CN108403651A - dezocine oral preparation - Google Patents
dezocine oral preparation Download PDFInfo
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- CN108403651A CN108403651A CN201810420839.9A CN201810420839A CN108403651A CN 108403651 A CN108403651 A CN 108403651A CN 201810420839 A CN201810420839 A CN 201810420839A CN 108403651 A CN108403651 A CN 108403651A
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- Prior art keywords
- dezocine
- oral preparation
- oral
- preparation
- cellulose
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- VTMVHDZWSFQSQP-VBNZEHGJSA-N dezocine Chemical compound C1CCCC[C@H]2CC3=CC=C(O)C=C3[C@]1(C)[C@H]2N VTMVHDZWSFQSQP-VBNZEHGJSA-N 0.000 title claims abstract description 149
- 229960003461 dezocine Drugs 0.000 title claims abstract description 148
- 238000002360 preparation method Methods 0.000 title claims abstract description 80
- 239000000463 material Substances 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 238000009472 formulation Methods 0.000 claims abstract description 7
- 239000003826 tablet Substances 0.000 claims description 34
- 239000007939 sustained release tablet Substances 0.000 claims description 30
- 208000002193 Pain Diseases 0.000 claims description 25
- 230000036407 pain Effects 0.000 claims description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- 229920002472 Starch Polymers 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 239000008187 granular material Substances 0.000 claims description 11
- 239000008107 starch Substances 0.000 claims description 11
- 235000019698 starch Nutrition 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 239000000945 filler Substances 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 235000019359 magnesium stearate Nutrition 0.000 claims description 7
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 6
- 239000001856 Ethyl cellulose Substances 0.000 claims description 5
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 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
- 239000011230 binding agent Substances 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 5
- 229920001249 ethyl cellulose Polymers 0.000 claims description 5
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 229940069328 povidone Drugs 0.000 claims description 5
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 229920000609 methyl cellulose Polymers 0.000 claims description 4
- 239000001923 methylcellulose Substances 0.000 claims description 4
- 235000010981 methylcellulose Nutrition 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 238000013268 sustained release Methods 0.000 claims description 4
- 239000012730 sustained-release form Substances 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- 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 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims 2
- 230000001070 adhesive effect Effects 0.000 claims 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims 2
- 239000000843 powder Substances 0.000 claims 2
- 239000000741 silica gel Substances 0.000 claims 2
- 229910002027 silica gel Inorganic materials 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000007950 delayed release tablet Substances 0.000 claims 1
- 238000013265 extended release Methods 0.000 claims 1
- 238000002347 injection Methods 0.000 abstract description 20
- 239000007924 injection Substances 0.000 abstract description 20
- 206010067484 Adverse reaction Diseases 0.000 abstract description 7
- 230000006838 adverse reaction Effects 0.000 abstract description 7
- 238000012360 testing method Methods 0.000 abstract description 7
- 239000008280 blood Substances 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 19
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 16
- 238000002156 mixing Methods 0.000 description 13
- 230000002411 adverse Effects 0.000 description 12
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- 239000002994 raw material Substances 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 229960005181 morphine Drugs 0.000 description 8
- 238000007873 sieving Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 238000011534 incubation Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 229940100688 oral solution Drugs 0.000 description 6
- 208000000094 Chronic Pain Diseases 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000002173 dizziness Diseases 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000003304 gavage Methods 0.000 description 4
- 239000007779 soft material Substances 0.000 description 4
- 206010028813 Nausea Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 238000013401 experimental design Methods 0.000 description 3
- 230000008693 nausea Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 230000008673 vomiting Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000008454 Hyperhidrosis 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
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 229960004667 ethyl cellulose Drugs 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960002900 methylcellulose Drugs 0.000 description 2
- 229960005195 morphine hydrochloride Drugs 0.000 description 2
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000035900 sweating Effects 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- COXBVZVJSNNECT-UHFFFAOYSA-N C=C1CC=CC=CC=C2C(=C1)C=CC(=C2)O Chemical compound C=C1CC=CC=CC=C2C(=C1)C=CC(=C2)O COXBVZVJSNNECT-UHFFFAOYSA-N 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 208000000114 Pain Threshold Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 239000013061 administrable dose form Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 230000023611 glucuronidation Effects 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 229950005770 hyprolose Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 229940124636 opioid drug Drugs 0.000 description 1
- 230000037040 pain threshold Effects 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of oral preparation of dezocine, the dezocine oral preparation is suitable for unit formulation comprising the auxiliary material of the dezocine of 5mg~150mg and optional pharmaceutically acceptable oral preparation.In addition, the invention also discloses the Preparation method and uses of above-mentioned oral preparation.Clinical test shows that in dosage range, dezocine oral preparation of the invention has similar blood concentration with commercially available dezocine injection, and adverse reaction is slight, and administration is more convenient.
Description
The application is a divisional application with application number 201510080325.X and invention name 'dezocine oral preparation' filed on 13/2/2015
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dezocine oral preparation, a preparation method of the dezocine oral preparation, and an application of the dezocine oral preparation in pain treatment.
Background
Dezocine (Dezocine), its chemical name is: 13-amino-5, 6,7,8,9,10,11, 12-octahydro-5-methyl-5, 11-methylenebenzocyclodecen-3-ol. CAS: 53648-55-8.
The structural formula is as follows:
dezocine is a powerful opioid analgesic, which has both agonist and antagonist effects, shows different characteristics by having affinity to receptor subtypes different from other opioid drugs, has stronger analgesic effect than pentazocine and smaller addiction, is mainly used for treating pains of patients suffering from moderate to severe pain and chronic pain after operation, visceral colic and late-stage cancer clinically, has the analgesic strength, the onset time, the action duration and the maximum analgesic effect equivalent to morphine and is 5-9 times stronger than dolantin, has slight side effect and good tolerance, and only markets a dezocine injection formulation at home and abroad at present.
Chinese patent CN104257615A describes a dezocine lyophilized pharmaceutical composition and its preparation method, wherein dezocine, cosolvent, excipient, stabilizer, and acid-base modifier are used to prepare a solution, and the lyophilized composition is obtained after lyophilization.
Chinese patent CN104224734A introduces a dezocine freeze-dried pharmaceutical composition and its preparation method, which comprises: dezocine, freeze-dried excipient, antioxidant, acid-base pH regulator, etc.
The above patents all only describe the preparation method of the lyophilized preparation for injection; compared with injection administration, oral administration is the most common and most convenient and economic means, the administration is convenient, no pain is caused, the stability of the medicine is high, and the dosage can be accurately calculated. However, the oral preparation is unstable in absorption, and when dezocine is administered by injection, glucuronidation occurs mainly in the liver, and excretion occurs mainly in the form of a conjugate of glucuronic acid. On the other hand, no report of oral administration adverse reactions of dezocine exists at present, adverse reactions different from injections may exist by oral administration of dezocine, and the adverse reactions need to pass through proper dosage and prescription so as to avoid adverse reactions. It is therefore very difficult to develop an oral formulation of dezocine according to the prior art.
Disclosure of Invention
The inventor finds out a dezocine oral preparation through a great deal of research, and achieves oral administration and treatment effects under a certain dosage.
The invention aims to provide an oral preparation of dezocine.
The second purpose of the invention is to provide a preparation method of the dezocine oral preparation.
The third purpose of the invention is to provide the application of the dezocine oral preparation.
Specifically, the invention provides an oral dezocine preparation, wherein each unit preparation of the oral dezocine preparation comprises 5-150 mg of dezocine and optional pharmaceutically acceptable auxiliary materials of the oral preparation. By unit formulation is meant each tablet in a tablet, each tube of oral solution, each bag of granules, or each capsule of capsules.
In a preferred embodiment of the present invention, the unit dosage form of the dezocine oral preparation provided by the present invention is orally taken three times a day, and the dezocine oral preparation comprises 5-50 mg of dezocine and optionally pharmaceutically acceptable auxiliary materials for oral preparation.
In a preferred embodiment of the present invention, the unit dosage form of the dezocine oral preparation provided by the present invention is orally taken once a day, and the dezocine oral preparation comprises 10-100 mg of dezocine and optionally pharmaceutically acceptable auxiliary materials for oral preparation.
In an embodiment of the present invention, the dezocine oral preparation provided by the present invention is selected from a pharmaceutical dosage form that can be orally administered, such as a tablet, a capsule, a granule, or an oral solution. Here, the tablets include tablets that can be orally administered, such as general tablets, sustained-release tablets, controlled-release tablets, or dispersible tablets; the capsule comprises a common capsule and various capsules such as a slow release capsule, a controlled release capsule and the like; the granules are sugar-containing or sugar-free granules.
In an embodiment of the present invention, the dezocine oral preparation provided by the present invention is preferably a tablet, more preferably a sustained release tablet.
In a preferred embodiment of the present invention, the dezocine oral preparation provided by the present invention is a dezocine tablet, wherein the pharmaceutically acceptable adjuvants of the oral preparation comprise a filler, a disintegrant, a binder and a lubricant.
In a preferred embodiment of the present invention, the dezocine oral preparation provided by the present invention is a dezocine sustained-release tablet, wherein the pharmaceutically acceptable excipients of the oral preparation comprise a filler, a sustained-release material, a binder and a lubricant.
In an embodiment of the present invention, the present invention provides an oral dezocine preparation, wherein the filler is selected from one or more of microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, and sorbitol, and is preferably microcrystalline cellulose.
In an embodiment of the present invention, the dezocine oral preparation provided by the invention, wherein the sustained-release material is selected from one or more of hypromellose, hyprolose, methylcellulose and ethylcellulose, and hypromellose is preferred.
In an embodiment of the present invention, the present invention provides an oral dezocine preparation, wherein the disintegrant is one or more selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, and dry starch.
In an embodiment of the present invention, the present invention provides an oral formulation of dezocine, wherein the binder is one or more of hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, povidone, or crospovidone.
In an embodiment of the present invention, the dezocine oral preparation provided by the present invention, wherein the lubricant is one or more of magnesium stearate, talc, aerosil and sodium fumarate stearate.
In a second aspect, the present invention provides a method for preparing the above dezocine oral preparation, which comprises mixing 5 mg-150 mg of dezocine with optional pharmaceutically acceptable adjuvants for oral preparation, and formulating into an orally administrable dosage form.
In a third aspect, the invention provides the use of the oral formulation of dezocine as described above for the preparation of a medicament for the treatment of patients with moderate to severe pain and chronic pain after surgery.
The dezocine oral preparation provided by the invention contains a specific amount of dezocine, can effectively treat moderate to severe pain and chronic pain after operation by being taken three times a day or once a day, realizes the treatment effect and has no toxic and adverse effect. Compared with the dezocine injection used for chronic pain in the prior art, the dezocine injection is administered once every 3-6 hours when needed; the oral dezocine preparation achieves the effect of injection administration through oral administration, and is taken once a day for chronic pain.
Drawings
FIG. 1: the time curve (N-5) of single oral administration of dezocine sustained release tablets with different specifications by healthy adult subjects.
FIG. 2: healthy adult subjects compared the drug profiles of oral administration of standard or sustained release tablets of dezocine (10mg) (N ═ 5).
FIG. 3: healthy adult subjects compared the drug profiles of oral administration of standard or sustained release tablets of dezocine (15mg) (N ═ 5).
FIG. 4: healthy adult subjects compared the time curve of oral administration of standard or sustained release tablets (20mg) of dezocine (N ═ 5).
FIG. 5: healthy adult subjects compared the time curve of oral administration of standard or sustained release tablets of dezocine (25mg) (N ═ 5).
FIG. 6: healthy adult subjects compared the drug profiles of oral administration of standard or sustained release tablets of dezocine (30mg) (N ═ 5).
FIG. 7: the dosing profile of dezocine (15mg) in healthy adult subjects was varied (N15).
Detailed Description
The following specific examples are provided to assist the reader in better understanding the present invention, but the following examples are not to be construed as limiting the invention.
Example 1: preparation of dezocine oral solution
Dezocine oral solution
The preparation method comprises the following steps: weighing the crushed and sieved dezocine raw material, adding the purified water and lactic acid according to the prescription amount, dissolving, adjusting the pH value to 3.8, filtering and sterilizing.
Example 2: preparation of dezocine tablet
Prescription of dezocine tablets:
the preparation method comprises the following steps: weighing the crushed and sieved dezocine raw material, mixing the dezocine raw material with lactose, microcrystalline cellulose and carboxymethyl starch sodium according to the formula amount, adding a proper amount of 10% hydroxypropyl methylcellulose solution, uniformly mixing to prepare a proper soft material, sieving by a 16-mesh sieve, preparing into granules, drying at 60 ℃, sieving the dry granules by a 20-mesh sieve, uniformly mixing with magnesium stearate, and tabletting.
Example 3: preparation of dezocine sustained-release tablets
Prescription of dezocine sustained-release tablets:
the preparation method comprises the following steps: weighing the crushed and sieved dezocine raw material, uniformly mixing the dezocine raw material with the microcrystalline cellulose and the povidone K30 according to the formula amount, adding 5% PVP 80% ethanol solution, mixing to prepare a proper soft material, sieving with a 16-mesh sieve, granulating, drying at 60 ℃, sieving dry granules with a 18-mesh sieve, granulating, adding hydroxypropyl methylcellulose (K4M) and magnesium stearate, uniformly mixing, tabletting and coating.
Example 4 preparation of Dizocine tablets
1. Dezocine tablet
Prescription:
the preparation method comprises the following steps: weighing the crushed and sieved dezocine raw material, mixing the dezocine raw material with lactose, microcrystalline cellulose and carboxymethyl starch sodium according to the formula amount, adding a proper amount of 10% hydroxypropyl methylcellulose solution, uniformly mixing to prepare a proper soft material, sieving by a 16-mesh sieve, preparing into granules, drying at 60 ℃, sieving the dry granules by a 20-mesh sieve, uniformly mixing with magnesium stearate, and tabletting.
Example 5: preparation of dezocine sustained-release tablets
Dezocine sustained release tablet
Prescription:
the preparation method comprises the following steps: weighing the crushed and sieved dezocine raw material, uniformly mixing the dezocine raw material with the microcrystalline cellulose and the povidone K30 according to the formula amount, adding 5% PVP 80% ethanol solution, mixing to prepare a proper soft material, sieving with a 16-mesh sieve, granulating, drying at 60 ℃, sieving dry granules with a 18-mesh sieve, granulating, adding hydroxypropyl methylcellulose (K4M) and magnesium stearate, uniformly mixing, tabletting and coating.
Effect example 1: study of pharmacodynamics
The only injection of dezocine is on the market at home and abroad, and no report of relevant oral curative effect exists, so that the influence of the dezocine and morphine on heat radiation and hot plate pain is adopted as the basis for judging whether the dezocine is effective or not after being orally taken compared with mice and rats.
The tested drugs are: dezocine oral solution as described in example 1
Positive drugs: morphine hydrochloride injection
The administration mode comprises the following steps: respectively adopting normal saline to dilute dezocine oral solution and morphine hydrochloride injection, and performing intragastric administration. Administration volume: 10 ml/kg.
Effect of dezocine on pain caused by heat radiation of mice
The method comprises the following steps: female ICR mice were gavaged with 5, 10, 20, 40mg/kg dezocine and 40mg/kg morphine, and controls were given the same volume of saline. After 20 minutes, the pain-causing latency of the mice was measured with a photothermal pain meter.
Table 1: influence of mouse gavage on incubation period of photo-thermal pain
The data in the table are mean ± SD, n is 10. P <0.05, P <0.01, P <0.001
As a result: when the mouse is administrated with dezocine at 10, 20 and 40mg/kg by gastric lavage, the incubation period of tail pain of the mouse caused by light and heat can be obviously prolonged. ED50 was 5.9mg/kg, ED95 was 9.9 mg/kg. Under the experimental condition, 40mg/kg of morphine also has the good effect of prolonging the tail flick incubation period.
Effect of dezocine on Hot plate-induced pain in mice
The method comprises the following steps: male ICR mice, placed on a 55 ℃ hot plate, were challenged with a first lick followed by a paw withdrawal. Mice with pain threshold of 20-35 seconds were selected, and 5 hours later, dezocine (10, 40, 100mg/kg), or morphine (100mg/kg) was gavaged, and the same volume of physiological saline was administered as a control. After 20 minutes, the mixture was placed on a hot plate at 55 ℃ and the time of the first licking was counted.
Table 2: influence of gavage dezocine on hot plate-induced licking latency of mice
The data in the table are mean ± SD, # P <0.001
As a result: when the mice are gavaged with dezocine of 10, 40 and 100mg/kg, the foot licking latency period of the mice can be obviously prolonged. ED50 was 9.4mg/kg and ED95 was 23.0 mg/kg. Under the experimental condition, 100mg/kg of morphine also has good effect of prolonging the latent period.
Effect of dezocine on pain caused by heat radiation of rats
The method comprises the following steps: male wistar rats, fasted for 12 hours, were gavaged with dezocine (1.25, 2.5, 5.0, 10.0, 20.0, 40.0mg/kg), or morphine (5.0, 10.0mg/kg), and controls were given the same volume of saline. After 20 minutes, the pain-causing latency of the rats was measured using a photothermal pain meter.
Table 3: effect of rat gavage on incubation period of photo-thermal pain
The latency data in the table are mean ± SD, # p <0.01, # p <0.001
As a result: see table 3 for details. When the gavage is administered to rats at a dose of more than 2.5mg/kg, the incubation period of tail pain of the rats caused by light and heat can be obviously prolonged. ED50 was 1.5mg/kg, ED95 was 1.9 mg/kg. Rats administered with 10mg/kg morphine also had a good effect of extending the incubation period.
And (4) conclusion: the results of the experiments show that oral dezocine has ED50 values of 5.9, 9.4 and 1.5mg/kg in mouse thermoalgesic, mouse hotplate and rat thermoalgesic models, respectively. The pain relieving effect of dezocine is stronger under the same dosage.
Effect example 2: single oral dezocine common tablet tolerance study in healthy subjects
And (3) experimental design:
30 healthy adult subjects, randomized into 6 groups of 5 persons each, were given the usual tablets of dezocine described in examples 2 and 4 at 5, 10, 15, 20, 25, 30mg doses, respectively, according to body weight. The medicine is taken with warm boiled water in the morning, and is taken once.
On the low to high dose basis, 1 study group was performed daily for safety reasons, and the next study group was performed after the previous group was confirmed to be safe to take the drug. If the number of cases with 1 serious adverse event or moderate or more adverse events in the previous dose group is more than or equal to 50 percent, the test is terminated and the next dose test is not carried out.
As a result:
the main pharmacokinetic parameters of healthy adult subjects taking different doses of standard tablets of dezocine are shown in table 1. Subject orally takes 5-30mg dezocine, dezocine is absorbed very quickly, Tmax1.0-1.2h, and is relatively slow to eliminate in vivo1/2Is 3.7-4.1 h. With increasing dosage, CmaxIn a linear increase, see fig. 1. In the range of 5-30mg, the subjects are safe and tolerant, and adverse events in the test process are mild and moderate. Adverse events occur with increasing doses, with a corresponding increase in frequency and extent. The main adverse events were: nausea, vomiting, dizziness, sweating, etc.
Table 4: major pharmacokinetic parameters of normal tablets of dezocine administered orally at different doses to healthy adult subjects (N ═ 5)
Effect example 3: a single time for healthy subjects: tolerance study of oral dezocine sustained-release tablets
And (3) experimental design:
25 healthy adult subjects, randomly divided into 5 groups by weight, 5 persons in each group, were administered with the dezocine sustained-release tablets of examples 3 and 5 of the present application at doses of 10, 15, 20, 25mg, and 30mg, respectively, once in the morning with warm and empty water.
On the low to high dose basis, 1 study group was performed daily for safety reasons, and the next study group was performed after the previous group was confirmed to be safe to take the drug. If the number of cases with 1 serious adverse event or moderate or more adverse events in the previous dose group is more than or equal to 50 percent, the test is terminated and the next dose test is not carried out.
As a result:
the main pharmacokinetic parameters of healthy adult subjects orally taking different dosages of dezocine sustained release tablets are shown in table 2. When the subject takes 10-30mg dezocine sustained release tablets orally, the absorption is obviously slowed compared with the common tablets, and Tmax2.6-2.8h, the elimination in vivo is also remarkably slowed, t1/2Is 5.7-5.9 h. With increasing dosage, CmaxThe increase is linear. In the range of 10-30mg, the subjects are safe and tolerant, and adverse events in the test process are mild and moderate. Adverse events occur with increasing frequency and extent of dosing. The main adverse events were: nausea, vomiting, dizziness, sweating, etc.
Compared with the common tablet with the same dosage, the dezocine sustained release tablet t1/2And TmaxSignificant elongation, CmaxAlthough slightly reduced, the change was not so great as to exhibit a significant sustained-release property, as shown in FIGS. 2 to 6.
Table 5: major pharmacokinetic parameters of healthy adult subjects orally taking different dosages of dezocine sustained release tablets (N ═ 5)
Effect example 4: comparison of pharmacokinetics of dezocine (15mg) in different modes of administration in healthy subjects
And (3) experimental design:
15 adult healthy subjects, randomized into 3 groups, were designed using a 3-preparation 3-cycle double 3 × 3 latin square trial. One group is taken by injection of 15mg of dezocine, oral common tablets (15mg) and oral sustained-release tablets (15mg) in sequence; the two groups are taken according to the sequence of oral sustained-release tablets (15mg), injection dezocine 15mg and oral ordinary tablets (15 mg); the three groups are taken in the order of oral common tablet (15mg), oral sustained release tablet (15mg) and injection dezocine 15 mg; the washing period is one week.
Results
The main pharmacokinetic parameters of dezocine (15mg) in different modes of administration in healthy adult subjects are given in table 3. Oral 15mg dezocine common tablet and sustained release tablet Cmax15.8 +/-3.2 and 13.9 +/-2.9 ng/ml respectively; oral 15mg dezocine common tablet and sustained release tabletmax1.1 +/-0.3 and 2.7 +/-0.7 hours respectively; injection of 15mg dezocine and oral administration of 15mg dezocine ordinary tablet or sustained release tablet1/2Respectively for 2.7 +/-0.8, 3.8 +/-1.4 and 5.7 +/-2.1 hours; AUC of 15mg dezocine injection and 15mg dezocine oral common tablet or sustained release tablet0-16hRespectively 85.6 + -9.4, 54.1 + -6.1 and 54.1 + -6.1 ug h/L, and the absolute bioavailability of the conventional dezocine tablet and the sustained-release tablet is 63.20% and 65.40%, respectively, as shown in FIG. 7. Adverse events: adverse events occurring with injection administration were nausea (2/15), vomiting (1/15), dizziness (1/15); the adverse events that occur with oral ordinary tablets are dizziness (1/15); the oral sustained-release tablet has no adverse event. Compared with injection administration, the oral dezocine does not produce gastrointestinal adverse reactions, and other adverse reactions are less than those of the injection.
Table 6: major pharmacokinetic parameters of different modes of administration of dezocine (15mg) in healthy adult subjects (N ═ 15)
Claims (9)
1. The unit preparation of the dezocine oral preparation comprises 1 mg-150 mg of dezocine and optional auxiliary materials of pharmaceutically acceptable oral preparations; preferably, the unit dosage form of the dezocine oral preparation contains 5-100 mg of dezocine, and more preferably, the unit dosage form of the dezocine oral preparation contains 5-50 mg of dezocine.
2. The dezocine oral preparation of claim 1, in the form of tablets, capsules, granules, or oral solutions, preferably plain tablets or extended release tablets.
3. The dezocine oral preparation of claim 2, wherein the dezocine oral preparation is a dezocine tablet, taken three times daily.
4. The dezocine oral preparation of claim 2, wherein the dezocine oral preparation is a delayed-release tablet of dezocine, and is orally administered once a day.
5. The dezocine oral preparation of claim 2, wherein the dezocine oral preparation is a conventional dezocine tablet, and the pharmaceutically acceptable auxiliary materials for oral preparation comprise a filler, a disintegrant, a binder and a lubricant;
preferably, the filler is selected from one or more of microcrystalline cellulose, lactose, starch, pre-crosslinked starch, mannitol and sorbitol, and is more preferably microcrystalline cellulose;
the disintegrating agent is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose and dry starch;
one or more of hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, povidone or cross-linked povidone serving as the adhesive;
the lubricant is one or more of magnesium stearate, talcum powder, superfine silica gel powder and fumaric acid sodium stearate.
6. The dezocine oral preparation of claim 2, wherein the dezocine oral preparation is a dezocine sustained release tablet, wherein the pharmaceutically acceptable auxiliary materials for oral preparation comprise a filler, a sustained release material, a binder and a lubricant;
preferably, the filler is selected from one or more of microcrystalline cellulose, lactose, starch, pre-crosslinked starch, mannitol and sorbitol, and is more preferably microcrystalline cellulose;
one or more of hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, povidone or cross-linked povidone serving as the adhesive;
the lubricant is one or more of magnesium stearate, talcum powder, superfine silica gel powder and sodium fumarate stearate;
the slow release material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and ethyl cellulose, and more preferably the hydroxypropyl methylcellulose.
7. The dezocine oral preparation of claim 5, wherein the dezocine oral preparation is a common dezocine tablet, and comprises the following components in percentage by weight:
or,
8. the dezocine oral preparation of claim 6, wherein the dezocine oral preparation is a dezocine sustained release tablet, and comprises the following components in percentage by weight:
or,
9. use of an oral formulation of dezocine as claimed in any of claims 1 to 8 for the preparation of a medicament for the treatment of pain.
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| CN108653446B (en) * | 2018-07-26 | 2019-05-28 | 四川大学华西医院 | Surface anesthesia medicine composition, microemulsion, preparation method and application thereof |
| CN111939145A (en) * | 2020-07-23 | 2020-11-17 | 深圳大学 | Application of dezocine in preparation of nicotinamide phosphoribosyltransferase inhibitor |
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| CN1741790A (en) * | 2003-01-23 | 2006-03-01 | 株式会社太平洋 | Sustained-release preparations and method for producing the same |
| CN101578094A (en) * | 2006-10-10 | 2009-11-11 | 潘威斯脱药物公司 | Robust sustained release formulations of oxymorphone and methods of use thereof |
| CN101578096A (en) * | 2006-10-10 | 2009-11-11 | 潘威斯脱药物公司 | Robust sustained release formulations |
| CN104257615A (en) * | 2014-09-15 | 2015-01-07 | 扬子江药业集团有限公司 | Dezocine freeze-dried pharmaceutical composition and preparation method thereof |
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| CN1741790A (en) * | 2003-01-23 | 2006-03-01 | 株式会社太平洋 | Sustained-release preparations and method for producing the same |
| CN101578094A (en) * | 2006-10-10 | 2009-11-11 | 潘威斯脱药物公司 | Robust sustained release formulations of oxymorphone and methods of use thereof |
| CN101578096A (en) * | 2006-10-10 | 2009-11-11 | 潘威斯脱药物公司 | Robust sustained release formulations |
| CN104257615A (en) * | 2014-09-15 | 2015-01-07 | 扬子江药业集团有限公司 | Dezocine freeze-dried pharmaceutical composition and preparation method thereof |
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| CN116217358A (en) * | 2021-12-03 | 2023-06-06 | 江苏恩华药业股份有限公司 | Bromopentyl substituted aromatic compound and preparation method and application thereof |
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