day | Content is a white powder | 10.8 | The glue shell easily punches, and powder easily sprays |
| 60℃ | 1 day | The glue shell dwindles, and embrittlement, content are white powder | 2.0 | Glue body, medicated cap are all broken, and powder from vestibule runs off |
| 25℃、 RH75％ | 5 days | Content is a white powder | 13.0 | The softgel shell compressive deformation, the aperture diminishes, and powder is difficult to ejection |
| 10 days | The glue shell is clamminess, deliquescing, and content is a white powder | 15.5 | Capsule deformation can't be punched, and can't use | |
| 25℃、 RH92.5 ％ | 1 day | The glue shell is clamminess, deliquescing, and content is a white powder | 18.4 | Capsule deformation can't be punched, and can't use |
The variation of two kinds of powder spray content and degraded thereof is as follows under high humidity:
| The vesicle type | Capsule-type | ||||
| Content (%) | Related substance (%) | Content (%) | Related substance (%) | ||
| 25℃、 RH75％ | 5 days 10 days | ??99.7 ??101.2 | ????1.35 ????1.28 | ??99.1 ??96.5 | ????1.50 ????2.07 |
| 25℃、H92.5％ | 5 days 10 days | ??98.6 ??94.8 | ????1.68 ????2.19 | Can't measure | |
By The above results as seen, under identical test condition, product quality of the present invention is better than the capsule-type powder spray.
Carry out local application's toxicity research and test of pesticide effectiveness result is as follows with product of the present invention: one. nose with the salmon calcitonin powder spray to rabbit mtd test animal subject 1.1. title: nose salmon calcitonin powder spray, lot number: 20000215 specifications: the 50IU/ grain 1.2. unit of providing: preparation portion of Shanghai Institute of Pharmaceutical Industry nose usefulness salmon calcitonin powder spray is special
The topic group.1.3. administering mode and dosage: the nasal cavity powder directly sprays into administration, and 200IU/ rabbit 2. animals: 2.1. source kind strain: Che Dun town, Shanghai Songjiang county, research grade rabbit mountain laboratory animal is good
Planting the field provides, the buying of animal science portion of Shanghai Second Emdical University.2.2. body weight: 2-2.5kg.2.3. sex: male and female half and half.2.4. number of animals: administration group, vehicle group, blank (normal saline) are organized each 4 greatly
Mus, all male and female half and half.3. dosage setting: it is every side nostril 25mg that the rabbit nasal cavity is sprayed into tolerant maximum powder amount, and promptly 2 vesicles (50IU) were administered twice in 4 hours, were equivalent to contain principal agent 200IU.4. dosage regimen: nasal cavity sprays into administration, and administration is 2 times in 4 hours.
Behind the maximum formulation dosage single administration, observed continuously 7 days.5. experimental control: corresponding vehicle group and blank group (normal saline, each every side nostril 0.05ml).6. test key step:
Experimental animal was raised after three days, began experiment.Before the administration, make the basic condition record earlier, comprise body weight, pupil, defecation, hair color and activity situation etc.Then, the every side nasal cavity of preparation group and vehicle group rabbit sprays into a vesicle drug powder or excipient respectively, and the every side nasal cavity of blank group rabbit then splashes into the 0.05ml normal saline; Repeat aforesaid operations after 2 hours.Reaction of instant animal and 7-14 days variation after the observation administration.Animal per was weighed once every 3 days, and relatively the difference of administration group and matched group was observed 7 days continuously at least.Put to death last day, gets nasal mucosa and make morphological observation and pathological section, and draw the maximum tolerated dose of sample.7. result of the test:
Nose sprays into administration with the salmon calcitonin powder spray to the rabbit nasal cavity, instant animal does not occur significantly unusual after the administration, observed for two weeks, two kinds of sex administration groups are compared there was no significant difference with vehicle group, blank group, aspects such as some basal conditions such as body weight, breathing, circulation and extremity activity are not seen has abnormal conditions to occur, more do not have the phenomena of mortality and occur, see Table 1.Respectively organize every zootomy after the off-test and do not see obvious substantial variation, the administration group is similar to the control animals situation.8. conclusion (of pressure testing):
Nose is 200IU with the salmon calcitonin powder spray to the maximum tolerated dose of rabbit nasal cavity powder administration.Be equivalent to 140 times of clinical daily dose by weight, then be equivalent to 48 times of daily dose in body surface area.
Adult's clinical dosage is 50IU/ time, 1-2 time on the one, so daily dose is 50 normal 100IU.
Two. nose is subjected to reagent thing: 1.1. with salmon calcitonin powder spray lot number with the salmon calcitonin powder spray to the local excitation of rabbit nasal mucosa test 1.: the 200002151.2. amount of showing: the 50IU1.3. unit of providing: the Drug Manufacturing Room of Shanghai Institute of Pharmaceutical Industry nose usefulness salmon calcitonin powder spray is special
| Observed content | The preparation group | Vehicle group | Blank group | ||||||||||
| ????1 | ????2 | ??3 | 4 | ????5 | ??6 | ????7 | ????8 | ????9 | ????10 | ????11 | ????12 | ||
| Body weight kg | Before the experiment | ????1.90 | ????2.21 | ??2.14 | 2.30 | ????1.97 | ??2.00 | ????2.12 | ????2.17 | ????1.98 | ????1.80 | ????1.95 | ????2.08 |
| In the experiment | ????2.00 | ????2.30 | ??2.20 | 2.40 | ????2.00 | ??2.05 | ????2.20 | ????2.20 | ????2.05 | ????1.90 | ????2.00 | ????2.10 | |
| After the experiment | ????2.05 | ????2.35 | ??2.25 | 2.45 | ????2.10 | ??2.15 | ????2.30 | ????2.30 | ????2.15 | ????2.00 | ????2.10 | ????2.20 | |
| Breathe | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | |
| Circulation | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | |
| Pupil | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | |
| The extremity activity | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | Normally | |
| Dead | Do not have | Do not have | Do not have | Do not have | Do not have | Do not have | Do not have | Do not have | Do not have | Do not have | Do not have | Do not have | |
The topic group.2. animal: 2.1. source kind strain: the research grade rabbit is by Che Dun town, Shanghai Songjiang county laboratory animal
Seed multiplication farm provides, animal science portion of Shanghai Second Emdical University
Buying.2.2. body weight: 2-2.5kg.2.3 sex: male and female half and half.2.4. number of animals: 3 every group.Corresponding vehicle group, blank group are established in the single or multiple administration respectively.2.5. animal housing's condition: 24 ± 2 ℃ of room temperatures, corresponding humidity 65 ± 10%.Animal is raised with mark
Accurate full nutrition pellet is freely ingested and is drunk water.3. test method:
Rabbit is pinned fixing, and head is steeved, and contacts at least 4 hours for guaranteeing medicated powder with nasal mucosa, medicated powder in the vesicle is divided spray into the animal nasal cavity, vesicle of every side nasal cavity by device 3 times in 4 hours.Vehicle group awards corresponding blank adjuvant with method, and the blank group then gives the 0.05ml normal saline at every turn.The single-dose group is put to death after 24 hours and is dissected; The multiple dosing group, administration every day continuous 7 days, was put to death in the last administration in 24 hours.Dissect to take out the nasal membrane of respectively organizing every rabbit, carry out morphological observation, relatively administration group and vehicle group nasal mucosa surface have or not phenomenons such as hemorrhage, congested, edema.The nasal membrane that takes out is used 10% formalin fixed, through dehydration step by step, and paraffin embedding, section, HE dyeing, on show, histopathology is observed.4. result of the test:
Morphological observation:
After single-dose group and the administration of multiple dosing group rabbit, reach viewing duration immediately and abnormal phenomena all do not occur.Off-test, the anesthesia blood-letting causes death, and dissects and takes out nasal membrane, phenomenons such as that morphological observation, each administration group and corresponding vehicle group nasal mucosa there is no is significantly hemorrhage, congested, edema, also no significant difference between three groups.
Histopathology is observed:
Single-dose was organized and the multiple dosing group in 24 hours, mucosal tissue 10% formaldehyde fixed, paraffin embedding, 6 μ that cut into slices, HE dyeing.The result shows, administration group, blank group and vehicle group vestibular portion epithelium are the stratified squamous epithelium of keratinization, progressively divide a word with a hyphen at the end of a line and become not keratinized stratified squamous epithelium, pseudostratified ciliated columnar epithelium until respiratory region, the epithelium queueing discipline, in see a small amount of goblet cell, basement membrane is clear not to be seen and thickens, lamina propria connective tissue not water breakthrough is swollen, and body of gland, blood vessel and hyaline cartilage do not see that the histology changes.Histological observation no significant difference between three groups of nasal mucosas.5. conclusion (of pressure testing):
With clinical dosage, the 100IU/ rabbit carries out single or multiple to the rabbit nasal cavity and sprays into administration nose with the salmon calcitonin powder spray, observes the irritant reaction to nasal mucosa, and morphology is observed with histopathology and be there is no the significantly irritant reaction relevant with medicine.Three. blood calcium effect laboratory animal and administering mode fall in the animal body:
16 of rabbits are divided into blank (normal saline) group (4, male and female half and half), intravenous injection group (6, male and female half and half), nasal-cavity administration group (6, male and female half and half).Raise after three days, begin experiment.Water purification is only drunk in fasting before the experiment.
Dosage: 4IU
Experimental design: each one group of blank (normal saline group) nasal-cavity administration, respectively at getting blood 0.5ml before the administration and after the administration in 1,2,2.5,3.0,3.5,4.5,5,6,7,8,10 hour.The intravenous injection group respectively at administration before and administration after 0.25,0.5,1,1.5,2,2.5,3.0,4,5,6,7 hour, get blood 0.5ml.
Assay method: measure calcium ion concentration in the blood plasma, method is with biological titration.
Measurement result:
Intravenous injection 4IU
| # 28 | Time (branch) | 0 | 16 | ??32 | ???60 | ??89 | ??128 | ??154 | ??193 | ??242 | ??301 | ??372 | ???422 |
| Ca(ug/ml) | 159.12 | 145.86 | ??143.52 | ???137.80 | ??133.38 | ??125.32 | ??147.42 | ??158.86 | ??161.20 | ??143.00 | ??149.76 | ???154.96 | |
| # 16 | Time (branch) | 0 | 18 | ??30 | ???60 | ??92 | ??126 | ??155 | ??192 | ??242 | ??308 | ??380 | ???422 |
| Ca(ug/ml) | 151.06 | 147.16 | ??144.04 | ???132.34 | ??108.94 | ??121.94 | ??140.92 | ??150.28 | ??139.10 | ??130.78 | ??141.44 | ???151.58 | |
| # 31 | Time (branch) | 0 | 18 | ??32 | ???60 | ??93 | ??127 | ??153 | ??187 | ??248 | ??311 | ??373 | ???423 |
| Ca(ug/ml) | 159.12 | 152.10 | ??143.00 | ???129.22 | ??110.24 | ??118.56 | ??145.60 | ??144.56 | ??135.20 | ??129.22 | ??144.56 | ???155.22 | |
| # 15 | Time (branch) | 0 | 17 | ??30 | ???61 | ??91 | ??126 | ??154 | ??192 | ??239 | ??309 | ??374 | ???424 |
| Ca(ug/ml) | 161.98 | 151.58 | ??138.32 | ???128.44 | ??100.36 | ??102.44 | ??109.98 | ??127.66 | ??144.04 | ??137.80 | ??144.82 | ???166.66 | |
| # 19 | Time (branch) | 0 | ??31 | ???60.5 | ??94.5 | ??126.5 | ??156.5 | ??182.5 | ??241.5 | ??321.5 | ??391.5 | ???463.5 | |
| Ca(ug/ml) | 174.98 | ??171.60 | ???135.20 | ??121.68 | ??132.86 | ??136.24 | ??145.60 | ??152.88 | ??143.00 | ??132.08 | ???152.36 | ||
| # 25 | Time (branch) | 0 | ??30 | ???61 | ??93.5 | ??121.5 | ??152.5 | ??180.5 | ??240.5 | ??319.5 | ??388.5 | ???460.5 | |
| Ca(ug/ml) | 162.24 | ??138.06 | ???113.36 | ??115.70 | ??126.10 | ??147.94 | ??151.58 | ??143.00 | ??137.02 | ??132.08 | ???161.20 |
Nasal cavity sprays into 4IU
| # 29 | Time (branch) | 0 | ????54 | ????119 | ????149 | ????236 | ||||||||
| Ca(ug/ml) | 163.28 | ????132.34 | ????110.76 | ????103.74 | ????132.08 | |||||||||
| # 11 | Time (branch) | 0 | ????56 | ????124 | ????152 | ??185 | ??220 | ????239 | ????281 | ?300 | ??358 | ?418 | ???477 | ??616 |
| Ca(ug/ml) | 151.32 | ????146.64 | ????138.06 | ????119.08 | ??145.60 | ??154.70 | ????149.50 | ????148.20 | ?141.18 | ??153.40 | ?151.84 | ???153.92 | ??156.52 | |
| # 17 | Time (branch) | 0 | ????58 | ????125 | ????152 | ??187 | ??220 | ????237 | ????268 | ?300 | ??360 | ?417 | ???476 | ??622 |
| Ca(ug/ml) | 187.20 | ????175.50 | ????149.24 | ????146.64 | ??137.02 | ??158.80 | ????155.22 | ????163.02 | ?179.14 | ??170.30 | ?153.14 | ???159.12 | ??182.52 | |
| # 18 | Time (branch) | 0 | ????59 | ????122 | ????155 | ??191 | ??221 | ????240 | ????270 | ?301 | ??371 | ?420 | ???480 | ??599 |
| Ca(ug/ml) | 157.30 | ????147.42 | ????143.52 | ????140.14 | ??130.26 | ??119.08 | ????151.06 | ????159.64 | ?144.04 | ??127.14 | ?139.88 | ???157.04 | ??155.22 | |
| # 30 | Time (branch) | 0 | ????59 | ????128 | ????155 | ??192 | ??222 | ????243 | ????271 | ?304 | ??355 | ?415 | ???474 | ??603 |
| Ca(ug/ml) | 181.48 | ????165.36 | ????158.60 | ????154.70 | ??147.94 | ??135.20 | ????140.40 | ????146.64 | ?161.72 | ??149.24 | ?161.52 | ???169.52 | ??179.14 | |
| # 27 | Time (branch) | 0 | ????60 | ????127 | ????155 | ??192 | ??224 | ????240 | ????275 | ?303 | ??367 | ?425 | ???486 | ??616 |
| Ca(ug/ml) | 158.60 | ????152.62 | ????145.60 | ????139.10 | ??129.48 | ??145.60 | ????147.42 | ????149.76 | ?144.30 | ??140.14 | ?147.42 | ???151.32 | ??15496 |
According to above-mentioned data, draw " medicine-time " curve chart, refer again to Wei Shuli chief editor " pharmacokinetics and the key to exercises " (Hunan science and technology publishing house, 1988) the described method of P100-103, blood calcium reduction value after the calculating administration, nose is 72% of a quiet notes administration group with the administration group.This shows, salmon falls after element makes powder nose inhalant, through the rabbit in vivo test, have and significantly fall the blood calcium effect, peak time is 3 hours (quiet notes are 1.5 hours), sustainable about 10 hours of action time (quiet notes are about 7 hours), show the administration of this product via intranasal application after, medicine can see through Nasal Mucosa Absorption, reaches the effect that reduces blood calcium.
Synthetic salmon calcitonin (Salcatonin) has obvious curative effects to postmenopausal osteoporosis, and calcitonin suppresses bone loss by suppressing the osteocyte activity, and salmon calcitonin is about 50 times of natural calcitonin in the effect aspect the inhibition osteoclast activity.Be used for osteoporosis with osteodynia or postmenopausal osteoporosis, hypercalcemia, malignant neoplastic osteolysis, scleromalacia etc.This preparation was particularly useful for menopause more than 5 years, was suitable for using estrogenic women's osteosporosis after menopause disease, and patient's the part of complying with obviously is better than injection.
Aggravation along with China's population senescence trend, patients with osteoporosis increases gradually, demand to the osteoporosis remedy thing also strengthens, survey result in 1996 shows, China has the population more than 1.1 hundred million 60 years old approximately, existing more than 8,400 ten thousand people suffer from degrees of osteoporotic, to calendar year 2001 this numeral will increase to 1.1 hundred million.In the medicine of treatment osteoporosis, calcitonin is reliably occupied an leading position with its curative effect, is admitted by doctor and vast patients with osteoporosis.The present invention adopts the preparation new technique, and the adjuvant of calcitonin with the tool bioadhesive mixed, and by special dry powder doser (in adorn two pastille vesicles) medicine is sucked nasal cavity, medicine after Nasal Mucosa Absorption, the performance general action.Powder all is sucked into nasal cavity in the vesicle, and residual quantity is extremely low in the device, and easilier deposits at site of action.Medicine exists with single dose solid form powder type, and stability obviously improves than liquid preparation, avoids because of in time not using the waste that causes.
Product price of the present invention is cheap, easy to use, has the patient infusion of alleviating misery, alleviates advantages such as health care expenditures, has huge economic benefit and social benefit.
Embodiment 1 prescription (in 10000)
Salmon calcitonin 500,000IU (about 0.5g)
Mannitol 5g
Poloxamer F68 0.25g
Sodium carboxymethyl cellulose 11g
Microcrystalline Cellulose 40g
Lactose 200g technology
A. contain the preparation of salmon calcitonin agglomerate freeze-dried powder:
With recipe quantity salmon calcitonin, mannitol, poloxamer F68 and 1g sodium carboxymethyl cellulose, be dissolved in the 100ml water, put and carry out lyophilizing in the freeze dryer, cross 100 mesh sieves, promptly.Freeze-drying curve is seen accompanying drawing 1: salmon calcitonin agglomerate freeze-drying curve figure.
B. powder spray preparing carriers: behind sodium carboxymethyl cellulose 10g and recipe quantity microcrystalline Cellulose, lactose mixing,, cross 30 mesh sieves and granulate with an amount of dehydrated alcohol system soft material, put 60 ℃ of about 30min of baking oven, take out, cross 40 sieve granulate, put 60 ℃ of oven for drying, cross 80 mesh sieves, promptly.
C. (contain salmon calcitonin 50 approximately, 000IU), add the about 25g of powder spray carrier, mixing is surveyed content, and qualified back fill promptly gets nose salmon calcitonin powder spray in right amount to get the 100 salmon calcitonin lyophilized powders that sieve.
Embodiment 2 prescriptions (in 10000)
Salmon calcitonin 500,000IU (about 0.5g)
B-cyclodextrin 11g
Mannitol 2.5g
Hydroxypropyl cellulose 1g
Polyoxyethylene sorbitan monoleate 0.25g
Hydroxypropyl emthylcellulose 10g
Microcrystalline Cellulose 30g
Lactose 200g
Technology
A, contain salmon calcitonin agglomerate freeze-dried powder preparation
With recipe quantity salmon calcitonin, mannitol, polyoxyethylene sorbitan monoleate, hydroxypropyl cellulose and 1g beta-schardinger dextrin-, be dissolved in the 100ml water, put and carry out lyophilizing in the freeze dryer, cross 100 mesh sieves, promptly.Freeze-drying curve such as embodiment 1.
B. powder spray preparing carriers
Behind beta-schardinger dextrin-10g and recipe quantity hydroxypropyl emthylcellulose, microcrystalline Cellulose, lactose mixing,, cross 30 mesh sieves and granulate with an amount of 0.1%HPMC aqueous solution system soft material, put 60 ℃ of about 30min of baking oven, take out, cross 40 mesh sieve granulate, put 60 ℃ of oven for drying, cross 80 mesh sieves, promptly.C. getting the salmon calcitonin agglomerate freeze-dried powder that contains of 100 mesh sieves, an amount of (contain salmon calcitonin 50 approximately, 000IU), add the about 25g of powder spray carrier, mixing is surveyed content, and qualified fill afterwards promptly gets nose salmon calcitonin powder spray.
Embodiment 3 prescriptions (in 10000)
Salmon calcitonin 500,000IU (about 0.5g)
Mannitol 2.5g
Carboxymethyl starch 2g
Brij 0.25g
Lactose 250g
An amount of technology A. of hydroxypropyl emthylcellulose (HPMC) 0.1% aqueous solution contains the preparation of salmon calcitonin agglomerate spray-dried powders:
Recipe quantity salmon calcitonin, mannitol, carboxymethyl starch, Brij are dissolved in the 500ml water, spray drying, charging rate 60ml/min, temperature of inlet air are 190 ℃, air mass flow 2.4m
3/ min, nozzle admission pressure 800NL, the spraying thing is crossed 100 mesh sieves promptly.B. powder spray preparing carriers:
Lactose is made soft material with 0.1%HPMC, cross 30 mesh sieves and granulate, put 60 ℃ of about 30min of baking oven, take out, cross 40 mesh sieve granulate, put 60 ℃ of oven for drying, cross 80 mesh sieves, promptly.
C. (contain salmon calcitonin 50 approximately, 000IU), add the about 25g of powder spray carrier, mixing is surveyed content, and qualified back fill promptly gets nose salmon calcitonin powder spray in right amount to get the 100 salmon calcitonin agglomerate spray drying dry powder that contain that sieve.
Embodiment 4 prescriptions (in 10000)
Salmon calcitonin 500,000IU (about 0.5g)
Hydroxypropyl cyclodextrin 1g
Hydroxypropyl emthylcellulose 0.5g
Hydroxypropyl cellulose 10g
Lactose 105g
Poloxamer 0.25g
Pregelatinized Starch 140g technology
A. contain the preparation of salmon calcitonin agglomerate spray-dried powders:
Recipe quantity salmon calcitonin, hydroxypropyl cyclodextrin, HPMC, poloxamer and lactose 5g are dissolved in the 500ml water, spray drying, the spraying thing is crossed 100 mesh sieves promptly, and spray condition is together
Embodiment 3.
B. powder spray preparing carriers:
Behind hydroxypropyl cellulose 10g and recipe quantity precoking starch, lactose 100g mixing, with an amount of dehydrated alcohol system soft material, cross 30 mesh sieves and granulate, put 60 ℃ of about 30min of baking oven, take out, cross 40 mesh sieve granulate, put 60 ℃ of oven for drying, 80 mesh sieves, promptly.
C. (contain salmon calcitonin 50 approximately, 000IU), add the about 25g of powder spray carrier, mixing is surveyed content, and qualified back fill promptly gets nose salmon calcitonin powder spray in right amount to get the 100 salmon calcitonin agglomerate spray drying powders that contain of sieving.
Claims (8)
1, a kind of salmon calcitonin snuff, it is characterized in that when said preparation system uses the dry powder formulations that sucks of per nasal initiatively, suck powder and form by the carrier that the pastille agglomerate and the 99-1% of 1-99% tool bioadhesive has good fluidity and adsorptivity by the patient; Wherein the pastille agglomerate is made up of 0.1-90.0% reactive compound salmon calcitonin, 9-50% bioadhesive material, 0-1% surfactant and 0-90% diluent, and pastille agglomerate particle diameter is 10-200 μ m; Carrier can be accepted powder body, 0-20% microcrystalline Cellulose, 0-2% absorption enhancer by 0-10% bioadhesive material, 70-100% physiology and form.
2, a kind of salmon calcitonin snuff as claimed in claim 1, the grain diameter that it is characterized in that pastille agglomerate 80% wherein is at 30-100 μ m.
3, a kind of salmon calcitonin snuff as claimed in claim 1, the bioadhesive material that it is characterized in that wherein said composition pastille agglomerate is sodium alginate, arabic gum, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, starch, carboxymethyl starch sodium, pregelatinized Starch and cyclodextrin.
4, a kind of salmon calcitonin snuff as claimed in claim 1 is characterized in that wherein said surfactant is Polysorbate, poloxamer and Brij.
5, a kind of salmon calcitonin snuff as claimed in claim 1 is characterized in that wherein said diluent is starch, lactose, mannitol, sorbitol, pregelatinized Starch and cyclodextrin.
6, a kind of salmon calcitonin snuff as claimed in claim 1 is characterized in that wherein said carrier powder body is starch, lactose, mannitol, sorbitol, pregelatinized Starch, cyclodextrin; The angle of repose of carrier should be less than 45 °.
7, a kind of salmon calcitonin snuff as claimed in claim 1 is characterized in that wherein said absorption enhancer is poloxamer, glycolate sodium or natrii tauroglycocholas.
8, a kind of preparation method of salmon calcitonin snuff as claimed in claim 1 is characterized in that this preparation method comprises the following steps:
(1) agglomerate preparation
Salmon calcitonin, 9-50% bioadhesive material, 0-1% surfactant and the 0-90% diluent of percentage by weight 0.1-90.0% are dissolved in the 10-100 times of water, placed the freeze dryer lyophilizing 10-20 hour or spray drying, promptly get the salmon calcitonin powder;
(2) powder spray preparing carriers
Get after 0-10% bioadhesive material, 70-100% physiology can accept powder body and 0-20% microcrystalline Cellulose, 0-2% absorption enhancer mixing, make soft material with suitable amount of adhesive, crossing 30 mesh sieves granulates, put 50-70 ℃ of oven drying 20 minutes to 1 hour, take out, cross 40 mesh sieve granulate, put 50-70 ℃ of oven for drying, cross 80 mesh sieves promptly;
(3) powder inhalation preparation
Getting percentage by weight is the pastille agglomerate that 1-99% crosses 100 mesh sieves, adds 99-1% powder spray carrier, makes in every gram powder spray to contain salmon calcitonin 1500-8000IU, presses the required dosage fill in vesicle, promptly gets nose calcitonin powder spray.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB01105431XA CN1193745C (en) | 2001-02-27 | 2001-02-27 | Salmon calcitonin snuff and its prepn |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB01105431XA CN1193745C (en) | 2001-02-27 | 2001-02-27 | Salmon calcitonin snuff and its prepn |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1370523A true CN1370523A (en) | 2002-09-25 |
| CN1193745C CN1193745C (en) | 2005-03-23 |
Family
ID=4654510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB01105431XA Expired - Fee Related CN1193745C (en) | 2001-02-27 | 2001-02-27 | Salmon calcitonin snuff and its prepn |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1193745C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005058289A1 (en) * | 2003-12-16 | 2005-06-30 | Fang Jin | A method of preparing intranasal dry powders inhalant of calcitonin |
| WO2011129120A1 (en) * | 2010-04-15 | 2011-10-20 | Shin Nippon Biomedical Laboratories, Ltd. | Methods and compositions for intranasal delivery |
| CN104888198A (en) * | 2015-04-21 | 2015-09-09 | 徐志强 | New application of calcitonin to preparing medicines for delaying brain aging |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100349611C (en) * | 2005-11-25 | 2007-11-21 | 中国药科大学 | Redfish calcitonin inhalation powder-atomizing agent and preparing method |
| CN108367977B (en) | 2015-12-25 | 2021-06-18 | 古河电气工业株式会社 | Method for manufacturing optical fiber wire and ultraviolet irradiation device |
-
2001
- 2001-02-27 CN CNB01105431XA patent/CN1193745C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005058289A1 (en) * | 2003-12-16 | 2005-06-30 | Fang Jin | A method of preparing intranasal dry powders inhalant of calcitonin |
| WO2011129120A1 (en) * | 2010-04-15 | 2011-10-20 | Shin Nippon Biomedical Laboratories, Ltd. | Methods and compositions for intranasal delivery |
| US9687536B2 (en) | 2010-04-15 | 2017-06-27 | Shin Nippon Biomedical Laboratories, Ltd. | Methods and compositions for intranasal delivery |
| US10463723B2 (en) | 2010-04-15 | 2019-11-05 | Shin Nippon Biomedical Laboratories, Ltd. | Methods and compositions for intranasal delivery |
| CN104888198A (en) * | 2015-04-21 | 2015-09-09 | 徐志强 | New application of calcitonin to preparing medicines for delaying brain aging |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1193745C (en) | 2005-03-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1176649C (en) | Inhalant of Shumaputan dry-powder and its preparation method | |
| CN1447704A (en) | Flow resistance modulated aerosolized active agent delivery | |
| CN1031940A (en) | Prescription by mucosa delivery and preparation method thereof | |
| CN1748777A (en) | Chinese medicine volatoile oil self-mciro emulsifying nano composition and preparing method | |
| CN1915215A (en) | Oral cavity disintegration preparation | |
| CN1809377B (en) | Orally dosed pharmaceutical compositions comprising a delivery agent in micronized form | |
| IT202000005026A1 (en) | Lactoferrin for inhalation use with antiviral action | |
| CN1857418A (en) | Chinese medicine powder inhalant and its preparing method and application | |
| CN1193745C (en) | Salmon calcitonin snuff and its prepn | |
| CN1857676A (en) | Zedoary oil microcapsule preparation and its preparing process | |
| CN102580056B (en) | Controlled-release injection containing antidiuresis components and preparation method thereof | |
| CN1943734A (en) | A Chinese traditional medicine for clearing away heat and toxic material | |
| CN1960743A (en) | Herbal composition | |
| CN101045158A (en) | Insulin analog dry powder composition and its preparing method | |
| CN1278709C (en) | Medicine for treating cold and its preparing process | |
| CN1850248A (en) | Chinese medicine capsule for treating hyperplasia mammary glands and preparing method | |
| CN1824099A (en) | Diffusing-freeing lung rectifying medicinal preparation and its new preparation method | |
| CN102861001B (en) | Novel application of cinnamic aldehyde for treating gastritis | |
| CN112190572B (en) | Application of methyl allyl trisulfide in preparation of medicine for treating acute lung injury | |
| CN101474399A (en) | Insulin powder spray for lung inhalation and preparation method thereof | |
| CN100335038C (en) | Preparation process and application of inorganic salt nanometer particle containing biological active material and enveloped Chinese medicinal ingredient | |
| CN1292738C (en) | Ginseng-pilose antler dripping pill for tonifying heart and kidney and its preparing method | |
| CN1879711A (en) | A Chinese medicinal composition for treating gastric disease, its preparation process and quality control method | |
| CN1565625A (en) | Preparing process of insulin powder inhalant | |
| CN1795914A (en) | Composition for treating throat oral disease, preparation and preparing method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PP01 | Preservation of patent right |
Effective date of registration: 20051114 Pledge (preservation): Preservation |
|
| PD01 | Discharge of preservation of patent |
Date of registration: 20061122 Pledge (preservation): Preservation |
|
| PP01 | Preservation of patent right |
Effective date of registration: 20070419 Pledge (preservation): Preservation |
|
| PD01 | Discharge of preservation of patent |
Date of cancellation: 20071019 Pledge (preservation): Preservation registration |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050323 Termination date: 20170227 |