CN101601662B - Alendronate sodium intestine-sol capsule and preparation method thereof - Google Patents
Alendronate sodium intestine-sol capsule and preparation method thereof Download PDFInfo
- Publication number
- CN101601662B CN101601662B CN2009100326950A CN200910032695A CN101601662B CN 101601662 B CN101601662 B CN 101601662B CN 2009100326950 A CN2009100326950 A CN 2009100326950A CN 200910032695 A CN200910032695 A CN 200910032695A CN 101601662 B CN101601662 B CN 101601662B
- Authority
- CN
- China
- Prior art keywords
- alendronate sodium
- capsule
- intestine
- sol
- preparation
- 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.)
- Active
Links
- 239000002775 capsule Substances 0.000 title claims abstract description 113
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 title claims abstract description 108
- 229960004343 alendronic acid Drugs 0.000 title claims abstract description 103
- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 239000003223 protective agent Substances 0.000 claims abstract description 16
- 239000000314 lubricant Substances 0.000 claims abstract description 10
- 239000003085 diluting agent Substances 0.000 claims abstract description 9
- 239000008187 granular material Substances 0.000 claims description 33
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 18
- 235000019359 magnesium stearate Nutrition 0.000 claims description 16
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 claims description 13
- 229920002472 Starch Polymers 0.000 claims description 13
- 229940082484 carbomer-934 Drugs 0.000 claims description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 13
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 13
- 235000019698 starch Nutrition 0.000 claims description 13
- 239000008107 starch Substances 0.000 claims description 13
- 238000005550 wet granulation Methods 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- 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 5
- 239000008101 lactose Substances 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 30
- 210000003238 esophagus Anatomy 0.000 abstract description 10
- 230000000968 intestinal effect Effects 0.000 abstract description 9
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 210000000214 mouth Anatomy 0.000 abstract description 2
- 206010067484 Adverse reaction Diseases 0.000 abstract 1
- 230000006838 adverse reaction Effects 0.000 abstract 1
- 239000008279 sol Substances 0.000 description 35
- 239000000243 solution Substances 0.000 description 35
- 238000012360 testing method Methods 0.000 description 23
- 238000005516 engineering process Methods 0.000 description 19
- 239000002253 acid Substances 0.000 description 17
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 10
- 229920002125 Sokalan® Polymers 0.000 description 9
- 229960001631 carbomer Drugs 0.000 description 9
- 210000001035 gastrointestinal tract Anatomy 0.000 description 9
- 238000000576 coating method Methods 0.000 description 8
- 208000001132 Osteoporosis Diseases 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000011248 coating agent Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 201000006549 dyspepsia Diseases 0.000 description 5
- 208000024798 heartburn Diseases 0.000 description 5
- 230000008676 import Effects 0.000 description 5
- 208000019505 Deglutition disease Diseases 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 210000004877 mucosa Anatomy 0.000 description 4
- 229920000178 Acrylic resin Polymers 0.000 description 3
- 239000004925 Acrylic resin Substances 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 229940001490 fosamax Drugs 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 210000002997 osteoclast Anatomy 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 235000015424 sodium Nutrition 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- 208000006386 Bone Resorption Diseases 0.000 description 2
- 206010008479 Chest Pain Diseases 0.000 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 description 2
- 229940062527 alendronate Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000011978 dissolution method Methods 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- JJJOZVFVARQUJV-UHFFFAOYSA-N 2-ethylhexylphosphonic acid Chemical compound CCCCC(CC)CP(O)(O)=O JJJOZVFVARQUJV-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 1
- 206010013082 Discomfort Diseases 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010030094 Odynophagia Diseases 0.000 description 1
- 206010070818 Oesophageal irritation Diseases 0.000 description 1
- 206010030201 Oesophageal ulcer Diseases 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940086737 allyl sucrose Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ZRBROGSAUIUIJE-UHFFFAOYSA-N azanium;azane;chloride Chemical compound N.[NH4+].[Cl-] ZRBROGSAUIUIJE-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 206010013864 duodenitis Diseases 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 208000028299 esophageal disease Diseases 0.000 description 1
- 208000019064 esophageal ulcer Diseases 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 230000001582 osteoblastic effect Effects 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 125000005499 phosphonyl group Chemical group 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000004206 stomach function Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an alendronate sodium intestine-sol capsule and a preparation method thereof; the intestine-sol capsule comprises the following compositions by weight parts: 10-20 parts of alendronate sodium, 70-100 parts of diluents, 0.5-5 parts of protective agents and 0.5-2 parts of lubricants. The alendronate sodium intestine-sol capsule is particularly added in the protective agents, so as to effectively prevent basic remedy from being released in oral cavity, esophagus and esophagus before reaching the absorption site of the intestinal canal, thereby improving the medicine quality, reducing the adverse reaction and improving the compliance of a patient; the preparation process is simple, the pollution to the environment is reduced by energy consumption and social cost is saved.
Description
Technical field
The present invention relates to the pharmaceutical technology field, be specifically related to a kind of alendronate sodium intestine-sol capsule and preparation method thereof.
Background technology
Osteoporosis is a middle-aged and elderly people, particularly a kind of common frdquently encountered disease of postmenopausal women.Its control medicine has become the focus of present new drug development.Alendronate sodium is a novel osteoporosis treatment and a prophylactic agent, belongs to third generation diphosphonates bone resorption inhibitor.
Alendronate sodium (Alendronate Sodium) chemical name is: (4-amino-1-hydroxy butylidene)-1, and 1-di 2 ethylhexyl phosphonic acid list sodium salt trihydrate, molecular structural formula:
Alendronate sodium is developed in advance by Italian Istituto Gentili company, after transfer U.S. Merck company and continue exploitation.External commodity Fosamax by name.This tablet from November, 1993 since Italian Initial Public Offering is used for the treatment of osteoporosis, successively in the listing of more than 50 state approvals.
Alendronate sodium is for the bone resorption position, particularly the site of action of osteoclast has stronger affinity, can combine with osteoclast, suppress its activity, and when reducing osteoclast activity, osteoblastic activity not influenced, can reduce bone effectively shifts, make bone formation surpass bone resorption, thereby the bone amount is increased, reach the treatment osteoporosis, alleviate clinical symptoms, the purpose of prevention fracture.But owing to Alendronate sodium is replaced by 2 phosphonyl groups because of two hydrogen atoms that link to each other with a carbon atom in its structure, so this compounds can discharge more H
+, when taking, easily stimulate digestion epithelium and mucosa allow the patient feel dysphagia, many discomforts such as esophagus, heartburn.
It below is import Alendronate sodium sheet (trade name: Fosamax
Mo Shadong pharmaceutical Co. Ltd) report in the description:
" Alendronate sodium is the same with other diphosphate, and this product may produce local excitation to the upper digestive tract mucosa.
In taking the patient of this product, the esophagus untoward reaction of having reported has esophagitis, esophageal ulcer and esophagus erosion, the report of rare esophagostenosis or perforation.Some case wherein is because of these untoward reaction seriously need hospitalization.Therefore, the doctor should watch out for any sings and symptoms that the esophagus reaction may take place, and answers patient directions if dysphagia, odynophagia, retrosternal pain or New Development heartburn or heartburn increase the weight of, and this product of stopping using is also sought medical advice.
The patient who couches after taking this product and/or still continue without the water delivery service medicine and/or after the symptom of prompting oesophageal irritation occurring to take medicine, the danger that serious esophagus untoward reaction takes place is bigger.Therefore, provide patient detailed medication guide, allowing it fully understand is very important (seeing [usage and dosage]).
Gastric duodenal ulcer is dangerous to be increased although observe in clinical experiment widely, and the minute quantity report is arranged after the listing, and some is comparatively serious and with complication.Yet the cause effect relation of they and medicine is determined as yet.Because this product has stimulation and might increase the weight of potential disease the upper digestive tract mucosa, so Ying Shen is used to suffer from activeness upper digestive disease and dysphagia, esophagel disease, gastritis, duodenitis, ulcer or gastrointestinal tract medical history (in nearly 1 year) arranged recently, as the patient of digestive tract ulcer or activeness gastrointestinal hemorrhage or operation on digestive tract (except pyloroplasty).
Thereby reduce stimulation for this product being delivered to stomach, answer patient directions with one glass of water medicine of swallowing, and at least 30 minutes, reach and before taking food for the first time the same day, do not couch esophagus.Patient should not chew or suck tablet, in case pars oralis pharyngis ulcer.Patient directions is not taken this product before going to bed preceding or getting up early in the morning especially, should tell patient, if uncomplaisance may increase the danger that the esophagus problem occurs.Patient should be told,, this product and the diagnoses and treatment of sending for a doctor should be withdrawn if the symptom (as dysphagia or pain, retrosternal pain or New Development heartburn or heartburn increase the weight of) of esophagel disease takes place.”
This shows that taking of the alendronic Acid preparation of sodium under the present condition is very inconvenient, has hindered this medicine to a certain extent and has served vast sufferers of osteoporosis face.In order to improve patient's the compliance of taking medicine, reduce the untoward reaction after taking medicine, make things convenient for the patient to take medicine under various conditions, we will develop novel alendronate sodium intestine-sol capsule, make things convenient for the patient to take medicine under multiple condition, improve the compliance of taking medicine.
Summary of the invention
Thereby the objective of the invention is to overcome the medicine alendronate sodium intestine-sol capsule that above-mentioned weak point provides a kind of treatment and prevention of osteoporosis disease.
The present invention also will provide the preparation method of the medicine alendronate sodium intestine-sol capsule of this treatment and prevention of osteoporosis disease, and this method technology is easy, is easy to produce.
Technical scheme of the present invention, is filled in the enteric coated capsule behind lubricant and protective agent mix homogeneously for Alendronate sodium and adjuvant are made granule, makes alendronate sodium intestine-sol capsule.Use enteric coated capsule medicine can be delivered directly to and carry out drug release behavior in the intestinal again, effectively avoided before reaching this effective absorption site of intestinal, Alendronate sodium contacts with oral mucosa, digestive tract and coat of the stomach; Protective agent then can be when capsule runs into special circumstances and breaks, and delays and stops the release of Alendronate sodium and release.The technical program is by the use enteric coated capsule and add protective agent, thereby digestive tract, gastric mucosa have been formed duplicate protection mechanism.In this programme carbomer is used as protective agent.
Carbomer (Carboxgpolmethylene) is the crosslinked high molecular polymer of acrylic acid and allyl sucrose, is recorded by Britain, American Pharmacopeia as a kind of adjuvant, is widely used in pharmaceuticals industry, day chemical industry and other relevant industrial field.Main as thickening agent, suspending agent and binding agent in medicament, also ointment gel preparation effect substrate that are used for more.This programme utilizes carbomer to meet the characteristic that water-soluble bulging becomes the thickness hydrogel; add carbomer in right amount at capsule 's content; make and to be detained under one's belt under special circumstances for a long time or other factors and when causing capsule to produce slight crack when capsule; carbomer can form layer of gel in inside capsule wall; stoped Alendronate sodium to discharge, can protect pill taker's digestive tract stomach function regulating to avoid stimulating to the external world.And the carbomer of the appropriate amount that the present invention optimizes does not influence normal release and the pharmacokinetics behavior of alendronate sodium intestine-sol capsule in intestinal.
The objective of the invention is to be achieved through the following technical solutions:
A kind of alendronate sodium intestine-sol capsule, mainly composed of the following components: Alendronate sodium 10-20 weight portion, diluent 70-100 weight portion, lubricant 0.5-2 weight portion and protective agent 0.5-5 weight portion.
Described diluent can be in starch, microcrystalline Cellulose and the lactose one or more with any than mixing; lubricant can be in magnesium stearate and the micropowder silica gel one or both with any than mixing, one or both among preferred carbomer 934 of protective agent or the 934P with any than mixing.
Alendronate sodium intestine-sol capsule of the present invention preferably mainly is made up of following component: 10 weight portion Alendronate sodiums, the starch of 80 weight portions, the magnesium stearate of 0.5 weight portion, the carbomer 934 P of 1 weight portion.
The preparation method of above-mentioned alendronate sodium intestine-sol capsule comprises the steps: a, each component is sieved, and gets the abundant mix homogeneously of Alendronate sodium and diluent; B, wet granulation, oven dry makes dried granule; C, granulate add lubricant and protective agent, and mixing is filled in the enteric capsule shell, promptly gets alendronate sodium intestine-sol capsule.
The preparation method of above-mentioned alendronate sodium intestine-sol capsule specifically comprises the steps preparation: a, Alendronate sodium is crossed 100 mesh sieves, and all the other components are crossed 80 mesh sieves, get the abundant mix homogeneously of Alendronate sodium and diluent; With 2% hypromellose (HPMC) solution (with the preparation of 50% ethanol) wet granulation, to cross 24 mesh sieves and make wet granular, oven drying at low temperature makes dried granule; Dried granule with 20 mesh sieve granulate, is added lubricant and protective agent, mix homogeneously, fill gets alendronate sodium intestine-sol capsule in enteric coated capsule.
Percentage composition of the present invention is weight percentage, and material therefor is all commercially available gets.
Chinese Pharmacopoeia (version appendix IE in 2005) is defined as enteric coated capsule: enteric coated capsule means that hard capsule or soft capsule are with suitable enteric material preparation and get, or uses the capsule of making through enteric material coated granules or piller capsule charge.Enteric coated capsule is insoluble to gastric juice, but can be in intestinal juice disintegrate and release of active ingredients.Tradition enteric coated capsule preparation technology has two big classes; one class is that medicine and adjuvant are prepared into micropill or granule earlier; enteric coated again; common material has acrylic resin or Opadry enteric solubility etc.; some specific drugs also will wrap one deck contagion gown earlier outside micropill and granule; wrap again with enteric coating, then the granule of wrapping clothing or micropill fill in conventional capsule.This method is more common technology at present in enteric coated capsule, under the good situation of granule or micropill coating effect, can guarantee to discharge medicine in intestinal, generally is not prone to situation about discharging in advance under one's belt.As omeprazole enteric-coated capsules common on the market, Lansoprazole sodium enteric coated capsule etc.This method coating effect is good, but shortcoming is a complex production process, and equipment and technical level of operators are required height, and production cost is higher, and there is certain potential safety hazard in the organic vapor that produces in the coating process, and antiknock device need be installed in the workshop.Another kind of technology is to adopt common granulation or pill method to prepare capsule 's content, and fill is in enteric coated capsule again.This method is comparatively simple and easy to do, is fit to most of common solid preparation workshop.But under existence conditions, the preparation technology of enteric hungry area softgel shell is not perfect, sometimes can appear at fracture phenomena in the gastric juice, can not ensure the quality of products fully.Adopt launch also rare of the enteric coated capsule that this method produces, particularly this need of Alendronate sodium are strict controlled in the outer medicine that discharges of intestinal, if direct this technology of employing has very big risk to patient's body health.
Beneficial effect of the present invention compared with the prior art: the present invention has added an amount of protective agent especially; guarantee the safety that the patient takes medicine under specific condition; even make enteric coated capsule run into comparatively under the exacting terms; can guarantee that also Alendronate sodium discharges in intestinal; avoid that Alendronate sodium directly contacts with mucosa in oral cavity, esophagus and stomach, patient body is caused discomfort.The present invention need not adopt granule or the enteric coated technology of micropill, adopts common granulation technique, just can finish the production of product, has simplified production technology.Therefore, the technology of the present invention lowers energy consumption and to the pollution of environment, has increased safety when ensuring drug quality, and helps obtaining good economic and social benefit.
The specific embodiment:
Further understand content of the present invention by embodiments of the invention given below, but the present invention is not subjected to the qualification of embodiment.
Embodiment 1 does not add protectant alendronate sodium intestine-sol capsule, hereinafter to be referred as capsule 1
#
Write out a prescription following (1000 amounts):
Alendronate sodium 10g
Starch 80g
2%HPMC solution (with the preparation of 50% ethanol) 30ml
Magnesium stearate 0.5g
Preparation technology: Alendronate sodium is crossed 100 mesh sieves, and starch, magnesium stearate are crossed 80 mesh sieves, get the Alendronate sodium and the abundant mix homogeneously of starch of formula ratio; With 2%HPMC solution (with the preparation of 50% ethanol) wet granulation, to cross 24 mesh sieves and make wet granular, 55 ℃ of oven dry make dried granule; Dried granule with 20 mesh sieve granulate, is added magnesium stearate, and mix homogeneously is filled in the enteric coated capsule, gets alendronate sodium intestine-sol capsule.
Embodiment 2 adopts the alendronate sodium intestine-sol capsule of common process, hereinafter to be referred as capsule 2
#
Write out a prescription following (1000 amounts):
Alendronate sodium 10g
Microcrystalline Cellulose 80g
2%HPMC solution (with the preparation of 50% ethanol) 30ml
Acrylic resin II 9g
Magnesium stearate 0.5g
Preparation technology: Alendronate sodium is crossed 100 mesh sieves, and microcrystalline Cellulose, magnesium stearate are crossed 80 mesh sieves, get the Alendronate sodium and the abundant mix homogeneously of microcrystalline Cellulose of formula ratio; With 2%HPMC solution (with the preparation of 50% ethanol) wet granulation, to cross 24 mesh sieves and make wet granular, 55 ℃ of oven dry make dried granule; In the granule coating machine, carry out coating, enteric coating liquid is acrylic resin II (is made into mass percent concentration be 5% aqueous solution), is sprayed on the granule coating weightening finish 10% uniformly, with the magnesium stearate mix homogeneously, be filled into the enteric capsulae vacuus after 40 ℃ of oven dry.
Embodiment 3 alendronate sodium intestine-sol capsules of the present invention are hereinafter to be referred as capsule 3
#
Write out a prescription following (1000 amounts):
Alendronate sodium 10g
Starch 80g
Carbomer 934 P 1g
2%HPMC solution (with the preparation of 50% ethanol) 30ml
Magnesium stearate 0.5g
Preparation technology: Alendronate sodium is crossed 100 mesh sieves, and starch, carbomer 934 P, magnesium stearate are crossed 80 mesh sieves, get the Alendronate sodium and the abundant mix homogeneously of starch of formula ratio; With 2%HPMC solution (with the preparation of 50% ethanol) wet granulation, to cross 24 mesh sieves and make wet granular, 55 ℃ of oven dry make dried granule; Dried granule with 20 mesh sieve granulate, is added carbomer 934 P and magnesium stearate, and mix homogeneously is filled in the enteric coated capsule, gets alendronate sodium intestine-sol capsule
Embodiment 4 alendronate sodium intestine-sol capsules of the present invention are hereinafter to be referred as capsule 4
#
Write out a prescription following (1000 amounts):
Alendronate sodium 15g
Starch 70g
Carbomer 934 4g
2%HPMC solution (with the preparation of 50% ethanol) 30ml
Micropowder silica gel 1g
Preparation technology: Alendronate sodium is crossed 100 mesh sieves, and starch, carbomer 934, magnesium stearate are crossed 80 mesh sieves, get the Alendronate sodium and the abundant mix homogeneously of starch of formula ratio; With 2%HPMC solution (with the preparation of 50% ethanol) wet granulation, to cross 24 mesh sieves and make wet granular, 55 ℃ of oven dry make dried granule; Dried granule with 20 mesh sieve granulate, is added carbomer 934 and micropowder silica gel, and mix homogeneously is filled in the enteric coated capsule, gets alendronate sodium intestine-sol capsule.
Embodiment 5 alendronate sodium intestine-sol capsules of the present invention are hereinafter to be referred as capsule 5
#
Write out a prescription following (1000 amounts):
Alendronate sodium 20g
Microcrystalline Cellulose and lactose (weight ratio 1: 1) 100g
Carbomer 934 P 5g
2%HPMC solution (with the preparation of 50% ethanol) 30ml
Micropowder silica gel and magnesium stearate (weight ratio 1: 1) 2g
Preparation technology: Alendronate sodium is crossed 100 mesh sieves, 80 mesh sieves are crossed in the mixture of microcrystalline Cellulose and lactose (weight ratio 1: 1), carbomer 934 P, micropowder silica gel, get fully mix homogeneously of the Alendronate sodium of formula ratio and the mixture of microcrystalline Cellulose and lactose (weight ratio 1: 1); With 2%HPMC solution (with the preparation of 50% ethanol) wet granulation, to cross 24 mesh sieves and make wet granular, 55 ℃ of oven dry make dried granule; Dried granule with 20 mesh sieve granulate, is added the mixture (weight ratio 1: 1) of carbomer 934 P and micropowder silica gel and magnesium stearate, and mix homogeneously is filled in the enteric coated capsule, gets alendronate sodium intestine-sol capsule.
Test below by release in the acid solution beneficial effect of the present invention is described, design is the environment of simulated gastric fluid, with reference to two appendix X of Chinese Pharmacopoeia version in 2005 C dissolution method, measure 0.1mol/L hydrochloric acid solution 250ml, inject each stripping rotor, heat and make solution temperature remain on 37 ℃ ± 0.5 ℃, the adjustment rotating speed is 100 rev/mins and keeps stable, gets each embodiment capsule respectively, drops in the stripping rotor, start apparatus working, respectively at 2 hours, observe the capsule outward appearance in the time of 3 hours, draw solution is an amount of simultaneously, microporous filter membrane through being not more than 0.8 micron filters immediately, measure, calculate burst size in every capsules acid, to contain the ratio value representation that accounts for labelled amount of Alendronate sodium, the internal control investigation standard that we formulate is: after 3 hours, the Alendronate sodium burst size must not surpass 10% in the dissolution fluid.
Test 1, alendronate sodium intestine-sol capsule 1
#Release test in the acid solution
Alendronate sodium intestine-sol capsule 1
#, 2 batches of each 6 capsules drop in the stripping rotor, and operation the results are shown in Table 1 according to the method described above.Capsule 1
#Soaked 2 hours in acid solution, have 2 capsules to produce little slight crack, the burst size of measuring Alendronate sodium in the acid solution has surpassed 10%, has surpassed limit.After 3 hours, the quantity that capsule produces slight crack has reached 5, measures the burst size of Alendronate sodium, has all surpassed 50%.As seen the enteric coated capsule of traditional handicraft is in acid solution in 2 hours (belonging to the Chinese Pharmacopoeia basic demand time), even can not guarantee protection to content fully; After 3 hours, the capsular burst size of nearly half goes beyond the limit.So the capsule that this formulation and technology prepares can't effectively be protected its content.
Table 1 capsule 1
#Release test in the acid solution
Test 2, alendronate sodium intestine-sol capsule 2
#Release test in the acid solution
Alendronate sodium intestine-sol capsule 2# has adopted granule coating technology, fill makes in common capsulae vacuus, the release test method is the same, because the conventional capsule shell is dissolved in the 0.1mol/L hydrochloric acid solution, so deliberated index is mainly the burst size of Alendronate sodium in dissolution fluid.The results are shown in Table 2, as seen, adopted granule coating technology, through testing in 2 hours the acid solution, the burst size of Alendronate sodium all is no more than 10%, can satisfy appraisal standards, but through release experiment in 3 hours the acid solution, in the capsule of half, the burst size of Alendronate sodium surpasses 10%, and indivedual capsules surpass 20%.
Table 2 capsule 2
#Release test in the acid solution
Test 3, alendronate sodium intestine-sol capsule 3
#, 4
#, 5
#Release test in the acid solution
Alendronate sodium intestine-sol capsule 3
#, 4
#, 5
#Adopt the preparation of this programme method, fill is in the enteric capsulae vacuus, so investigate canonical reference 1
#The enteric coated capsule test.Through testing in 2 hours the acid solution, the minority capsules break, but release is very low, and the Alendronate sodium release of ruptured capsules is lower than 3%; After 3 hours, the part enteric coated capsule breaks, but the burst size of Alendronate sodium all is lower than 10%.The results are shown in Table 3, table 4, table 5.As seen adopted the capsule of this case method preparation, the release of blocking the content in the ruptured capsules has been played good effect.
Table 3 capsule 3
#Release test in the acid solution
Table 4 capsule 4
#Release test in the acid solution
Table 5 capsule 5
#Release test in the acid solution
Test 4, alendronate sodium intestine-sol capsule 3
#, 4
#, 5
#Conventional release inspection.
Get this product, according to drug release determination method (Chinese Pharmacopoeia version in 2005 two appendix X D second method (two) method), adopt the device (two appendix X of Chinese Pharmacopoeia version in 2005 C) of the dissolution method three therapeutic methods of traditional Chinese medicine, 250ml is a release medium with hydrochloric acid solution (9 → 1000), rotating speed is that per minute 100 changes, operation in accordance with the law, in the time of 2 hours, immediately stirring arm is risen from liquid level, discards the acid solution in each stripping rotor, in each stripping rotor, add immediately be preheated to 37 ℃ ± 0.5 ℃ ammonia-ammonium chloride buffer (pH8.0) 100ml as release medium, rotating speed is constant, continue operation in accordance with the law, in the time of 45 minutes, get solution, filter, measure, calculate the burst size of Alendronate sodium, limit is 80% of a labelled amount.Result of the test as seen, 3
#, 4
#, 5
#The release result of alendronate sodium intestine-sol capsule is all good, and an amount of protective agent carbomer does not influence the normal release of principal agent in intestinal, does not influence conventional release check result.Carbomer has certain slow releasing function, so used in amounts will get by experiment sieving in suitable scope, otherwise can influence the normal release of medicine.Capsule 4
#, 5
#Contain the more of carbomer, so release is not as capsule 3
#, wherein capsule 5
#Release near 80%.
Table 6 alendronate sodium intestine-sol capsule 3
#, 4
#, 5
#The release test
| 3 #Capsule | 4 #Capsule | 5 #Capsule | |
| The capsule numbering | Release % | Release % | Release % |
| 1 | 92.4 | 86.3 | 84.3 |
| 2 | 93.2 | 87.5 | 82.5 |
| 3 | 90.6 | 89.3 | 81.3 |
| 4 | 96.4 | 85.5 | 83.9 |
| 5 | 95.2 | 88.2 | 82.5 |
| 6 | 92.3 | 87.0 | 82.8 |
| Average % | 93.4 | 87.3 | 82.8 |
Test the pharmacokinetics situation comparable situation of investigating this programme capsule and import tablet by bioavailability more below.Reference preparation is an import Alendronate sodium sheet (Fosamax
Hangzhou Mo Shadong pharmaceutical Co. Ltd import lot number of the repackaged products 08323 every contain Alendronate sodium 70mg), for test preparation be alendronate sodium intestine-sol capsule (according to embodiment 3 methods make lot number 20080812 every contain Alendronate sodium 10mg)
Random screening goes out 24 healthy volunteers, and the range of age is between 19～40 years old, and body weight is at 48～90kg, height 151～183cm.All experimenters pass through clinical screening, (experimenter is divided into 2 groups by randomly assigne according to 2 * 2 cross-mode of standard, two cycles intersected was spaced apart for 1 week), two groups of volunteers take 1 alendronic Acid sheet (containing Alendronate sodium 70mg) or 7 of alendronate sodium intestine-sol capsules (containing Alendronate sodium 70mg altogether) respectively, between each dosage are arranged 6 days elimination phase.Take medicine the back respectively at 0.25,0.5,0.75,1,1.5,2,3,4,5,6 and 7 hours, respectively get blood once, from intubate, extract the blood sample of about 7ml, get blood at every turn after, wash intubate with 1 milliliter of heparin injecting normal saline solution.Every part of blood sample is centrifugal immediately, and blood plasma detects the plasma concentration of Alendronate sodium-70 ℃ of chilled storages until HPLC-FD.
Clinical observation shows, take among the reference preparation group experimenter of Alendronate sodium sheet slight side reaction is arranged, muscular soreness (2 people), tired (3 people), gastrointestinal symptom (4 people), and the slight side reaction of preparation group of being had a try of taking the alendronate sodium intestine-sol capsule of the inventive method preparation, muscular soreness (1 people), tired (2 people) do not see the reaction of gastrointestinal tract ill symptoms.
Pharmacokinetic analysis shows, will be subjected to the AUC of test preparation and reference preparation
0-7h, Cmax is through to the two one-side t checks of the laggard capable variance analysis of number conversion and Su Shiman, the result shows variance analysis there was no significant difference between two preparations.According to the bioequivalence criterion, be subjected to 90% confidence interval of test preparation AUC drop on reference preparation 80%～125% between, show that 2 kinds of preparations meet bioequivalence.Added protectant alendronate sodium intestine-sol capsule and consistent bioequivalence has been arranged with the import ordinary tablet.See table 7 for details.
Table 7 reference tablet and confession test piece agent pharmacokinetic parameter
Explain: AUC: peak area under curve during medicine; C
Max: maximum plasma concentration; T
Max: peak time; CL/F: clearance rate; V/F: apparent volume of distribution; Kel: remove constant; Ka: one-level absorption rate constant; t
1/2: the half-life; Tlag: lag time
Claims (4)
1. an alendronate sodium intestine-sol capsule is characterized in that this enteric coated capsule is mainly composed of the following components: Alendronate sodium 10-20 weight portion, diluent 70-100 weight portion, protective agent 0.5-5 weight portion and lubricant 0.5-2 weight portion; Wherein, described diluent be in starch, microcrystalline Cellulose and the lactose one or more with any than mixing; Described lubricant be in magnesium stearate and the micropowder silica gel one or both with any than mixing; Described protective agent be among carbomer 934 and the 934P one or both with any than mixing.
2. alendronate sodium intestine-sol capsule according to claim 1 is characterized in that described alendronate sodium intestine-sol capsule mainly by Alendronate sodium 10 weight portions, starch 80 weight portions, and 1 weight portion carbomer 934 P, magnesium stearate 0.5 weight portion is formed.
3. the preparation method of the described alendronate sodium intestine-sol capsule of claim 1 is characterized in that this method specifically comprises the steps:
A, each component is sieved, get the abundant mix homogeneously of Alendronate sodium and diluent;
B, wet granulation, oven dry makes dried granule;
C, granulate add lubricant and protective agent, and mixing is filled in the enteric capsule shell, promptly gets alendronate sodium intestine-sol capsule.
4. the preparation method of alendronate sodium intestine-sol capsule according to claim 3 is characterized in that this method comprises the steps:
A, Alendronate sodium is crossed 100 mesh sieves, all the other components are crossed 80 mesh sieves, get the abundant mix homogeneously of Alendronate sodium and diluent;
B, employing concentration are 2% hypromellose solution wet granulation of 50% ethanol preparation, cross 24 mesh sieves, make wet granular, and oven dry makes dried granule;
C, with dried granule with 20 mesh sieve granulate, add lubricant and protective agent, mix homogeneously is filled in the enteric capsule shell, alendronate sodium intestine-sol capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100326950A CN101601662B (en) | 2009-06-30 | 2009-06-30 | Alendronate sodium intestine-sol capsule and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100326950A CN101601662B (en) | 2009-06-30 | 2009-06-30 | Alendronate sodium intestine-sol capsule and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101601662A CN101601662A (en) | 2009-12-16 |
| CN101601662B true CN101601662B (en) | 2011-08-31 |
Family
ID=41467660
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100326950A Active CN101601662B (en) | 2009-06-30 | 2009-06-30 | Alendronate sodium intestine-sol capsule and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101601662B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002009631A1 (en) * | 2000-07-27 | 2002-02-07 | Umd, Inc. | Vaginal delivery of bisphosphonates |
| CN1582949A (en) * | 2004-06-02 | 2005-02-23 | 石家庄制药集团欧意药业有限公司 | Enteric soluble preparation of Alun phosphorate and its preparing method |
-
2009
- 2009-06-30 CN CN2009100326950A patent/CN101601662B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002009631A1 (en) * | 2000-07-27 | 2002-02-07 | Umd, Inc. | Vaginal delivery of bisphosphonates |
| CN1582949A (en) * | 2004-06-02 | 2005-02-23 | 石家庄制药集团欧意药业有限公司 | Enteric soluble preparation of Alun phosphorate and its preparing method |
Non-Patent Citations (2)
| Title |
|---|
| 于莲等.4_氨基水杨酸钠结肠靶向胶囊定位研究.《黑龙江医药科学》.2009,第32卷(第1期),6-7. * |
| 王宪英等.卡波姆作为药用辅料的应用进展.《中国药业》.2003,第12卷(第7期),74-75. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101601662A (en) | 2009-12-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK172236B1 (en) | Drug containing dipyridamole or mopidamole and o-acetylsalicylic acid or physiologically acceptable salts thereof | |
| CN101596165B (en) | Pantoprazole sodium enteric-coated pellet | |
| FI87528C (en) | FOERFARANDE FOER FRAMSTAELLNING AV EN ORAL DOSENHET AV POTASSIUM CHLORIDE | |
| CN105338958A (en) | Gastro-retentive sustained-release oral dosage form of a bile acid sequestrant | |
| TW200534844A (en) | Oral matrix formulations comprising licarbazepine | |
| MXPA06010809A (en) | Disintegrating tablets comprising licarbazepine. | |
| CN101991561B (en) | 3,4-dichlorophenyl-propenoyl-sec-butylamine composition | |
| CN101601662B (en) | Alendronate sodium intestine-sol capsule and preparation method thereof | |
| CN108175849A (en) | Polaprezinc oral preparation and the application in ulcerative colitis drug is prepared | |
| CN106361718B (en) | The colon target biology adhesion tablet of monosialotetrahexose ganglioside sodium | |
| CN105919979A (en) | Tetrodotoxin enteric-coated and sustained-release pellet, and preparation method and application thereof | |
| CN105147709B (en) | A kind of purposes of tenofovir dipivoxil or its pharmaceutical salts | |
| CN101543483B (en) | Sinetipin capsule and preparation method and quality detection method thereof | |
| CN102144982B (en) | Minodronate tablets and preparation method thereof | |
| CN102552206B (en) | Medicinal composition with anti-inflammatory and analgesic effects | |
| CN106511344A (en) | Novel application of gastric acid secretion inhibitor | |
| CN105687225B (en) | A kind of pharmaceutical composition for treating irritable bowel syndrome and its preparation method and application | |
| CN105250232B (en) | A kind of Yi Luduo quinolines enteric coatel tablets and preparation method thereof | |
| CN113521067B (en) | Famotidine zinc gluconate preparation composition and preparation method thereof | |
| CN104840444B (en) | It is a kind of to be used to treat pharmaceutical preparation of osteoporosis and preparation method thereof | |
| CN102579389B (en) | Medicine composition | |
| WO2021083089A1 (en) | Pharmaceutical composition containing alginate oligosaccharide diacid | |
| CN101785761A (en) | Compound hemostasis medicine and preparation method thereof | |
| CN104857017A (en) | Ilaprazole pharmaceutical composition | |
| Bhasha | Generic Formulation Development of Misoprostol 200 Tablet and Its Evaluation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 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 | ||
| ASS | Succession or assignment of patent right |
Owner name: JIANGSU SHENLONG PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: HU CHUANLIANG Effective date: 20120409 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 210008 NANJING, JIANGSU PROVINCE TO: 224200 YANCHENG, JIANGSU PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20120409 Address after: 224200 Jiangsu Province, Yancheng City Dongtai City Ho duo Road No. 18 Patentee after: Jiangsu Shenlong Pharmaceutical Co., Ltd. Address before: 210008 Jiangsu Honghui Pharmaceutical Co., Ltd., 6 West Beijing Road, Jiangsu, Nanjing Patentee before: Hu Chuanliang |
|
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 224200 Jiangsu Province, Yancheng City Dongtai City Ho duo Road No. 18 Patentee after: Jiangsu Shenlong pharmaceutical Limited by Share Ltd Address before: 224200 Jiangsu Province, Yancheng City Dongtai City Ho duo Road No. 18 Patentee before: Jiangsu Shenlong Pharmaceutical Co., Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 224200, No. 18 North Road, Dongtai, Jiangsu, Yancheng City Patentee after: JIANGSU SHENLONG PHARMACEUTICAL Co.,Ltd. Address before: 224200, No. 18 North Road, Dongtai, Jiangsu, Yancheng City Patentee before: JIANGSU SHENLONG PHARMACEUTICAL Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: No.15 Weiba Road, Dongtai City, Yancheng City, Jiangsu Province 224200 Patentee after: JIANGSU SHENLONG PHARMACEUTICAL Co.,Ltd. Address before: 224200, No. 18 North Road, Dongtai, Jiangsu, Yancheng City Patentee before: JIANGSU SHENLONG PHARMACEUTICAL Co.,Ltd. |