CN1981746A - Fluoxetine hydrochloride oral disintegrant tablets and their production - Google Patents
Fluoxetine hydrochloride oral disintegrant tablets and their production Download PDFInfo
- Publication number
- CN1981746A CN1981746A CN 200510129939 CN200510129939A CN1981746A CN 1981746 A CN1981746 A CN 1981746A CN 200510129939 CN200510129939 CN 200510129939 CN 200510129939 A CN200510129939 A CN 200510129939A CN 1981746 A CN1981746 A CN 1981746A
- Authority
- CN
- China
- Prior art keywords
- oral cavity
- disintegration tablet
- cavity disintegration
- fluoxetine hydrochloride
- exchange resin
- 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.)
- Pending
Links
- GIYXAJPCNFJEHY-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine hydrochloride (1:1) Chemical compound Cl.C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 GIYXAJPCNFJEHY-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 229960000389 fluoxetine hydrochloride Drugs 0.000 title claims abstract description 43
- 238000004519 manufacturing process Methods 0.000 title description 2
- 239000007884 disintegrant Substances 0.000 title 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000003456 ion exchange resin Substances 0.000 claims abstract description 30
- 229920003303 ion-exchange polymer Polymers 0.000 claims abstract description 30
- 210000000214 mouth Anatomy 0.000 claims description 55
- 239000003814 drug Substances 0.000 claims description 39
- 229920005989 resin Polymers 0.000 claims description 37
- 239000011347 resin Substances 0.000 claims description 37
- 229920001429 chelating resin Polymers 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 21
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000004373 Pullulan Substances 0.000 claims description 12
- 229920001218 Pullulan Polymers 0.000 claims description 12
- 235000019423 pullulan Nutrition 0.000 claims description 12
- 239000006228 supernatant Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 9
- 239000004471 Glycine Substances 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000000230 xanthan gum Substances 0.000 claims description 7
- 229920001285 xanthan gum Polymers 0.000 claims description 7
- 235000010493 xanthan gum Nutrition 0.000 claims description 7
- 229940082509 xanthan gum Drugs 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000004108 freeze drying Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000007710 freezing Methods 0.000 claims description 5
- 230000008014 freezing Effects 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 150000005846 sugar alcohols Chemical class 0.000 claims description 5
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 4
- 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 4
- 229920002307 Dextran Polymers 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 235000001014 amino acid Nutrition 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 229960002464 fluoxetine Drugs 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- LUEWUZLMQUOBSB-FSKGGBMCSA-N (2s,3s,4s,5s,6r)-2-[(2r,3s,4r,5r,6s)-6-[(2r,3s,4r,5s,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5s,6r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol 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]2[C@H](O[C@@H](OC3[C@H](O[C@@H](O)[C@@H](O)[C@H]3O)CO)[C@@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-FSKGGBMCSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 229920000936 Agarose Polymers 0.000 claims description 2
- 235000001206 Amorphophallus rivieri Nutrition 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 229920002581 Glucomannan Polymers 0.000 claims description 2
- 229920002752 Konjac Polymers 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 2
- 229920002125 Sokalan® Polymers 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
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 229960001631 carbomer Drugs 0.000 claims description 2
- 229940046240 glucomannan Drugs 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 239000000252 konjac Substances 0.000 claims description 2
- 235000010485 konjac Nutrition 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 238000002061 vacuum sublimation Methods 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims 2
- 241001312219 Amorphophallus konjac Species 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 17
- 235000019658 bitter taste Nutrition 0.000 abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 235000019640 taste Nutrition 0.000 description 13
- 239000008213 purified water Substances 0.000 description 12
- 230000000873 masking effect Effects 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 210000003296 saliva Anatomy 0.000 description 6
- 238000001179 sorption measurement Methods 0.000 description 6
- 238000007907 direct compression Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000003729 cation exchange resin Substances 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- SNIXRMIHFOIVBB-UHFFFAOYSA-N N-Hydroxyl-tryptamine Chemical compound C1=CC=C2C(CCNO)=CNC2=C1 SNIXRMIHFOIVBB-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000005057 refrigeration Methods 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000004576 sand Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 210000001779 taste bud Anatomy 0.000 description 2
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 description 1
- 244000247812 Amorphophallus rivieri Species 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 101100412856 Mus musculus Rhod gene Proteins 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 240000005373 Panax quinquefolius Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 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 1
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 1
- 229960005174 ambroxol Drugs 0.000 description 1
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005178 buccal mucosa Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- -1 carboxy-propyl Chemical group 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 229940119744 dextran 40 Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002650 habitual effect Effects 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 230000014860 sensory perception of taste Effects 0.000 description 1
- 239000010117 shenhua Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
An oral disintegrating tablet of fluoxetine hydrochloride features that the bitter taste of fluoxetine hydrochloride is masked by ion exchange resin. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to a kind of fluoxetine Hydrochloride oral cavity disintegration tablet and preparation method thereof, particularly a kind of oral cavity disintegration tablet that ion exchange resin carries out taste masking and preparation method thereof that adopts.
Background technology
Fluoxetine is the reuptake inhibitor of a kind of selectivity five hydroxytryptamine, optionally suppresses the reuptake after central nervous system's presynaptic five hydroxytryptamine discharges, thereby improves the concentration of synaptic space five hydroxytryptamine, produces tangible antidepressant effect.Because of it is very little to other neurotransmitter influences, so animal and human's brain is not had sedation.Abroad, this medicine has been widely used in the clinical treatment of depression.For this chemical compound oral administration is top-priority, and in order to reach this purpose and to guarantee to absorb rapidly the bioavailability of becoming reconciled, the form of the salt of solubility is top-priority, especially has good solubility and nontoxic hydrochlorate.Main sale is fluoxetine hydrochloride capsules in the market.But this single dosage form has seriously hindered the application of fluoxetine Hydrochloride.
Oral disintegrated preparation refer to can be in the oral cavity disintegrate or dissolved preparation rapidly, this type of preparation runs into saliva disintegrate and most of dissolving rapidly in the oral cavity, need not water and just can take.Oral disintegrated preparation comes across the later stage seventies 20th century, and employing Freeze Drying Techniques such as Gregory have been made the pharmaceutical carrier of high porosity, this carrier after the oral cavity runs into saliva can 5-10 in second disintegrate complete.Oral cavity disintegration tablet has the advantage of solid dosage forms, for example: good stability, accurate dose, be easy to produce, little Package size, be easy to carry etc. for the patient.Oral cavity disintegration tablet also has the advantage of liquid dosage form, for example is easy to take, can may stop up the danger that occurs suffocating because of physics as solid dosage forms.The commonplace crowd who is suitable for taking oral cavity disintegration tablet comprises the child, and the old people is bedfast, or the disability patient, and the patient of habitual vomiting, also has anhydrous people at one's side.Certainly the application of oral cavity disintegration tablet also can extend to the patient that need take heavy dose of medicine those every days.Because there is data to show that oral cavity disintegration tablet can reduce dosage under the prerequisite that does not affect the treatment.From the angle of pharmaceuticals industry, oral cavity disintegration tablet can be used as the new way that those patent protection periods are continued the protection of most medicine.
Because tablet can be at Orally disintegrating, the rapid dispersing and dissolving of medicine also can be through buccal mucosa, pharyngeal, gastrointestinal region absorption.Therefore, the bioavailability of the quick acting of medicine and Geng Gao is possible.Because the absorption before the gastrointestinal can be avoided first pass effect, therefore for those through the tangible medicine of liver metabolism, its dosage can be cut down.
Oral disintegrated preparation more and more is subjected to liking of patient with its unique advantages.Therefore have the people to imagine fluoxetine Hydrochloride is prepared into oral cavity disintegration tablet, but because the Orally disintegrating sector-meeting makes the drug component high degree of dispersion in the oral cavity on tongue after the disintegrate, it is clean to need the long period to be removed by excretory saliva.In addition, about 10,000 taste buds are arranged on the tongue according to statistics, the nearly 60-100 of each a taste bud recipient cell.These recipient cells and the medicine ion or the molecule that are dissolved in the saliva react that can produce or the bad sense of taste.Fluoxetine Hydrochloride has good water-solubility, has extremely bitter taste in saliva of buccal cavity after the dissolving, considers the requirement of patient's compliance, and mouthfeel is to estimate one of most important parameter of oral drugs.Therefore if be prepared into oral cavity disintegration tablet, fluoxetine Hydrochloride need be carried out taste masking.Flavoring or taste masking method at present relatively more commonly used mainly contain: the one, and can add correctives or sweeting agent for the medicine that slight disagreeable taste is arranged, but this method when being arranged for solution, the taste masking problem of medicine of utmost point bitter taste cuts little ice almost; Two are to use the polymer coating that can protect drug component in mouth, active component is enclosed in the microcapsule, yet the not only complicated cost of this technology but also high also can bring bioequivalent problem; The 3rd, medicine activity component is used with the form that is insoluble in water, though this method is feasible in theory, but in practice, usually be difficult to find the dissolubility that makes drug component low to complete insipid form in mouth, because tongue even can feel very small amount of material especially has the material of strong taste.And when adopting this method, when obtaining the low solubility drugs form, can generate other high-dissolvability composition simultaneously usually, the height when this can cause oral cavity disintegration tablet to be placed in air draws moist, and then influences the stability of oral cavity disintegration tablet.For example in the taste masking that utilizes sodium bicarbonate to ambroxol hydrochloride, though can access the low solubility form of ambroxol, the sodium chloride of Sheng Chenging has and high draws moistly simultaneously, and this has caused tablet very fast hygroscopic deformation under the condition of ambient temperature and moisture.In addition, absorb in the blood, also need after medicine is swallowed, the insoluble form of drug component dissolve immediately in order to make drug component.
Ion exchange resin is a class functional macromolecule polymer, is applied to a plurality of fields such as water treatment, protein chemistry, analytical chemistry for a long time.From the 1950's, along with the continuous expansion of medicine controlled releasing drug-supplying system research, and the self-growth of polymer material science, ion exchange resin has begun to be used to delay drug release, to improve medicine stability etc.The theoretical basis that ion exchange resin is applied to medicine absorption be can dissociated acidity on the ion exchange resin or basic group can combine with the medicine of positively charged or negative electricity and form insoluble medical resin.This insoluble medical resin discharges medicine hardly under the pH of saliva of buccal cavity condition, and ion exchange resin itself is tasteless, therefore can not experienced any taste by tongue.And when medical resin entered the sour environment in gastro-intestinal digestion road, medicine can moment dissociates from resin, and with ionic form by fast Absorption.
The advantage that is used for taste masking just because of ion exchange resin, therefore inventor's primary study of the present invention ion exchange resin cover up the bitterness of fluoxetine Hydrochloride, but find to adopt common ion exchange resin that fluoxetine Hydrochloride is carried out taste masking, have following problem: at first the granule of conventional ion exchanger resin is all bigger, generally in 0.3～1.2mm scope, major part is between 0.4～0.6mm for the size of resin particle.If adopt so big granule that medicine is adsorbed taste masking, when oral cavity disintegration tablet during disintegrate, though have the effect of well covering up bitterness, can make the people feel tangible sand feeling, even cause dysphagia in the oral cavity; In addition, the adsorption rate of conventional ion exchanger resin is all lower, the absorption medication amount of common every gram ion exchanger resin is about 500 milligrams, medicine for doses, must adopt many above-mentioned ion exchange resin just can cover up the bitterness of medicine, will increase the weight and volume of tablet like this, this can cause the bad sensation in the oral cavity after the oral cavity disintegration tablet disintegrate equally, particularly when adopting cryodesiccated method to prepare, because the principle of its disintegrate is by means of the tablet high voidage, the space of tablet is owing to capillarity absorbs water and disintegrate rapidly, and use traditional ion exchange resin can cause the voidage of oral cavity disintegration tablet to reduce in a large number, thereby cause the prolongation of disintegration time, and for the strong dose thing, need the amount of the ion exchange resin of interpolation also to increase accordingly thereupon, thereby may cause the quality standard of this oral cavity disintegration tablet not meet the relevant regulations that country formulates at oral cavity disintegration tablet.
Cover up fluoxetine Hydrochloride oral cavity disintegration tablet bitterness during disintegrate in the oral cavity so press for a kind of new method at present, thereby prepare the fluoxetine Hydrochloride oral cavity disintegration tablet.
Summary of the invention
Technical problem to be solved by this invention provides the bitterness that a kind of consumption ion exchange resin is seldom covered up fluoxetine Hydrochloride.And imperceptible sand feeling and disintegrate are rapid during the not western orally disintegration tablet Orally disintegrating of the hydrochloric acid that utilizes the preparation of this ion exchange resin.
The present invention provides a kind of method that is very suitable for preparing above-mentioned fluoxetine Hydrochloride oral cavity disintegration tablet on the other hand.
The oral cavity disintegration tablet that the present invention relates to comprises:
Fluoxetine Hydrochloride, ion exchange resin amberlite IRP88, other acceptable adjuvant pharmaceutically.Ion exchange resin Amberlite IRP88 is the copolymer of methacrylic acid and divinylbenzene, is a kind of Subacidity cation type exchanger resin, and its particle size distribution is the 10-120 micron, and 70% below 50 microns, by (the Rohm﹠amp of U.S. Rhom and Hass; Haas Ltd.) produces.
Above-described adjuvant comprises binding agent, skeleton proppant, suspensoid, can also add other sweeting agent, aromatic etc. as required.Binding agent when described binding agent can be the preparation oral cavity disintegration tablet known to the people of this area, preferred, be selected from dextran, Pullulan, sodium alginate, polyvinyl alcohol, chitosan; More preferably dextran, Pullulan, sodium alginate or their mixture, preferred especially Pullulan; Described skeleton proppant can be the adjuvant that plays skeleton support effect known to those of skill in the art, preferably, be selected from sugar, sugar alcohol, inorganic salt, aminoacid or above mixture, more preferably sugar alcohol and aminoacid, particularly preferably be mannitol, erythritol, glycine, serine, arginine or their mixture, most preferably mannitol and glycine.
Because it is water insoluble that the usefulness that the present invention relates to has been adsorbed the ion exchange resin of medicine, therefore need to add suspensoid, suspensoid involved in the present invention can be any suspensoid of this area, preferably, be selected from arabic gum, xanthan gum, carbomer, agarose, Konjac glucomannan, more preferably xanthan gum.
The preparation of the fluoxetine Hydrochloride oral cavity disintegration tablet that the present invention relates to can be adopted all methods of the preparation oral cavity disintegration tablet of present employing, for example direct compression process, freeze-drying etc.
When adopting direct compression process to prepare the oral cavity disintegration tablet that the present invention relates to, must add disintegrating agent, common disintegrating agent has sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, microcrystalline Cellulose, pregelatinized Starch, low-substituted hydroxypropyl cellulose.
In addition, when the oral cavity disintegration tablet that adopts the direct compression process preparation the present invention relates to,, make its mix homogeneously, can also add such as magnesium stearate, the such fluidizer of silicon dioxide in order to increase the flowability of medicine and adjuvant.
The oral cavity disintegration tablet that preparation the present invention relates to preferably adopts freeze-drying, and described freeze-drying comprises:
A) medical resin that will be loaded with fluoxetine mixes with described excipient substance in certain prescription ratio, then freezing;
B) with above-mentioned refrigerated solution for vacuum sublimation drying, drying obtains the agent of porous feeler.
Another aspect of the present invention provides a kind of method for preparing above-mentioned fluoxetine Hydrochloride oral cavity disintegration tablet, and this method comprises:
A) ion exchange resin Amberlite IRP88 is placed container, add certain density fluoxetine Hydrochloride solution then, fully stir;
B) solution left standstill that a) step is obtained is removed supernatant then, has obtained adsorbing the ion exchange resin of medicine;
C) repeat a) step, no longer change up to the supernatant concentration of taking out is the same with the concentration that adds fashionable fluoxetine Hydrochloride.
The concentration of the fluoxetine Hydrochloride that adopts in said method is 8-14mg/ml, but 14mg/ml more preferably.
The specific embodiment
Detailed by the following examples explanation the present invention.
The assay method of ion exchange resin adsorption rate:
The resin of getting it filled is an amount of, the accurate title, decide, put into and put conical flask, add 1mol/l HCl solution 250ml, under 60 ℃ of conditions, constant temperature jolting 2 hours, filter, get subsequent filtrate and measure absorbance at the 226nm place, calculate the content of medical resin Chinese medicine, and then draw the adsorption rate of ion exchange resin medicine.
Embodiment 1
Fluoxetine Hydrochloride (general Lip river, the Zhejiang chemical industry company limited) solution of configuration 14mg/ml, join then in the beaker that fills 10mg cation exchange resin Amberlite IRP88 (production of Rohm and Haas company), evenly stirred 2 hours, leave standstill, remove supernatant, the precipitate deionized water wash then adds the fluoxetine Hydrochloride solution of 14mg/ml again, repeat above-mentioned steps, till the concentration of supernatant is 14mg/ml.Be drying to obtain medical resin at 40 ℃ at last.
By analysis, recording the fluoxetine Hydrochloride that every gram Amberlite IRP88 adsorbs in the said medicine resin is 2.00 grams
(Hayashibara Co.Ltd., Japan) mixing add an amount of purified water, and room temperature is stirred well to whole dissolvings with 12mg glycine (Beijing essence is asked chemical industry Co., Ltd) and 14mg Pullulan; With 0.32mg xanthan gum (Beijing pharmaceutcal corporation, Ltd of Shenhua) separately with after the abundant swelling of purified water, the medical resin that adds above-mentioned preparation then, mixing, then with above-mentioned glycine and Pullulan solution mix homogeneously after, add an amount of purified water, make that the total amount of the above purified water that all adds is 343.68mg, make the medical resin medicinal liquid; Medical resin medicinal liquid vacuum stirring is outgased, use electronic liquor-transferring rifle (Beijing Ji Nuosi scientific ﹠ trading Co., Ltd., 720,110 710040) accurately to be injected in 0.4 milliliter of mould then, through liquid nitrogen (the practical gas company limited of Beijing Praxair, XL-45) spray refrigeration at-110 ℃ after freezing 5 minutes, change freeze dryer (day Science and Technology Ltd. during Beijing speed is former over to, GLZ-0.8) in, in 0.5 millibar of pressure ,-20 ℃ lyophilizing 5 hours to 25 ℃ the condition, promptly obtain fluoxetine Hydrochloride oral cavity disintegration tablet of the present invention.
Embodiment 2
The fluoxetine Hydrochloride solution of configuration 8mg/ml, join then in the beaker that fills 9.5mg cation exchange resin Amberlite IRP88, evenly stirred 4 hours, leave standstill, remove supernatant, the precipitate deionized water wash then adds the fluoxetine Hydrochloride solution of 14mg/ml again, repeat above-mentioned steps, till the concentration of supernatant is 8mg/ml.Be drying to obtain medical resin at 40 ℃ at last.
By analysis, recording the fluoxetine Hydrochloride that every gram Amberlite IRP88 adsorbs in the said medicine resin is 2.10 grams.
With 12mg mannitol (Beijing essence is asked chemical industry Co., Ltd) and 16mg Pullulan mixing, add an amount of purified water, room temperature is stirred well to whole dissolvings; With the 0.32mg xanthan gum separately with after the abundant swelling of purified water, the medical resin that adds above-mentioned preparation then, mixing, then with above-mentioned glycine and Pullulan solution mix homogeneously after, add an amount of purified water, make that the total amount of the above purified water that all adds is 342.18mg, make the medical resin medicinal liquid; Medical resin medicinal liquid vacuum stirring is outgased, use the electronic liquor-transferring rifle accurately to be injected in 0.4 milliliter of mould then, through liquid nitrogen spraying refrigeration at-120 ℃ after freezing 4 minutes, change in the freeze dryer, in 0.5 millibar of pressure ,-20 ℃ lyophilizing 6 hours to 25 ℃ the condition, promptly obtain fluoxetine Hydrochloride oral cavity disintegration tablet of the present invention.
Embodiment 3
The fluoxetine Hydrochloride solution of configuration 14mg/ml, join then in the beaker that fills 9.6mg cation exchange resin Amberlite IRP88, evenly stirred 2 hours, leave standstill, remove supernatant, the precipitate deionized water wash then adds the fluoxetine Hydrochloride solution of 14mg/ml again, repeat above-mentioned steps, till the concentration of supernatant is 14mg/ml.Be drying to obtain medical resin at 40 ℃ at last.
By analysis, recording the fluoxetine Hydrochloride that every gram Amberlite IRP88 adsorbs in the said medicine resin is 2.08 grams.
Dextran 40 (Jiangsu Province's Huanghai Sea pharmaceutcal corporation, Ltd) mixing with 10mg glycine and 10mg Pullulan and 6mg adds an amount of purified water, and room temperature is stirred well to whole dissolvings; With the 0.32mg xanthan gum separately with after the abundant swelling of purified water, the medical resin that adds above-mentioned preparation then, mixing, then with above-mentioned glycine and Pullulan solution mix homogeneously after, add an amount of purified water, make that the total amount of the above purified water that all adds is 344.08mg, make the medical resin medicinal liquid; Medical resin medicinal liquid vacuum stirring is outgased, use the electronic liquor-transferring rifle accurately to be injected in 0.4 milliliter of mould then, through liquid nitrogen spraying refrigeration at-120 ℃ after freezing 5 minutes, change in the freeze dryer, in 0.5 millibar of pressure ,-20 ℃ lyophilizing 5 hours to 25 ℃ the condition, promptly obtain fluoxetine Hydrochloride oral cavity disintegration tablet of the present invention.
Embodiment 4
The fluoxetine Hydrochloride solution of configuration 14mg/ml, join then in the beaker that fills 9.9mg cation exchange resin Amberlite IRP88, evenly stirred 2 hours, leave standstill, remove supernatant, the precipitate deionized water wash then adds the fluoxetine Hydrochloride solution of 14mg/ml again, repeat above-mentioned steps, till the concentration of supernatant is 14mg/ml.Be drying to obtain medical resin at 40 ℃ at last.
By analysis, recording the fluoxetine Hydrochloride that every gram Amberlite IRP88 adsorbs in the said medicine resin is 2.01 grams.
Low replacement carboxy-propyl cellulose, the 26.92mg microcrystalline Cellulose of 242.28mg are mixed with the dehydrated alcohol wet granulation, mix with magnesium stearate and the above-mentioned medical resin that obtains of 39mg again through 60 ℃ of dryings, stir, use direct compression machine direct compression then, the fluoxetine Hydrochloride oral cavity disintegration tablet that obtains the present invention relates to.
The mensuration of comparative example ion exchange resin adsorption rate commonly used
Comparative example 1
Except ion exchange resin Amberlite IRP88 is changed into the Amberlite IRP64, remaining is the same with embodiment 1, prepares the medical resin with Amberlite IRP64 taste masking.
Carry out the mensuration of ion exchange resin adsorption rate for the medical resin of method for preparing, the fluoxetine Hydrochloride that obtains every gram ion exchanger resin Amberlite IRP69 absorption is for being 0.35 to restrain.
Comparative example 2
Except ion exchange resin Amberlite IRP88 is changed into the Amberlite IRP69, remaining is the same with embodiment 1, prepares the medical resin with Amberlite IRP69 taste masking.
Carry out the mensuration of ion exchange resin adsorption rate for the medical resin of method for preparing, the fluoxetine Hydrochloride that obtains every gram ion exchanger resin Amberlite IRP69 absorption is 0.75 gram.
Claims (15)
1. oral cavity disintegration tablet comprises fluoxetine Hydrochloride, ion exchange resin amberlite IRP88, other acceptable adjuvant pharmaceutically.
2. oral cavity disintegration tablet as claimed in claim 1, wherein said adjuvant comprise binding agent, skeleton proppant, suspensoid.
3. oral cavity disintegration tablet as claimed in claim 2, wherein said binding agent is selected from dextran, Pullulan, sodium alginate, polyvinyl alcohol, chitosan.
4. oral cavity disintegration tablet as claimed in claim 3, wherein said binding agent is selected from dextran, Pullulan.
5. oral cavity disintegration tablet as claimed in claim 4, wherein said binding agent are Pullulan.
6. oral cavity disintegration tablet as claimed in claim 2, wherein said skeleton proppant is selected from sugar, sugar alcohol, inorganic salt and aminoacid.
7. oral cavity disintegration tablet as claimed in claim 6, wherein said sugar alcohol are selected from mannitol, red county sugar alcohol.
8. oral cavity disintegration tablet as claimed in claim 6, wherein said aminoacid is selected from glycine, serine, arginine.
9. oral cavity disintegration tablet as claimed in claim 2, wherein said suspension is selected from arabic gum, xanthan gum, carbomer, agarose, Konjac glucomannan.
10. oral cavity disintegration tablet as claimed in claim, wherein said suspension is an xanthan gum.
11. as any described oral cavity disintegration tablet of claim 1-10, its preparation method that adopts is a freeze-drying.
12. oral cavity disintegration tablet as claimed in claim 11, wherein said freeze-drying comprises:
A) medical resin that will be loaded with fluoxetine mixes with described excipient substance in certain prescription ratio, then freezing;
B) with above-mentioned refrigerated solution for vacuum sublimation drying, drying obtains the agent of porous feeler.
13. the preparation method of a fluoxetine oral cavity disintegration tablet comprises:
A) ion exchange resin amberlite IRP88 is placed container, add certain density fluoxetine Hydrochloride solution then, fully stir;
B) solution left standstill that a) step is obtained is removed supernatant then, has obtained adsorbing the ion exchange resin of medicine.
C) repeat a) step, no longer change up to the supernatant concentration of taking out is identical with the concentration that adds fashionable fluoxetine Hydrochloride.
14. preparation method as claimed in claim 13, wherein said finite concentration are 8-14mg/ml.
15. preparation method as claimed in claim 14, the preferred 14mg/ml of wherein said concentration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510129939 CN1981746A (en) | 2005-12-13 | 2005-12-13 | Fluoxetine hydrochloride oral disintegrant tablets and their production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510129939 CN1981746A (en) | 2005-12-13 | 2005-12-13 | Fluoxetine hydrochloride oral disintegrant tablets and their production |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011103943475A Division CN102430122A (en) | 2005-12-13 | 2005-12-13 | Fluoxertine hydrochloride orally disintegrating tablet and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1981746A true CN1981746A (en) | 2007-06-20 |
Family
ID=38164781
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510129939 Pending CN1981746A (en) | 2005-12-13 | 2005-12-13 | Fluoxetine hydrochloride oral disintegrant tablets and their production |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1981746A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102429883A (en) * | 2011-12-29 | 2012-05-02 | 天津市嵩锐医药科技有限公司 | Fluoxetine hydrochloride oral cavity disintegrating pharmaceutical composition |
| CN102525972A (en) * | 2010-12-31 | 2012-07-04 | 量子高科（北京）研究院有限公司 | Calcium-ion antagonist orally disintegrating tablet and preparation method thereof |
| CN103301467A (en) * | 2013-06-20 | 2013-09-18 | 北京阜康仁生物制药科技有限公司 | Stable taste-masking ambroxol hydrochloride compound and preparation method thereof |
| CN105232502A (en) * | 2015-02-10 | 2016-01-13 | 万全万特制药江苏有限公司 | Orally disintegrating tablet containing polacrilin potassium-fluoxertine hydrochloride compound and preparation method of orally disintegrating tablet |
| CN106491545A (en) * | 2016-09-22 | 2017-03-15 | 万特制药(海南)有限公司 | Fluoxetine hydrochloride oral disintegrating tablet and preparation method thereof |
-
2005
- 2005-12-13 CN CN 200510129939 patent/CN1981746A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102525972A (en) * | 2010-12-31 | 2012-07-04 | 量子高科（北京）研究院有限公司 | Calcium-ion antagonist orally disintegrating tablet and preparation method thereof |
| CN102525972B (en) * | 2010-12-31 | 2015-09-30 | 量子高科（北京）研究院有限公司 | A kind of calcium ion antagonist oral cavity disintegration tablet and preparation method thereof |
| CN102429883A (en) * | 2011-12-29 | 2012-05-02 | 天津市嵩锐医药科技有限公司 | Fluoxetine hydrochloride oral cavity disintegrating pharmaceutical composition |
| CN103301467A (en) * | 2013-06-20 | 2013-09-18 | 北京阜康仁生物制药科技有限公司 | Stable taste-masking ambroxol hydrochloride compound and preparation method thereof |
| CN105232502A (en) * | 2015-02-10 | 2016-01-13 | 万全万特制药江苏有限公司 | Orally disintegrating tablet containing polacrilin potassium-fluoxertine hydrochloride compound and preparation method of orally disintegrating tablet |
| CN106491545A (en) * | 2016-09-22 | 2017-03-15 | 万特制药(海南)有限公司 | Fluoxetine hydrochloride oral disintegrating tablet and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2256485T3 (en) | COVERED GRANULES OF AN INHIBITOR OF THE ANGIOTENSIN CONVERSION ENZYME. | |
| ES2347968T3 (en) | SOLID PREPARATION THAT DISAPPEARS RAPIDLY. | |
| US8840924B2 (en) | Compositions and methods of making rapidly dissolving ionically masked formulations | |
| CA2134611C (en) | Process for preparing solid pharmaceutical dosage forms | |
| KR101590115B1 (en) | Pharmaceutical compositions | |
| JP5053865B2 (en) | Method for producing orally disintegrating solid preparation | |
| RU2391115C2 (en) | Compositions and methods of active pharmaceutical ingredient stabilisation | |
| JP4989733B2 (en) | Orally disintegrating tablets | |
| BRPI0620185A2 (en) | pharmaceutical formulation, tablets, and process for the preparation of a pharmaceutical formulation | |
| BRPI0707044A2 (en) | matrix tablets, manufacturing process of matrix tablets and use of a pharmaceutical composition in the form of tablets | |
| EA024945B1 (en) | Nalbuphine-based formulations and uses thereof | |
| CN103813785A (en) | New abuse-resistant pharmaceutical composition for the treatment of opioid dependence | |
| JP6062168B2 (en) | Formulation containing herbal medicine-derived component and method for producing the same | |
| JP4074675B2 (en) | Rapidly disintegrating drug form of tramadol or tramadol salt | |
| KR20090088564A (en) | Pharmaceutical preparation containing choline alfoscerate | |
| BRPI0407116B1 (en) | ACTIVE PRINCIPLE COATED PARTICLE, PHARMACEUTICAL OR COSMETIC COMPOSITION, AND METHOD FOR PRODUCTION OF ACTIVE PRINCIPLE COATED PARTICLE | |
| JP2007517011A (en) | Multiparticulate formulation for oral delivery | |
| CN1981746A (en) | Fluoxetine hydrochloride oral disintegrant tablets and their production | |
| US6726928B2 (en) | Process for preparing solid dosage forms for unpalatable pharmaceuticals | |
| CN105213425A (en) | One treats hypertensive compound recipe reserpine oral cavity disintegration tablet and preparation method thereof | |
| CN106018618B (en) | Escitalopram oxalate tablet composition and quality control method | |
| EP2387993B1 (en) | Orally disintegrating tablets of zolmitriptan and process for preparing the same | |
| WO2009001146A1 (en) | Pharmaceutical composition containing acetylcholine esterase inhibitor and method for the preparation thereof | |
| JP2018525338A (en) | Ornithine aspartate foaming compound | |
| CN102430122A (en) | Fluoxertine hydrochloride orally disintegrating tablet and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20070620 |