CN105560202A - Preparation method and application of nalbuphine hydrochloride gel matrix sustained-release tablet - Google Patents
Preparation method and application of nalbuphine hydrochloride gel matrix sustained-release tablet Download PDFInfo
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- CN105560202A CN105560202A CN201610140556.XA CN201610140556A CN105560202A CN 105560202 A CN105560202 A CN 105560202A CN 201610140556 A CN201610140556 A CN 201610140556A CN 105560202 A CN105560202 A CN 105560202A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 239000011159 matrix material Substances 0.000 title abstract description 9
- 229960001513 nalbuphine hydrochloride Drugs 0.000 title abstract 9
- YZLZPSJXMWGIFH-BCXQGASESA-N nalbuphine hydrochloride Chemical compound [H+].[Cl-].C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 YZLZPSJXMWGIFH-BCXQGASESA-N 0.000 title abstract 9
- 239000007939 sustained release tablet Substances 0.000 title abstract 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 80
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 40
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 37
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 37
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 37
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 37
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims abstract description 21
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 86
- 239000000499 gel Substances 0.000 claims description 40
- -1 hydroxypropyl Chemical group 0.000 claims description 20
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 20
- 239000000741 silica gel Substances 0.000 claims description 20
- 229910002027 silica gel Inorganic materials 0.000 claims description 20
- 239000002245 particle Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 12
- 238000007873 sieving Methods 0.000 claims description 10
- 230000001139 anti-pruritic effect Effects 0.000 claims description 9
- 239000003908 antipruritic agent Substances 0.000 claims description 8
- 208000003251 Pruritus Diseases 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000013268 sustained release Methods 0.000 abstract description 3
- 239000012730 sustained-release form Substances 0.000 abstract description 3
- 229910002012 Aerosil® Inorganic materials 0.000 abstract 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 abstract 1
- 229960000913 crospovidone Drugs 0.000 abstract 1
- 230000007547 defect Effects 0.000 abstract 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 abstract 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 abstract 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 abstract 1
- 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 abstract 1
- 238000002156 mixing Methods 0.000 description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 239000008187 granular material Substances 0.000 description 6
- 230000007812 deficiency Effects 0.000 description 5
- 239000000230 xanthan gum Substances 0.000 description 5
- 235000010493 xanthan gum Nutrition 0.000 description 5
- 229920001285 xanthan gum Polymers 0.000 description 5
- 229940082509 xanthan gum Drugs 0.000 description 5
- 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 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- PASHVRUKOFIRIK-UHFFFAOYSA-L calcium sulfate dihydrate Chemical compound O.O.[Ca+2].[O-]S([O-])(=O)=O PASHVRUKOFIRIK-UHFFFAOYSA-L 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229920000161 Locust bean gum Polymers 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000711 locust bean gum Substances 0.000 description 3
- 235000010420 locust bean gum Nutrition 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 244000046052 Phaseolus vulgaris Species 0.000 description 2
- 241001495449 Robinia pseudoacacia Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 235000021332 kidney beans Nutrition 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 2
- 229960000805 nalbuphine Drugs 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 206010063409 Acarodermatitis Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 206010004663 Biliary colic Diseases 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229940121954 Opioid receptor agonist Drugs 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000447727 Scabies Species 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 241000130764 Tinea Species 0.000 description 1
- 239000006061 abrasive grain Substances 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
- 230000009471 action Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 208000019804 backache Diseases 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 210000003746 feather Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000004744 fore-foot Anatomy 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 210000004013 groin Anatomy 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000002632 kappa opiate receptor agonist Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000002623 mu opiate receptor antagonist Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000003402 opiate agonist Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000005687 scabies Diseases 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of medicinal preparations, and in particular relates to a preparation method and application of a nalbuphine hydrochloride gel matrix sustained-release tablet. The invention provides the nalbuphine hydrochloride gel matrix sustained-release tablet, which comprises the following raw materials: nalbuphine hydrochloride, hydroxypropyl methyl cellulose, microcrystalline cellulose, magnesium stearate, aerosil and crospovidone. The invention also provides the preparation method of the nalbuphine hydrochloride gel matrix sustained-release tablet and the application of the nalbuphine hydrochloride gel matrix sustained-release tablet or a product obtained through the preparation method to anti-pruritus. By using the preparation method and the application of the nalbuphine hydrochloride gel matrix sustained-release tablet, which are provided by the invention, the technical defect that the reproducibility of a release curve of a matrix sustained-release layer of a nalbuphine hydrochloride sustained-release tablet is poor in the prior art is solved effectively. Meanwhile, the preparation method and the application of the nalbuphine hydrochloride gel matrix sustained-release tablet also have the advantages that raw materials are easily obtained, and the production cost is low.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly relate to a kind of preparation method and application of nalbuphlne hydrochloride gel skeleton slow releasing tablet.
Background technology
Nalbuphlne hydrochloride is a kind of opioid receptor agonist, and at present listing injection indication comprises: 1, moderate is to the pain relieving of severe pain as wound, postoperative, cancer, kidney or biliary colic: 2, the pain relieving of myocardial infarction and Patients With Angina Pectoris.Nalbuphlne hydrochloride μ receptor antagonist and kappa receptor agonist have double action mechanism, research shows, in zooscopy and human clinical trial's display, nalbuphlne hydrochloride has the curative effect of antipruritic, chronic pruritus is the feature of multiple dermatosis, as: atopic eczema, psoriasis, flat tinea and scabies etc.; Also occur in various non-skin disease, as: cholestasis, chronic renal disease, myeloproliferative disease and hyperthyroidism etc.; Nerve reason (as: backache pain, brachioradialis pruritus and arm are itched) and Nervous and Mental Factors also may cause chronic pruritus.Chronic pruritus generally can continue six weeks, and it may relate to whole skin or only occur in specific field, as: scalp, upper back, arm or groin etc.The sickness rate of chronic pruritus increases along with the increase at age, can have a strong impact on patient sleeps and cause patient's madness, anxiety and depression emotion, extreme influence life matter, shows according to data, antipruritic medicine world market potentiality have 30,000,000,000 dollars, and therefore this medicine market prospect is very wide.
Therefore, existing those skilled in the art develop nalbuphlne hydrochloride slow releasing tablet and have carried out clinical trial.But the skeleton slow release layer release profiles repeatability that prior art is prepared is bad; And the hydrophilic gel matrix material xanthan gum used in prior art and thorn Robinia pseudoacacia L. fresh kidney beans, non-common adjuvant, originate less, production cost is high.
Therefore, develop a kind of preparation method and application of nalbuphlne hydrochloride gel skeleton slow releasing tablet, for solving in prior art, the technological deficiency that the skeleton slow release layer release profiles repeatability of nalbuphlne hydrochloride slow releasing tablet is bad, becomes those skilled in the art's problem demanding prompt solution.
Summary of the invention
In view of this, the invention provides a kind of preparation method and application of nalbuphlne hydrochloride gel skeleton slow releasing tablet, for solving in prior art, the technological deficiency that the skeleton slow release layer release profiles repeatability of nalbuphlne hydrochloride slow releasing tablet is bad.
The invention provides a kind of nalbuphlne hydrochloride gel skeleton slow releasing tablet, the raw material of described nalbuphlne hydrochloride gel skeleton slow releasing tablet comprises: nalbuphlne hydrochloride, hydroxypropyl emthylcellulose, microcrystalline Cellulose, magnesium stearate, micropowder silica gel and polyvinylpolypyrrolidone.
Preferably, in mass parts, the raw material of described nalbuphlne hydrochloride gel skeleton slow releasing tablet comprises: nalbuphlne hydrochloride 40 ~ 70 parts, hydroxypropyl emthylcellulose 40 ~ 60 parts, microcrystalline Cellulose 100 ~ 140 parts, magnesium stearate 15 ~ 25 parts, micropowder silica gel 5 ~ 10 parts and polyvinylpolypyrrolidone 2 ~ 6 parts.
Preferably, in mass parts, the raw material of described nalbuphlne hydrochloride gel skeleton slow releasing tablet comprises: nalbuphlne hydrochloride 50 ~ 60 parts, hydroxypropyl emthylcellulose 45 ~ 55 parts, microcrystalline Cellulose 110 ~ 130 parts, magnesium stearate 16 ~ 20 parts, micropowder silica gel 7 ~ 10 parts and polyvinylpolypyrrolidone 3 ~ 5 parts.
Preferably, in mass parts, the raw material of described nalbuphlne hydrochloride gel skeleton slow releasing tablet comprises: nalbuphlne hydrochloride 60 parts, hydroxypropyl emthylcellulose 50 parts, microcrystalline Cellulose 130 parts, magnesium stearate 18 parts, micropowder silica gel 9 parts and polyvinylpolypyrrolidone 3 parts.
Present invention also offers the preparation method of the raw material of the nalbuphlne hydrochloride gel skeleton slow releasing tablet comprised described in above any one, described preparation method is: step one, take the first deal nalbuphlne hydrochloride, hydroxypropyl emthylcellulose, the first deal microcrystalline Cellulose and the first deal magnesium stearate, mix after sieving respectively, obtain slow release layer; Step 2, take the second deal nalbuphlne hydrochloride, the second deal microcrystalline Cellulose, micropowder silica gel, polyvinylpolypyrrolidone and the second deal magnesium stearate, mix after sieving respectively, obtain release layer; Step 3, described slow release layer and described release layer are prepared double-layer tablet, obtain product.
Preferably, the mass ratio of described first deal nalbuphlne hydrochloride and described second deal nalbuphlne hydrochloride is 3:1, described first deal microcrystalline Cellulose and described second deal microcrystalline Cellulose mass ratio be 10:3, the mass ratio of described first deal magnesium stearate and described second deal magnesium stearate is 5:1.
Preferably, particle diameter after described first deal nalbuphlne hydrochloride sieves is 20 ~ 40 orders, particle diameter after described hydroxypropyl emthylcellulose sieves is 20 ~ 40 orders, particle diameter after described first deal microcrystalline Cellulose sieves is 20 ~ 40 orders, and the particle diameter after described first deal Magnesium Stearate is 20 ~ 40 orders.
Preferably, particle diameter after described second deal nalbuphlne hydrochloride sieves is 20 ~ 40 orders, particle diameter after described second deal microcrystalline Cellulose sieves is 20 ~ 40 orders, described micropowder silica gel sieve after particle diameter be 20 ~ 40 orders, particle diameter after described polyvinylpolypyrrolidone sieves is 20 ~ 40 orders, and the particle diameter after described second deal Magnesium Stearate is 20 ~ 40 orders.
Preferably, the hardness of described product is 11 ~ 16Kp.
Present invention also offers the application of product in antipruritic comprising the preparation method of nalbuphlne hydrochloride gel skeleton slow releasing tablet described in above any one or more described in any one and obtain.
In sum, the invention provides a kind of nalbuphlne hydrochloride gel skeleton slow releasing tablet, the raw material of described nalbuphlne hydrochloride gel skeleton slow releasing tablet comprises: nalbuphlne hydrochloride, hydroxypropyl emthylcellulose, microcrystalline Cellulose, magnesium stearate, micropowder silica gel and polyvinylpolypyrrolidone.Present invention also offers the preparation method of the raw material of the nalbuphlne hydrochloride gel skeleton slow releasing tablet comprised described in above any one, described preparation method is: step one, take the first deal nalbuphlne hydrochloride, hydroxypropyl emthylcellulose, the first deal microcrystalline Cellulose and the first deal magnesium stearate, mix after sieving respectively, obtain slow release layer; Step 2, take the second deal nalbuphlne hydrochloride, the second deal microcrystalline Cellulose, micropowder silica gel, polyvinylpolypyrrolidone and the second deal magnesium stearate, mix after sieving respectively, obtain release layer; Step 3, described slow release layer and described release layer are prepared double-layer tablet, obtain product.Present invention also offers the application of product in antipruritic comprising the preparation method of nalbuphlne hydrochloride gel skeleton slow releasing tablet described in above any one or more described in any one and obtain.The preparation method of a kind of nalbuphlne hydrochloride gel skeleton slow releasing tablet provided by the invention and application, efficiently solve in prior art, the technological deficiency that the skeleton slow release layer release profiles repeatability of nalbuphlne hydrochloride slow releasing tablet is bad.Meanwhile, the preparation method of a kind of nalbuphlne hydrochloride gel skeleton slow releasing tablet provided by the invention and application, also have the advantage that raw material is easy to get and production cost is low.
Detailed description of the invention
Be clearly and completely described to the technical scheme in the embodiment of the present invention below, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
In order to be described in more detail the present invention, below in conjunction with embodiment to the preparation method of a kind of nalbuphlne hydrochloride gel skeleton slow releasing tablet provided by the invention and application, describe particularly.
Embodiment 1
Present embodiments provide the preparation method of the nalbuphlne hydrochloride gel skeleton slow releasing tablet of preparation 1000 60mg specifications.
Take that nalbuphlne hydrochloride 45g is screened to 30 orders, hydroxypropyl emthylcellulose 40g is screened to 30 orders, microcrystalline Cellulose 100g is screened to 30 orders and after magnesium stearate 15g is screened to 30 orders, mixing, obtains slow release layer 1.
Take that nalbuphlne hydrochloride 15g is screened to 30 orders, microcrystalline Cellulose 30g is screened to 30 orders, micropowder silica gel 9g is screened to 30 orders, polyvinylpolypyrrolidone 3g is screened to 30 orders and after magnesium stearate 3g is screened to 30 orders, mixing, obtains release layer 1.
Adopt bi-layer tablet press to prepare double-layer tablet slow release layer 1 and release layer 1, obtain product 1, the hardness of product 1 is 12Kp.
Embodiment 2
Present embodiments provide the preparation method of the nalbuphlne hydrochloride gel skeleton slow releasing tablet of preparation 1000 60mg specifications.
Take that nalbuphlne hydrochloride 45g is screened to 40 orders, hydroxypropyl emthylcellulose 50g is screened to 20 orders, microcrystalline Cellulose 100g is screened to 30 orders and after magnesium stearate 15g is screened to 30 orders, mixing, obtains slow release layer 2.
Take that nalbuphlne hydrochloride 15g is screened to 20 orders, microcrystalline Cellulose 30g is screened to 20 orders, micropowder silica gel 9g is screened to 20 orders, polyvinylpolypyrrolidone 3g is screened to 20 orders and after magnesium stearate 3g is screened to 20 orders, mixing, obtains release layer 2.
Adopt bi-layer tablet press to prepare double-layer tablet slow release layer 2 and release layer 2, obtain product 2, the hardness of product 2 is 11Kp.
Embodiment 3
Present embodiments provide the preparation method of the nalbuphlne hydrochloride gel skeleton slow releasing tablet of preparation 660 90mg specifications.
Take that nalbuphlne hydrochloride 45g is screened to 30 orders, hydroxypropyl emthylcellulose 50g is screened to 40 orders, microcrystalline Cellulose 100g is screened to 30 orders and after magnesium stearate 15g is screened to 30 orders, mixing, obtains slow release layer 3.
Take that nalbuphlne hydrochloride 15g is screened to 40 orders, microcrystalline Cellulose 40g is screened to 40 orders, micropowder silica gel 9g is screened to 40 orders, polyvinylpolypyrrolidone 3g is screened to 40 orders and after magnesium stearate 3g is screened to 40 orders, mixing, obtains release layer 3.
Adopt bi-layer tablet press to prepare double-layer tablet slow release layer 3 and release layer 3, obtain product 3, the hardness of product 3 is 15Kp.
Embodiment 4
Present embodiments provide the preparation method of the nalbuphlne hydrochloride gel skeleton slow releasing tablet of preparation 500 120mg specifications.
Take that nalbuphlne hydrochloride 45g is screened to 30 orders, hydroxypropyl emthylcellulose 50g is screened to 30 orders, microcrystalline Cellulose 100g is screened to 30 orders and after magnesium stearate 15g is screened to 30 orders, mixing, obtains slow release layer 4.
Take that nalbuphlne hydrochloride 15g is screened to 30 orders, microcrystalline Cellulose 30g is screened to 30 orders, micropowder silica gel 9g is screened to 30 orders, polyvinylpolypyrrolidone 3g is screened to 30 orders and after magnesium stearate 3g is screened to 30 orders, mixing, obtains release layer 4.
Adopt bi-layer tablet press to prepare double-layer tablet slow release layer 4 and release layer 4, obtain product 4, the hardness of product 4 is 15Kp.
Comparative example 1
This comparative example provides in prior art, prepares the method for nalbuphlne hydrochloride slow releasing tablet.
Comparative example prescription is as follows, slow release layer: nalbuphlne hydrochloride 45g, xanthan gum 24g, Robinia pseudoacacia L. fresh kidney beans 36g, mannitol 120g, calcium sulphate dihydrate 20g and magnesium stearate 0.8g;
Release layer: nalbuphlne hydrochloride 15g, xanthan gum 0.726g, locust bean gum 1.089g, calcium sulphate dihydrate 0.605g and mannitol 3.63g mixture amount to 6.05g, microcrystalline Cellulose 35.7g, cross-linked carboxymethyl fiber receives 3.0g and magnesium stearate 0.3g.
The preparation technology of comparative example is:
(1), the preparation of xanthan gum, locust bean gum, calcium sulphate dihydrate and mannitol mixture granule: by xanthan gum, locust bean gum, calcium sulphate dihydrate and mannitol dry blending 3 minutes in super mixer/granulator; when running chipper/impeller; to the blended mixts spray water of drying; granulating 6 minutes again; then stop granulation process and remove blender/granulating dish; when running chipper/impeller, granule is remixed 1 minute.After detecting the concordance of granule, when running chipper/impeller, extra water to be added in granule and granulating 3.5 minutes again, then particle drying being less than about 4wt% to LOD (loss on drying), then using No. 1521-0033 sieve abrasive grains.
(2), total mixed pressure sheet: for slow release layer, nalbuphine is mixed 3 minutes with Sustained release delivery system in high shear granulator.Mixture water is carried out granulating until obtain consistent granule, then by wet stock in fluidized bed dryer 70 DEG C of dryings 20 minutes.For release layer, by nalbuphine and Sustained release delivery system, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose, in V-blender blended 10 minutes, make magnesium stearate by #30 order bolter.Respectively the ground granule of releasing layer is at a slow speed mixed 5 minutes with the magnesium stearate of sieving in V-type blender, and the dry blends of release layer is mixed 5 minutes with the magnesium stearate of sieving in V-type blender, be respectively charged into barrel, adopt bi-layer tablet press tabletting; Hardness 10-13Kp.Obtained 100 specifications are the nalbuphlne hydrochloride slow releasing tablet of 60mg/ sheet altogether, are product 5.
Embodiment 5
Present embodiments provide the determination experiment of product 1, product 2, product 3, product 4 and product 5 release in vitro rate.
Adopt existing routine techniques to measure the release in vitro rate of product, in the present embodiment, the instrument of use is USPTypeIII/250mL.Test pH change, 37 DEG C, carry out under the condition of 15dpm.The change of pH is as follows: first hour pH is 1.2, second hour pH be after 4.5, second hour and test duration pH be 6.8, experimental results is in table 1.
Table 1: product release in vitro rate
Can obtain from table 1, the repeatability of the release in vitro rate of product 1, product 2, product 3 and product 4 is due to product 5, preparation method and the application of a kind of nalbuphlne hydrochloride gel skeleton slow releasing tablet provided by the invention are described, efficiently solve in prior art, the technological deficiency that the skeleton slow release layer release profiles repeatability of nalbuphlne hydrochloride slow releasing tablet is bad.
Embodiment 6
The present embodiment is the antipruritic experiment of product 1, product 2, product 3 and product 4.
Rabbit pruritus model is set up: strange card rabbit 30, body weight 2.2 ~ 3.8Kg, male and female dual-purpose, when testing experiment in first 1 day with 1% sodium sulfide by animal, slough for subsequent use by hair of rabbit head right neck ear rear section skin, the skin region area that loses hair or feathers is 1.5cm × 1.5cm.6 groups are divided at random, continuous 5 days, ear intravenous injection dextran 0.85mgkg by very blocking rabbit
-1, simultaneously give made products every day and take with pure water, one time 2, every day three times, scratch trunk as pruritus indication using scratch one's head portion, rear solid end of rabbit fore paw, record rabbit pruritus number of times after 5 days, and compare group difference.
Table 2 difference group strange card rabbit pruritus number of times compares
Known by table 2, prepared product all can antipruritic, and the higher antipruritic effect of dosage is more obvious
In sum, the invention provides a kind of nalbuphlne hydrochloride gel skeleton slow releasing tablet, the raw material of described nalbuphlne hydrochloride gel skeleton slow releasing tablet comprises: nalbuphlne hydrochloride, hydroxypropyl emthylcellulose, microcrystalline Cellulose, magnesium stearate, micropowder silica gel and polyvinylpolypyrrolidone.Present invention also offers the preparation method of the raw material of the nalbuphlne hydrochloride gel skeleton slow releasing tablet comprised described in above any one, described preparation method is: step one, take the first deal nalbuphlne hydrochloride, hydroxypropyl emthylcellulose, the first deal microcrystalline Cellulose and the first deal magnesium stearate, mix after sieving respectively, obtain slow release layer; Step 2, take the second deal nalbuphlne hydrochloride, the second deal microcrystalline Cellulose, micropowder silica gel, polyvinylpolypyrrolidone and the second deal magnesium stearate, mix after sieving respectively, obtain release layer; Step 3, described slow release layer and described release layer are prepared double-layer tablet, obtain product.Present invention also offers the application of product in antipruritic comprising the preparation method of nalbuphlne hydrochloride gel skeleton slow releasing tablet described in above any one or more described in any one and obtain.The preparation method of a kind of nalbuphlne hydrochloride gel skeleton slow releasing tablet provided by the invention and application, efficiently solve in prior art, the technological deficiency that the skeleton slow release layer release profiles repeatability of nalbuphlne hydrochloride slow releasing tablet is bad.Meanwhile, the preparation method of a kind of nalbuphlne hydrochloride gel skeleton slow releasing tablet provided by the invention and application, also have the advantage that adjuvant is easy to get and production cost is low.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a nalbuphlne hydrochloride gel skeleton slow releasing tablet, is characterized in that, the raw material of described nalbuphlne hydrochloride gel skeleton slow releasing tablet comprises: nalbuphlne hydrochloride, hydroxypropyl emthylcellulose, microcrystalline Cellulose, magnesium stearate, micropowder silica gel and polyvinylpolypyrrolidone.
2. nalbuphlne hydrochloride gel skeleton slow releasing tablet according to claim 1, it is characterized in that, in mass parts, the raw material of described nalbuphlne hydrochloride gel skeleton slow releasing tablet comprises: nalbuphlne hydrochloride 40 ~ 70 parts, hydroxypropyl emthylcellulose 40 ~ 60 parts, microcrystalline Cellulose 100 ~ 140 parts, magnesium stearate 15 ~ 25 parts, micropowder silica gel 5 ~ 10 parts and polyvinylpolypyrrolidone 2 ~ 6 parts.
3. nalbuphlne hydrochloride gel skeleton slow releasing tablet according to claim 2, it is characterized in that, in mass parts, the raw material of described nalbuphlne hydrochloride gel skeleton slow releasing tablet comprises: nalbuphlne hydrochloride 50 ~ 60 parts, hydroxypropyl emthylcellulose 45 ~ 55 parts, microcrystalline Cellulose 110 ~ 130 parts, magnesium stearate 16 ~ 20 parts, micropowder silica gel 7 ~ 10 parts and polyvinylpolypyrrolidone 3 ~ 5 parts.
4. nalbuphlne hydrochloride gel skeleton slow releasing tablet according to claim 3, it is characterized in that, in mass parts, the raw material of described nalbuphlne hydrochloride gel skeleton slow releasing tablet comprises: nalbuphlne hydrochloride 60 parts, hydroxypropyl emthylcellulose 50 parts, microcrystalline Cellulose 130 parts, magnesium stearate 18 parts, micropowder silica gel 9 parts and polyvinylpolypyrrolidone 3 parts.
5. comprise a preparation method for the raw material of the nalbuphlne hydrochloride gel skeleton slow releasing tablet described in Claims 1-4 any one, it is characterized in that, described preparation method is:
Step one, take the first deal nalbuphlne hydrochloride, hydroxypropyl emthylcellulose, the first deal microcrystalline Cellulose and the first deal magnesium stearate, mix after sieving respectively, obtain slow release layer;
Step 2, take the second deal nalbuphlne hydrochloride, the second deal microcrystalline Cellulose, micropowder silica gel, polyvinylpolypyrrolidone and the second deal magnesium stearate, mix after sieving respectively, obtain release layer;
Step 3, described slow release layer and described release layer are prepared double-layer tablet, obtain product.
6. preparation method according to claim 5, it is characterized in that, the mass ratio of described first deal nalbuphlne hydrochloride and described second deal nalbuphlne hydrochloride is 3:1, described first deal microcrystalline Cellulose and described second deal microcrystalline Cellulose mass ratio be 10:3, the mass ratio of described first deal magnesium stearate and described second deal magnesium stearate is 5:1.
7. preparation method according to claim 5, it is characterized in that, particle diameter after described first deal nalbuphlne hydrochloride sieves is 20 ~ 40 orders, particle diameter after described hydroxypropyl emthylcellulose sieves is 20 ~ 40 orders, particle diameter after described first deal microcrystalline Cellulose sieves is 20 ~ 40 orders, and the particle diameter after described first deal Magnesium Stearate is 20 ~ 40 orders.
8. preparation method according to claim 5, it is characterized in that, particle diameter after described second deal nalbuphlne hydrochloride sieves is 20 ~ 40 orders, particle diameter after described second deal microcrystalline Cellulose sieves is 20 ~ 40 orders, described micropowder silica gel sieve after particle diameter be 20 ~ 40 orders, particle diameter after described polyvinylpolypyrrolidone sieves is 20 ~ 40 orders, and the particle diameter after described second deal Magnesium Stearate is 20 ~ 40 orders.
9. preparation method according to claim 5, is characterized in that, the hardness of described product is 11 ~ 16Kp.
10. the application of product in antipruritic comprising the nalbuphlne hydrochloride gel skeleton slow releasing tablet described in Claims 1-4 any one or the preparation method described in claim 5 to 9 any one and obtain.
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| CN109862895A (en) * | 2016-10-25 | 2019-06-07 | 特雷维治疗股份有限公司 | Treatment of prurigo nodularis |
| US11660296B2 (en) | 2018-07-23 | 2023-05-30 | Trevi Therapeutics, Inc. | Treatment of chronic cough, breathlessness and dyspnea |
| US12274696B2 (en) | 2020-01-10 | 2025-04-15 | Trevi Therapeutics, Inc. | Methods of administering nalbuphine |
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| EP2606879A1 (en) * | 2011-12-21 | 2013-06-26 | Hexal AG | Multiple unit pellet tablet formulation comprising an opioid |
| US8637538B1 (en) * | 2012-12-14 | 2014-01-28 | Trevi Therapeutics, Inc. | Methods for treatment of pruritis |
| US8771732B2 (en) * | 2005-08-24 | 2014-07-08 | Endo Pharmaceuticals Inc | Sustained release formulations of nalbuphine |
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| CN103025317A (en) * | 2010-08-20 | 2013-04-03 | D&A制药 | Nabuphine preparations and their uses |
| EP2606879A1 (en) * | 2011-12-21 | 2013-06-26 | Hexal AG | Multiple unit pellet tablet formulation comprising an opioid |
| US8637538B1 (en) * | 2012-12-14 | 2014-01-28 | Trevi Therapeutics, Inc. | Methods for treatment of pruritis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109862895A (en) * | 2016-10-25 | 2019-06-07 | 特雷维治疗股份有限公司 | Treatment of prurigo nodularis |
| US11660296B2 (en) | 2018-07-23 | 2023-05-30 | Trevi Therapeutics, Inc. | Treatment of chronic cough, breathlessness and dyspnea |
| US12274696B2 (en) | 2020-01-10 | 2025-04-15 | Trevi Therapeutics, Inc. | Methods of administering nalbuphine |
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