CN104873473A - Potassium chloride sustained-release tablet and preparation method thereof - Google Patents
Potassium chloride sustained-release tablet and preparation method thereof Download PDFInfo
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- CN104873473A CN104873473A CN201510335341.9A CN201510335341A CN104873473A CN 104873473 A CN104873473 A CN 104873473A CN 201510335341 A CN201510335341 A CN 201510335341A CN 104873473 A CN104873473 A CN 104873473A
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- Prior art keywords
- release
- potassium chloride
- slow
- acrylic resin
- modified
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- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 title claims abstract description 144
- 239000001103 potassium chloride Substances 0.000 title claims abstract description 72
- 235000011164 potassium chloride Nutrition 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 239000007939 sustained release tablet Substances 0.000 title abstract description 5
- 239000004925 Acrylic resin Substances 0.000 claims abstract description 26
- 229920000178 Acrylic resin Polymers 0.000 claims abstract description 26
- 239000008188 pellet Substances 0.000 claims abstract description 26
- 238000013268 sustained release Methods 0.000 claims abstract description 25
- 239000012730 sustained-release form Substances 0.000 claims abstract description 25
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000004094 surface-active agent Substances 0.000 claims abstract description 12
- 239000007912 modified release tablet Substances 0.000 claims description 27
- 230000002496 gastric effect Effects 0.000 claims description 25
- 239000006187 pill Substances 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 238000013019 agitation Methods 0.000 claims description 20
- 229940057995 liquid paraffin Drugs 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 230000001804 emulsifying effect Effects 0.000 claims description 10
- 239000000839 emulsion Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 9
- NWGKJDSIEKMTRX-MDZDMXLPSA-N Sorbitan oleate Chemical group CCCCCCCC\C=C\CCCCCCCC(=O)OCC(O)C1OCC(O)C1O NWGKJDSIEKMTRX-MDZDMXLPSA-N 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- 239000002671 adjuvant Substances 0.000 claims description 6
- 239000012467 final product Substances 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 229920000881 Modified starch Polymers 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 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 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 239000011148 porous material Substances 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- 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 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims description 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 description 2
- 238000007907 direct compression Methods 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 23
- 229940079593 drug Drugs 0.000 abstract description 16
- 239000000463 material Substances 0.000 abstract description 7
- 239000003826 tablet Substances 0.000 description 12
- 238000000576 coating method Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000011248 coating agent Substances 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 4
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- 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 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 229960003943 hypromellose Drugs 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 229950005770 hyprolose Drugs 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- NCYVXEGFNDZQCU-UHFFFAOYSA-N nikethamide Chemical compound CCN(CC)C(=O)C1=CC=CN=C1 NCYVXEGFNDZQCU-UHFFFAOYSA-N 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 231100000572 poisoning Toxicity 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- 206010003671 Atrioventricular Block Diseases 0.000 description 1
- 208000012904 Bartter disease Diseases 0.000 description 1
- 208000010062 Bartter syndrome Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- 206010013554 Diverticulum Diseases 0.000 description 1
- 208000007217 Esophageal Stenosis Diseases 0.000 description 1
- 206010061974 Gastrointestinal obstruction Diseases 0.000 description 1
- 208000010271 Heart Block Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000019025 Hypokalemia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030194 Oesophageal stenosis Diseases 0.000 description 1
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000013563 matrix tablet Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- XMXNVYPJWBTAHN-UHFFFAOYSA-N potassium chromate Chemical compound [K+].[K+].[O-][Cr]([O-])(=O)=O XMXNVYPJWBTAHN-UHFFFAOYSA-N 0.000 description 1
- 208000024896 potassium deficiency disease Diseases 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 208000026775 severe diarrhea Diseases 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
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- 238000004448 titration Methods 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a potassium chloride sustained release tablet and a preparation method thereof. The potassium chloride sustained release tablet is formed by directly tabletting gastric-soluble sustained-release pellets, enteric-coated sustained-release pellets and other pharmaceutically acceptable auxiliary materials, wherein the gastric-soluble sustained-release pellets comprise potassium chloride, mesoporous carbon, acrylic resin IV and surfactant; the enteric-coated sustained-release pellets comprise potassium chloride, mesoporous carbon, acrylic resins I-III and surfactant. According to the invention, the potassium chloride sustained release tablet is smooth in drug release, good in drug release stability, and free from burst release.
Description
Technical field
The invention belongs to technical field of medicine, in particular to a kind of slow releasing tablet containing potassium chloride and preparation method thereof.
Background technology
Potassium chloride is clinical conventional electrolyte balance regulating, and clinical efficacy is definite, is widely used in clinical departments room.Be used for the treatment of and prevent the hypokalemia that a variety of causes (hypoalimentation, vomiting, severe diarrhea, application row's potassium diuretic or prolonged application sugar cortex stimulin and adrenal cortex stimulin, lose potassium nephropathy, Bartter syndrome etc.) causes, frequent, the polyphyly premature beat that also can be used for that the poisoning by cardiotonic glycoside such as the heart, renal edema and Folium Digitalis Purpureae cause or rapid heart rate not normal.
As everyone knows, potassium chloride is irritant to gastrointestinal tract, usually cause nausea, vomit, abdominal part do not accommodate diarrhoea.Weakness, weakness, confusion, hypotension, dizzy, heart block may be caused time heavy dose of, even cause death.Often occur poisoning signal when taking potassium chloride, administration that therefore must be very careful for ordinary preparation, in order to reach therapeutic purposes, every day, the potassium chloride dosage of 1-2g usually needed point to take for 2-6 time, and the compliance of patient is very poor.Therefore, potassium chloride can be considered to make sustained-release preparation.The slow releasing tablet listing of existing potassium chloride at home, but because potassium chloride water solublity is very good, existing slow releasing preparation is usually difficult to the release controlling medicine preferably, often there is the prominent generation releasing phenomenon, there is larger potential risk, as released because of prominent the cation potassium causing high local concentrations in gastrointestinal system, cause the symptoms such as gastrointestinal ulceration, hemorrhage and perforation.In addition, existing slow releasing tablet belongs to individual unit system, and stimulating gastrointestinal when Gastrointestinal Obstruction, esophageal stricture, diverticulum, intestinal atonia increases further, can increase the weight of the state of an illness.
CN103006696B discloses a kind of manufacture method of modified-release tablets of potassium chloride, and with hypromellose E15 for slow-release material prepares slow release label, with acrylic resin RS100, acrylic resin RL100 for slow-release material bag is by extended release coatings, and bag is by sugar-coat.
CN102961363B discloses a kind of potassium chloride slow release capsule, the content of described potassium chloride slow release capsule is slow-release micro-pill, slow-release micro-pill is by the supplementary material potassium chloride 70 ~ 97% of percentage by weight, moulding material 0 ~ 10%, slow-release material 2 ~ 20%, plasticizer 0.5 ~ 5% and antiplastering aid 0 ~ 10% form.By potassium chloride and moulding material mix homogeneously, dry granulating machine is adopted to be prepared into medicine carrying micropill; Then slow-release material, plasticizer and antiplastering aid are mixed with into slow release layer coating solution; Medicine carrying micropill is placed in fluid bed, and is injected in fluid bed by the slow release layer coating solution be prepared into, medicine carrying micropill is conventionally carried out coating, prepares slow-release micro-pill, slow-release micro-pill incapsulates, preparation cost invention product potassium chloride slow release capsule.
CN102144985A relates to formula and the technique of Potassium chloride controlled release tablet, adopt ethyl cellulose, polyvinylpyrrolidone, hypromellose etc. for release blocker, in addition with inert excipient acceptable in pharmacy, lubricant, coloring agent according to certain ratio, label is prepared by suitable technique, again with cellulose acetate and be equipped with suitable coating additive prepare parcel label semipermeable membrane, and on film, produce release path, form monocompartment osmotic pump-type controlled release system, the Zero order release of potassium chloride is provided.
The main method reaching slow release in prior art is the diffusion rate being controlled medicine by matrix diffusion, coating membrane diffusion or the use in conjunction of the two, thus reaches slow effect.Widely used potassium chloride slow releasing preparation comprises matrix tablet, film controlled release tablet, slow-release micro-pill etc. clinically, the matrix type release that its slow release releasing mechanism is main or traditional or film controlling type release.There is release heterogeneity, easily prominent releasing or the incomplete problem of release occur in matrix sustained release tablet.
Summary of the invention
In view of the deficiencies in the prior art, the object of the present invention is to provide a kind of drug release steadily, high, the simple modified-release tablets of potassium chloride of preparation method of good stability, bioavailability.
In order to realize object of the present invention, inventor is studied by lot of experiments and updates, and finally obtains following technical scheme:
A kind of modified-release tablets of potassium chloride, it is formed by gastric solubleness slow-release micro-pill, enteric sustained-release pellet and other pharmaceutically acceptable adjuvant direct compression, described gastric solubleness slow-release micro-pill is 1:(0.3-0.5 by mass ratio): (0.3-0.5): the potassium chloride of (0.01-0.03), mesoporous carbon, acrylic resin IV and surfactant form, and described enteric sustained-release pellet is 1:(0.3-0.5 by mass ratio): (0.3-0.5): the potassium chloride of (0.01-0.03), mesoporous carbon, acrylic resin I-III and surfactant form.
Preferably, modified-release tablets of potassium chloride as above, gastric solubleness slow-release micro-pill wherein and the weight ratio of enteric sustained-release pellet are 1:(2-4), preferred weight ratio is 1:3.
Preferably, modified-release tablets of potassium chloride as above, acrylic resin I-III is wherein selected from one or more of acrylic resin I, acrylic resin II and acrylic resin III.
Further preferably, modified-release tablets of potassium chloride as above, pharmaceutically acceptable adjuvant wherein comprises filler, disintegrating agent and lubricant.Further preferably, described filler is selected from one or more in lactose, microcrystalline Cellulose, pregelatinized Starch and starch; Described disintegrating agent is selected from one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and carboxymethyl starch sodium; Described lubricant is selected from one or more in magnesium stearate, silicon dioxide, sodium stearyl fumarate and Pulvis Talci.
Further preferably, modified-release tablets of potassium chloride as above, mesoporous carbon is wherein specific surface area is 1018 ~ 1058m
2/ g, pore volume are 0.51 ~ 0.86cm
3the mesoporous carbon of/g.
Present invention also offers a kind of preparation method of modified-release tablets of potassium chloride, the method comprises the steps:
(1) preparation of gastric solubleness slow-release micro-pill:
1. potassium chloride is dissolved in 0.05-0.2mol/L hydrochloric acid solution, adds mesoporous carbon and stir, then add acrylic resin IV successively, surfactant is stirred to and dissolves completely;
2. the mixed liquor 1. prepared is added in liquid paraffin, even to emulsifying by the rotating speed rapid stirring of 1000 ~ 1500rpm;
3. the emulsion 2. prepared is heated to 100 DEG C under agitation, Keep agitation removing hydrochloric acid, filters, washing liquid paraffin, dry, obtains gastric solubleness slow-release micro-pill;
(2) preparation of enteric sustained-release pellet:
1. potassium chloride is dissolved in saturated ammonia, adds mesoporous carbon and stir, then add acrylic resin I-III successively, surfactant is stirred to and dissolves completely;
2. the mixed solution 1. prepared is added in liquid paraffin, even to emulsifying by the rotating speed rapid stirring of 1000 ~ 1500rpm;
3. the emulsion 2. prepared is heated to 100 DEG C under agitation, Keep agitation removing ammonia, filters, washing liquid paraffin, dry, obtains enteric sustained-release pellet;
(3) will obtain gastric solubleness slow-release micro-pill, enteric sustained-release pellet is mixed homogeneously with other pharmaceutically acceptable adjuvant, tabletting, to obtain final product.
It should be noted that, in the preparation method of modified-release tablets of potassium chloride of the present invention, wherein adopted surfactant is preferably sorbester p17.
Compared with prior art, the modified-release tablets of potassium chloride that the present invention relates to can improve medicine and gastrointestinal contact area, makes drug absorption complete, thus improves bioavailability; Combined by the micropill of several different drug release rate, can obtain desirable rate of releasing drug, drug release is steady, obtains the blood drug level of expection, and can maintain longer action time, and not existing dashes forward releases phenomenon, can avoid untoward reaction such as the stimulations of gastric mucosa; Its drug release behavior is multiple micropill composition compound recipe impact of a composition dosage, and absorption in vivo has good repeatability; Medicine is seldom subject to the impact of gastric emptying change in vivo, and absorption in vivo has good repeatability; Micropill has uniform particle sizes, good fluidity, and not easily the advantage such as crushing, particularly in fine pellet core surface coatings, makes slow releasing preparation, and technique is simple, can avoid tablet etc. due to coating uneven and the risk of medicine pulse may be caused, safety coefficient is high.
Detailed description of the invention
Now further describe preparation process of the present invention and implementation result by following examples, but protection scope of the present invention is not limited to following examples.Those skilled in the art, according to announcement of the present invention, do not depart from improvement that scope makes and amendment all should within protection scope of the present invention.It should be noted that, the mesoporous carbon that embodiment adopts is specific surface area is 1018 ~ 1058m
2/ g, pore volume are 0.51 ~ 0.86cm
3the mesoporous carbon of/g.
Embodiment 1: the preparation of modified-release tablets of potassium chloride
(1) gastric solubleness slow-release micro-pill
(2) enteric sustained-release pellet
(3) slow releasing tablet
Preparation method:
(1) potassium chloride is dissolved in 0.1mol/L hydrochloric acid solution, adds mesoporous carbon and stir, add acrylic resin IV and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing hydrochloric acid solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride gastric solubleness slow-release micro-pill.
(2) potassium chloride is dissolved in saturated ammonia, adds mesoporous carbon and stir, add acrylic resin I and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing sodium hydroxide solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride enteric sustained-release pellet.
(3) gastric solubleness of preparation, enteric sustained-release pellet are mixed homogeneously with pregelatinized Starch, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, the stamping of Φ 20 × 9.5mm scrobicula of bonding, controls about hardness 100-120N, to obtain final product.
Embodiment 2: the preparation of modified-release tablets of potassium chloride
(1) gastric solubleness slow-release micro-pill
(2) enteric sustained-release pellet
(3) slow releasing tablet
Preparation method:
(1) potassium chloride is dissolved in 0.1mol/L hydrochloric acid solution, adds mesoporous carbon and stir, add acrylic resin IV and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing hydrochloric acid solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride gastric solubleness slow-release micro-pill.
(2) potassium chloride is dissolved in saturated ammonia, adds mesoporous carbon and stir, add acrylic resin I and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing sodium hydroxide solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride enteric sustained-release pellet.
(3) gastric solubleness of preparation, enteric sustained-release pellet are mixed homogeneously with microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate, the stamping of Φ 20 × 9.5mm scrobicula of bonding, controls about hardness 100-120N, to obtain final product.
Embodiment 3: the preparation of modified-release tablets of potassium chloride
(1) gastric solubleness slow-release micro-pill
(2) enteric sustained-release pellet
(3) slow releasing tablet
Preparation method:
(1) potassium chloride is dissolved in 0.1mol/L hydrochloric acid solution, adds mesoporous carbon and stir, add acrylic resin IV and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing hydrochloric acid solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride gastric solubleness slow-release micro-pill.
(2) potassium chloride is dissolved in saturated ammonia, adds mesoporous carbon and stir, add acrylic resin I and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing sodium hydroxide solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride enteric sustained-release pellet.
(3) gastric solubleness of preparation, enteric sustained-release pellet are mixed homogeneously with lactose, polyvinylpolypyrrolidone, magnesium stearate, the stamping of Φ 20 × 9.5mm scrobicula of bonding, controls about hardness 100-120N, to obtain final product.
Comparative example 1: the preparation of modified-release tablets of potassium chloride
Preparation method:
Potassium chloride pulverized 100 mesh sieves, mixs homogeneously, add alcohol granulation with microcrystalline Cellulose, hypromellose, crossed 18 mesh sieves, 60 DEG C of dryings, cross 18 mesh sieve granulate, add recipe quantity magnesium stearate, mix homogeneously, Φ 12mm stamping, controls about hardness 90-110N, to obtain final product.
Comparative example 2: the preparation of modified-release tablets of potassium chloride
(1) Core formulation
(2) coating prescription
Ethyl cellulose 5g
Hyprolose 1g
Ethanol 100g
Preparation method:
Potassium chloride pulverized 100 mesh sieves, mixed homogeneously with microcrystalline Cellulose, polyvidone, added 50% alcohol granulation, crossed 18 mesh sieves, 60 DEG C of dryings, cross 18 mesh sieve granulate, add recipe quantity magnesium stearate, mix homogeneously, Φ 12mm stamping, controls about hardness 90-110N, obtains label.Ethyl cellulose and hyprolose are dissolved in ethanol, to the label coating of preparation, to weightening finish about 20%.
Embodiment 4: the drug release determination of modified-release tablets of potassium chloride
Get this product, according to drug release determination method (Chinese Pharmacopoeia version annex X D second method in 2010), adopt dissolution method second subtraction unit (Chinese Pharmacopoeia version annex X C in 2010), with 0-2h with pH1.2 hydrochloric acid solution 500ml for solvent, the pH6.8 phosphate buffer solution 400ml of preheating is added after 2h sampling, rotating speed is 75 turns per minute, operate in accordance with the law, when 1,2,4,6 and 8h, get solution 25ml respectively, filter, and instant release medium of supplementing identical temperature, same volume in process container; Get subsequent filtrate as need testing solution; Another potassium chloride reference substance is appropriate, is dissolved in water and dilutes and make, and is dissolved in water and quantitatively dilutes the solution made about containing 80 μ g in every lml, product solution in contrast.Precision measures need testing solution and gets subsequent filtrate 20mL, adds Neutral potassium chromate indicator 4 respectively, and with 0.01mol/L silver nitrate (specification 0.01mol/L, F=1.013) titration, and adopt blank solvent to correct, drug release determination the results are shown in Table.
Table 1: modified-release tablets of potassium chloride drug release determination result (%)
From the experiment statistics result of table 1, modified-release tablets of potassium chloride prepared by embodiment 1-3 is in 2h release about 25%, mainly because gastric solubleness slow-release micro-pill discharges completely under pH1.2 condition, and enteric coated micropill can not discharge in acid condition, therefore slow releasing tablet of the present invention can not exist and prominent releases phenomenon; Enteric coated micropill has good slow release effect under pH6.8 condition, and 8h medicine releases substantially entirely.Comparative example 1 is ordinary gel type slow releasing tablet, and comparative example 2 is film controlling type slow releasing tablet, and all there is the prominent risk released, the result caused is that in drug release determination process, each sample release differs greatly.
Claims (8)
1. a modified-release tablets of potassium chloride, it is characterized in that, formed by gastric solubleness slow-release micro-pill, enteric sustained-release pellet and other pharmaceutically acceptable adjuvant direct compression, described gastric solubleness slow-release micro-pill is 1:(0.3-0.5 by mass ratio): (0.3-0.5): the potassium chloride of (0.01-0.03), mesoporous carbon, acrylic resin IV and surfactant form, and described enteric sustained-release pellet is 1:(0.3-0.5 by mass ratio): (0.3-0.5): the potassium chloride of (0.01-0.03), mesoporous carbon, acrylic resin I-III and surfactant form.
2. modified-release tablets of potassium chloride according to claim 1, is characterized in that, described gastric solubleness slow-release micro-pill and the weight ratio of enteric sustained-release pellet are 1:(2-4), preferred weight ratio is 1:3.
3. modified-release tablets of potassium chloride according to claim 1, is characterized in that, described acrylic resin I-III is selected from one or more of acrylic resin I, acrylic resin II and acrylic resin III.
4. according to the modified-release tablets of potassium chloride of claim 1 or 2 or 3, it is characterized in that, described pharmaceutically acceptable adjuvant comprises filler, disintegrating agent and lubricant.
5. modified-release tablets of potassium chloride according to claim 4, is characterized in that, described filler is selected from one or more in lactose, microcrystalline Cellulose, pregelatinized Starch and starch; Described disintegrating agent is selected from one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and carboxymethyl starch sodium; Described lubricant is selected from one or more in magnesium stearate, silicon dioxide, sodium stearyl fumarate and Pulvis Talci.
6. according to the modified-release tablets of potassium chloride of claim 1 or 2 or 3, it is characterized in that, described mesoporous carbon is specific surface area is 1018 ~ 1058m
2/ g, pore volume are 0.51 ~ 0.86cm
3the mesoporous carbon of/g.
7. a preparation method for modified-release tablets of potassium chloride, is characterized in that, the method comprises the steps:
(1) preparation of gastric solubleness slow-release micro-pill:
1. potassium chloride is dissolved in 0.05-0.2mol/L hydrochloric acid solution, adds mesoporous carbon and stir, then add acrylic resin IV successively, surfactant is stirred to and dissolves completely;
2. the mixed liquor 1. prepared is added in liquid paraffin, even to emulsifying by the rotating speed rapid stirring of 1000 ~ 1500rpm;
3. the emulsion 2. prepared is heated to 100 DEG C under agitation, Keep agitation removing hydrochloric acid, filters, washing liquid paraffin, dry, obtains gastric solubleness slow-release micro-pill;
(2) preparation of enteric sustained-release pellet:
1. potassium chloride is dissolved in saturated ammonia, adds mesoporous carbon and stir, then add acrylic resin I-III successively, surfactant is stirred to and dissolves completely;
2. the mixed solution 1. prepared is added in liquid paraffin, even to emulsifying by the rotating speed rapid stirring of 1000 ~ 1500rpm;
3. the emulsion 2. prepared is heated to 100 DEG C under agitation, Keep agitation removing ammonia, filters, washing liquid paraffin, dry, obtains enteric sustained-release pellet;
(3) will obtain gastric solubleness slow-release micro-pill, enteric sustained-release pellet is mixed homogeneously with other pharmaceutically acceptable adjuvant, tabletting, to obtain final product.
8. the preparation method of modified-release tablets of potassium chloride according to claim 7, it is characterized in that, described surfactant is sorbester p17.
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| CN110755399A (en) * | 2019-10-29 | 2020-02-07 | 白喜平 | Potassium chloride sustained-release tablet and preparation method thereof |
| CN115554258A (en) * | 2022-10-09 | 2023-01-03 | 广州誉东健康制药有限公司 | Preparation equipment and preparation method of oral potassium chloride sustained-release tablet |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105250239A (en) * | 2015-11-16 | 2016-01-20 | 遵义医学院 | Bilobalide nanometer controlled-release oral preparation and preparation method thereof |
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| CN107823189A (en) * | 2017-11-25 | 2018-03-23 | 杭州高成生物营养技术有限公司 | A kind of chlorination potassium sustained-release pellet and preparation method and application |
| CN110755399A (en) * | 2019-10-29 | 2020-02-07 | 白喜平 | Potassium chloride sustained-release tablet and preparation method thereof |
| CN115554258A (en) * | 2022-10-09 | 2023-01-03 | 广州誉东健康制药有限公司 | Preparation equipment and preparation method of oral potassium chloride sustained-release tablet |
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| CN104873473B (en) | 2017-12-01 |
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Denomination of invention: The invention relates to a potassium chloride sustained-release tablet and a preparation method thereof Effective date of registration: 20220301 Granted publication date: 20171201 Pledgee: Shenzhen high tech investment and financing Company limited by guarantee Pledgor: SHENZHEN ZHONGLIAN PHARMACEUTICAL CO.,LTD. Registration number: Y2022980002008 |
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