CN117398364A - Controlled-release hydroxypropyl methylcellulose hollow capsule and preparation method thereof - Google Patents
Controlled-release hydroxypropyl methylcellulose hollow capsule and preparation method thereof Download PDFInfo
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- CN117398364A CN117398364A CN202311594311.0A CN202311594311A CN117398364A CN 117398364 A CN117398364 A CN 117398364A CN 202311594311 A CN202311594311 A CN 202311594311A CN 117398364 A CN117398364 A CN 117398364A
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- 239000002775 capsule Substances 0.000 title claims abstract description 83
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 title claims abstract description 67
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 title claims abstract description 67
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 title claims abstract description 67
- 238000013270 controlled release Methods 0.000 title claims abstract description 34
- 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 title claims description 17
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 229960003943 hypromellose Drugs 0.000 claims abstract description 50
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 18
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims abstract description 10
- 239000011591 potassium Substances 0.000 claims abstract description 7
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 7
- 239000003292 glue Substances 0.000 claims description 69
- 238000003756 stirring Methods 0.000 claims description 48
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 claims description 47
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 39
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 39
- 239000000811 xylitol Substances 0.000 claims description 39
- 235000010447 xylitol Nutrition 0.000 claims description 39
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 39
- 229960002675 xylitol Drugs 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical group [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 24
- 239000008213 purified water Substances 0.000 claims description 23
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 22
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 20
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 18
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 18
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 18
- 235000011056 potassium acetate Nutrition 0.000 claims description 12
- 239000000679 carrageenan Substances 0.000 claims description 10
- 235000010418 carrageenan Nutrition 0.000 claims description 10
- 229920001525 carrageenan Polymers 0.000 claims description 10
- 229940113118 carrageenan Drugs 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 238000007598 dipping method Methods 0.000 claims description 10
- 238000007689 inspection Methods 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 238000000465 moulding Methods 0.000 claims description 10
- 238000004321 preservation Methods 0.000 claims description 10
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000000049 pigment Substances 0.000 claims description 9
- 239000001508 potassium citrate Substances 0.000 claims description 8
- 229960002635 potassium citrate Drugs 0.000 claims description 8
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 8
- 235000011082 potassium citrates Nutrition 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000000230 xanthan gum Substances 0.000 claims description 8
- 229920001285 xanthan gum Polymers 0.000 claims description 8
- 235000010493 xanthan gum Nutrition 0.000 claims description 8
- 229940082509 xanthan gum Drugs 0.000 claims description 8
- 229960003975 potassium Drugs 0.000 claims description 6
- 229920002148 Gellan gum Polymers 0.000 claims description 4
- 239000000216 gellan gum Substances 0.000 claims description 4
- 235000010492 gellan gum Nutrition 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 29
- 229910001414 potassium ion Inorganic materials 0.000 abstract description 12
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 230000000052 comparative effect Effects 0.000 description 39
- 239000000243 solution Substances 0.000 description 34
- 239000003814 drug Substances 0.000 description 13
- 244000248349 Citrus limon Species 0.000 description 12
- 235000005979 Citrus limon Nutrition 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 230000001276 controlling effect Effects 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 6
- 239000010452 phosphate Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical group C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009507 drug disintegration testing Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- -1 polytetrafluoroethylene Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000002023 wood 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a controlled-release hypromellose hollow capsule and a preparation method thereof. The invention adopts triethanolamine as an anti-potassium agent, and the triethanolamine is complexed with potassium ions in potassium salt, so that the sensitivity of the capsule shell to the potassium ions is reduced, and the technical problem that the disintegration and dissolution of the capsule shell are limited by the potassium ions is solved.
Description
Technical Field
The invention relates to the technical field of empty capsules, in particular to a controlled-release hydroxypropyl methylcellulose empty capsule and a preparation method thereof.
Background
The hollow medicinal capsule has important effects on drug release, safety and effectiveness of the drug and clinical curative effect, and plays a vital role in new drug creation, drug quality control and the like. In recent years, research and application of plant empty capsules are gradually rising, the main application is hydroxypropyl methylcellulose empty capsules, and along with implementation of relevant policy regulations such as simulation drug consistency evaluation and the like of the national delivery, development of the hydroxypropyl methylcellulose empty capsules capable of meeting the requirement of drug disintegration and dissolution is particularly important.
The invention patent No. CN103877067A discloses a hollow capsule capable of controlling disintegration time limit, the hollow capsule contains coagulant aid potassium chloride, and the hollow capsule is easily limited by potassium ions during disintegration and dissolution, so that the disintegration time is influenced, and therefore, a controlled release hydroxypropyl methylcellulose hollow capsule with low sensitivity to potassium ions is needed.
Disclosure of Invention
In view of the above, the invention provides a controlled release hypromellose hollow capsule with low sensitivity to potassium ions and a preparation method thereof.
The technical scheme of the invention is realized as follows: in one aspect, the invention provides a controlled release hypromellose hollow capsule comprising hypromellose, a solidifying agent, a potassium salt, sodium dodecyl sulfate, a solubilizing agent, and triethanolamine.
On the basis of the technical scheme, the composition preferably comprises the following components in parts by weight: comprises 15-25 parts of hydroxypropyl methylcellulose, 0.1-5 parts of curing agent, 0.1-3 parts of potassium salt, 0.1-5 parts of sodium dodecyl sulfate, 0.5-1 part of solubilizer and 0.5-1 part of triethanolamine.
On the basis of the technical scheme, the xylitol-containing beverage also preferably comprises 0.1-3 parts by weight of xylitol.
On the basis of the technical scheme, the silicified microcrystalline cellulose is preferably further comprises 0.1-3 parts by weight.
On the basis of the above technical scheme, preferably, the silicified microcrystalline cellulose D90 is 100-300 μm, and the D50 is 50-100 μm.
On the basis of the technical scheme, preferably, the curing agent is one or a combination of more of carrageenan, xanthan gum and gellan gum.
Based on the technical scheme, preferably, the solubilizing agent is tween 20.
On the basis of the technical scheme, preferably, the potassium salt is potassium acetate or potassium citrate.
In another aspect, the invention provides a method for preparing a controlled release hypromellose hollow capsule, comprising the following steps:
s1, sol: adding hydroxypropyl methylcellulose and xylitol into purified water at 80-90 ℃, stirring for 30-60min, adding silicified microcrystalline cellulose, continuously stirring for 30-60min, adding 0.1-5 parts of curing agent, continuously stirring for 30-60min, cooling the glue solution, adding potassium salt, solubilizer, sodium dodecyl sulfate and potassium resisting agent, vacuumizing for 30-60min under stirring, maintaining the temperature of the glue solution at 50-60 ℃, and transferring the glue solution into a glue raising barrel for standby;
s2, heat preservation and color mixing: adding pigment into a glue raising barrel, stirring uniformly, and standing for 3-6h for standby;
s3, molding: dipping in glue at 50-60 deg.c and setting at 15-30 deg.c;
s4, drying: drying at 20-40deg.C;
s5, demolding, cutting and sleeving: and demolding the dried blank, and cutting and sleeving to obtain the hollow capsule after quality inspection is qualified.
On the basis of the technical scheme, preferably, after defoaming, the viscosity of the glue solution is controlled to be 400-1500 mPa.s, and then the glue solution is transferred to a glue raising barrel.
The controlled-release hypromellose hollow capsule and the preparation method thereof have the following beneficial effects compared with the prior art:
(1) The invention adopts triethanolamine as an anti-potassium agent, and the triethanolamine is complexed with potassium ions in potassium salt, so that the sensitivity of the capsule shell to the potassium ions is reduced, and the technical problem that the disintegration and dissolution of the capsule shell are limited by the potassium ions is effectively solved.
(2) The technical problem that the disintegration and dissolution of the capsule shell are limited by potassium ions is solved after the anti-potassium agent is added, but the disintegration and dissolution time is longer, so that the pore-forming agent xylitol is added, and the xylitol is dissolved in water to form a pore canal, so that the disintegration and dissolution process of the hollow capsule is further regulated.
(3) After the pore-forming agent is added, the strength of the hollow capsule is affected to a certain extent, and therefore, siliconized microcrystalline cellulose is added as a reinforcing agent, on one hand, the siliconized microcrystalline cellulose is uniformly dispersed in the capsule shell as a filler, so that the mechanical strength of the hollow capsule is improved, and the friability is reduced; on the other hand, the strong hydrophilicity of the silicified microcrystalline cellulose improves the sol-gel conversion performance of the hollow capsule, and solves the problems that the solidifying agent is slowly disintegrated in an acidic medium and is not beneficial to the dissolution of the medicine.
Detailed Description
The following description of the embodiments of the present invention will clearly and fully describe the technical aspects of the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, are intended to fall within the scope of the present invention.
The materials used for the hollow capsule are purchased from the market, wherein the hydroxypropyl methylcellulose is purchased from Japanese Xinyue, and the specification is E3/E5/E15/E30/E50; silicified microcrystalline cellulose was purchased from Shenzhen Utility medicine Co., ltd, specification TMS 635L; xylitol is purchased from Shanghai Yuan Yes Biotechnology Co., ltd., product No. S11039, and the pigment used is medicinal grade pigment lemon yellow.
Example 1
The controlled release hypromellose hollow capsule of this embodiment comprises, by weight: 150g of hypromellose having a viscosity of 3 mPa.s, 1g of carrageenan, 1g of potassium acetate, 1g of sodium dodecyl sulfate, 5g of Tween 20, 5g of triethanolamine, 10g of lemon yellow and 600g of purified water.
The preparation method of the controlled-release hypromellose hollow capsule in the embodiment comprises the following steps:
s1, sol: adding hypromellose into purified water at 80 ℃, stirring for 30min, adding carrageenan, continuing stirring for 30min, cooling the glue solution, adding potassium acetate, tween 20, sodium dodecyl sulfate and triethanolamine, stirring, vacuumizing and defoaming for 30min, maintaining the glue solution temperature at 50 ℃, controlling the glue solution viscosity at 400 mPa.s, and transferring the glue solution into a glue raising barrel for standby;
s2, heat preservation and color mixing: adding lemon yellow into a glue raising barrel, uniformly stirring, and standing for 3 hours for standby;
s3, molding: dipping in glue at 50 ℃ and setting at 15 ℃;
s4, drying: drying at 20deg.C;
s5, demolding, cutting and sleeving: and demolding the dried blank, and cutting and sleeving to obtain the hollow capsule after quality inspection is qualified.
Example 2
The controlled release hypromellose hollow capsule of this embodiment comprises, by weight: 150g of hypromellose having a viscosity of 3 mPa.s, 1g of carrageenan, 1g of potassium acetate, 1g of sodium dodecyl sulfate, 5g of Tween 20, 5g of triethanolamine, 1g of xylitol, 10g of lemon yellow and 600g of purified water.
S1, sol: adding hypromellose and xylitol into purified water at 80deg.C, stirring for 30min, adding carrageenan, stirring for 30min, cooling the glue solution, adding potassium acetate, tween 20, sodium dodecyl sulfate and triethanolamine, stirring, vacuumizing and defoaming for 30min, maintaining the glue solution temperature at 50deg.C, controlling the glue solution viscosity at 400 mPa.s, and transferring the glue solution into a glue raising barrel for standby;
s2, heat preservation and color mixing: adding lemon yellow into a glue raising barrel, uniformly stirring, and standing for 3 hours for standby;
s3, molding: dipping in glue at 50 ℃ and setting at 15 ℃;
s4, drying: drying at 20deg.C;
s5, demolding, cutting and sleeving: and demolding the dried blank, and cutting and sleeving to obtain the hollow capsule after quality inspection is qualified.
Example 3
The controlled release hypromellose hollow capsule of this embodiment comprises, by weight: 150g of hypromellose having a viscosity of 3 mPa.s, 1g of carrageenan, 1g of potassium acetate, 1g of sodium dodecyl sulfate, 5g of Tween 20, 5g of triethanolamine, 1g of xylitol, 1g of silicified microcrystalline cellulose, 10g of lemon yellow and 600g of purified water, the silicified microcrystalline cellulose having a D90 of 100. Mu.m, and a D50 of 50. Mu.m.
The preparation method of the controlled-release hypromellose hollow capsule in the embodiment comprises the following steps:
s1, sol: adding hydroxypropyl methylcellulose and xylitol into purified water at 80 ℃, stirring for 30min, adding silicified microcrystalline cellulose, continuously stirring for 30min, adding carrageenan, continuously stirring for 30min, starting cooling the glue solution, adding potassium acetate, tween 20, sodium dodecyl sulfate and triethanolamine, vacuumizing for 30min under stirring, maintaining the temperature of the glue solution at 50 ℃, controlling the viscosity of the glue solution at 400 mPa.s, and transferring the glue solution into a glue raising barrel for standby;
s2, heat preservation and color mixing: adding lemon yellow into a glue raising barrel, uniformly stirring, and standing for 3 hours for standby;
s3, molding: dipping in glue at 50 ℃ and setting at 15 ℃;
s4, drying: drying at 20deg.C;
s5, demolding, cutting and sleeving: and demolding the dried blank, and cutting and sleeving to obtain the hollow capsule after quality inspection is qualified.
Example 4
The controlled release hypromellose hollow capsule of this embodiment comprises, by weight: 250g of hypromellose having a viscosity of 3 mPa.s, 50g of xanthan gum, 30g of potassium citrate, 50g of sodium lauryl sulfate, 10g of Tween 20, 10g of triethanolamine, 30g of xylitol, 30g of silicified microcrystalline cellulose, 50g of pigment and 600g of purified water, wherein D90 of silicified microcrystalline cellulose is 110 μm and D50 of silicified microcrystalline cellulose is 60 μm.
The preparation method of the controlled-release hypromellose hollow capsule in the embodiment comprises the following steps:
s1, sol: adding hydroxypropyl methylcellulose and xylitol into purified water at 90 ℃, stirring for 60min, adding silicified microcrystalline cellulose, continuously stirring for 60min, adding xanthan gum, continuously stirring for 60min, cooling the glue solution, adding potassium citrate, tween 20, sodium dodecyl sulfate and triethanolamine, vacuumizing for 60min under stirring, maintaining the glue solution temperature at 60 ℃, controlling the glue solution viscosity at 1500 mPa.s, and transferring the glue solution into a glue raising barrel for standby;
s2, heat preservation and color mixing: adding lemon yellow into a glue raising barrel, uniformly stirring, and standing for 6 hours for standby;
s3, molding: dipping in glue at 60 ℃ and setting at 30 ℃;
s4, drying: drying at 40deg.C;
s5, demolding, cutting and sleeving: and demolding the dried blank, and cutting and sleeving to obtain the hollow capsule after quality inspection is qualified.
Example 5
The controlled release hypromellose hollow capsule of this embodiment comprises, by weight: 220g of hypromellose with a viscosity of 5 mPa.s, 40g of gellan gum, 20g of potassium acetate, 30g of sodium dodecyl sulfate, 8g of Tween 20, 8g of triethanolamine, 20g of xylitol, 25g of silicified microcrystalline cellulose, 40g of pigment and 670 parts of purified water, wherein D90 of silicified microcrystalline cellulose is 150 μm and D50 of silicified microcrystalline cellulose is 65 μm.
The preparation method of the controlled-release hypromellose hollow capsule in the embodiment comprises the following steps:
s1, sol: adding hydroxypropyl methylcellulose and xylitol into purified water at 85 ℃, stirring for 55min, adding silicified microcrystalline cellulose, continuously stirring for 50min, adding gellan gum, continuously stirring for 50min, starting cooling the gum liquid, adding potassium acetate, tween 20, sodium dodecyl sulfate and triethanolamine, stirring, vacuumizing for 50min, maintaining the gum liquid temperature at 55 ℃, controlling the gum liquid viscosity at 1200 mPa.s, and transferring the gum liquid into a gum raising barrel for standby;
s2, heat preservation and color mixing: adding lemon yellow into a glue raising barrel, uniformly stirring, and standing for 4 hours for standby;
s3, molding: dipping in glue at 55 ℃ and setting at 25 ℃;
s4, drying: drying at 30deg.C;
s5, demolding, cutting and sleeving: and demolding the dried blank, and cutting and sleeving to obtain the hollow capsule after quality inspection is qualified.
Example 6
The controlled release hypromellose hollow capsule of this embodiment comprises, by weight: 200g of hypromellose with a viscosity of 15 mPa.s, 30g of carrageenan, 10g of potassium acetate, 10g of sodium dodecyl sulfate, 6g of Tween 20, 10g of triethanolamine, 10g of xylitol, 20g of silicified microcrystalline cellulose, 30g of pigment and 720 parts of purified water, wherein D90 of silicified microcrystalline cellulose is 150 μm and D50 of silicified microcrystalline cellulose is 70 μm.
The preparation method of the controlled-release hypromellose hollow capsule in the embodiment comprises the following steps:
s1, sol: adding hydroxypropyl methylcellulose and xylitol into purified water at 80 ℃, stirring for 50min, adding silicified microcrystalline cellulose, continuously stirring for 50min, adding carrageenan, continuously stirring for 50min, starting cooling the glue solution, adding potassium acetate, tween 20, sodium dodecyl sulfate and triethanolamine, vacuumizing for 50min under stirring, maintaining the temperature of the glue solution at 50 ℃, controlling the viscosity of the glue solution at 1000 mPa.s, and transferring the glue solution into a glue raising barrel for standby;
s2, heat preservation and color mixing: adding lemon yellow into a glue raising barrel, uniformly stirring, and standing for 4 hours for standby;
s3, molding: dipping in glue at 55 ℃ and setting at 20 ℃;
s4, drying: drying at 25deg.C;
s5, demolding, cutting and sleeving: and demolding the dried blank, and cutting and sleeving to obtain the hollow capsule after quality inspection is qualified.
Example 7
The controlled release hypromellose hollow capsule of this embodiment comprises, by weight: 180g of hypromellose having a viscosity of 30 mPa.s, 15g of xanthan gum, 10g of potassium citrate, 5g of sodium dodecyl sulfate, 5g of Tween 20, 5g of triethanolamine, 20g of xylitol, 10g of silicified microcrystalline cellulose, 20g of pigment and 750 parts of purified water, wherein D90 of silicified microcrystalline cellulose is 200 μm and D50 of silicified microcrystalline cellulose is 90 μm.
The preparation method of the controlled-release hypromellose hollow capsule in the embodiment comprises the following steps:
s1, sol: adding hydroxypropyl methylcellulose and xylitol into purified water at 80 ℃, stirring for 40min, adding silicified microcrystalline cellulose, continuously stirring for 40min, adding xanthan gum, continuously stirring for 40min, cooling the glue solution, adding potassium citrate, tween 20, sodium dodecyl sulfate and triethanolamine, vacuumizing for 40min under stirring, maintaining the glue solution temperature at 50 ℃, controlling the glue solution viscosity at 800 mPa.s, and transferring the glue solution into a glue raising barrel for standby;
s2, heat preservation and color mixing: adding lemon yellow into a glue raising barrel, uniformly stirring, and standing for 4 hours for standby;
s3, molding: dipping in glue at 50 ℃ and setting at 20 ℃;
s4, drying: drying at 25deg.C;
s5, demolding, cutting and sleeving: and demolding the dried blank, and cutting and sleeving to obtain the hollow capsule after quality inspection is qualified.
Example 8
The controlled release hypromellose hollow capsule of this embodiment comprises, by weight: 150g of hypromellose having a viscosity of 50 mPa.s, 10g of xanthan gum, 5g of potassium citrate, 10g of sodium dodecyl sulfate, 5g of Tween 20, 5g of triethanolamine, 10g of xylitol, 10g of silicified microcrystalline cellulose, 10g of pigment and 800 parts of purified water, wherein D90 of silicified microcrystalline cellulose is 300 μm and D50 of silicified microcrystalline cellulose is 100 μm.
The preparation method of the controlled-release hypromellose hollow capsule in the embodiment comprises the following steps:
s1, sol: adding hydroxypropyl methylcellulose and xylitol into purified water at 85 ℃, stirring for 30min, adding silicified microcrystalline cellulose, continuously stirring for 30min, adding xanthan gum, continuously stirring for 30min, cooling the glue solution, adding potassium citrate, tween 20, sodium dodecyl sulfate and triethanolamine, vacuumizing for 30min under stirring, maintaining the temperature of the glue solution at 50 ℃, controlling the viscosity of the glue solution at 600 mPa.s, and transferring the glue solution into a glue raising barrel for standby;
s2, heat preservation and color mixing: adding lemon yellow into a glue raising barrel, uniformly stirring, and standing for 3 hours for standby;
s3, molding: dipping in glue at 50 ℃ and setting at 15 ℃;
s4, drying: drying at 20deg.C;
s5, demolding, cutting and sleeving: and demolding the dried blank, and cutting and sleeving to obtain the hollow capsule after quality inspection is qualified.
Comparative example 1
Comparative example 1 differs from example 1 by the absence of triethanolamine and the remaining components are the same.
Comparative example 2
Comparative example 2 differs from example 2 in the absence of triethanolamine, the xylitol remaining, and the remaining components being the same.
Comparative example 3
Comparative example 3 differs from example 3 in the absence of triethanolamine, the xylitol and silicified microcrystalline cellulose remaining as the same components.
Comparative example 4
Comparative example 4 differs from example 3 in the absence of triethanolamine and xylitol, the silicified microcrystalline cellulose remaining, and the remaining components are the same.
Comparative example 5
Comparative example 5 differs from example 3 in the absence of xylitol, retention of triethanolamine and silicified microcrystalline cellulose, and the remaining components are the same.
Comparative example 6
Comparative example 6 differs from example 8 in that the hypromellose has a viscosity of 60 mPa.s, the viscosity of the dope is controlled to 1800 mPa.s, and the remaining components are the same beyond the scope of the present invention.
Comparative example 7
Comparative example 7 was different from example 3 in that xylitol was used in an amount of 0.5g, and the remaining components were the same.
Comparative example 8
Comparative example 8 differs from example 4 in that xylitol was used in an amount of 60g, which is beyond the limit of the present invention, and the remaining components were the same.
Comparative example 9
Comparative example 9 differs from example 3 in that silicified microcrystalline cellulose was used in an amount of 0.3g, which is beyond the limit of the present invention, and the remaining components were the same.
Comparative example 10
Comparative example 10 differs from example 4 in that silicified microcrystalline cellulose was used in an amount of 40g, which is beyond the limit of the present invention, and the remaining components were the same.
The empty capsules prepared in examples and comparative examples were tested for friability, disintegration time and drug dissolution properties. The test methods are as follows, and the test results are shown in tables 1 to 3.
Friability test: taking 100 grains of the product, evenly placing the grains in 2 surface dishes, placing the surface dishes containing the samples into a dryer containing blue silica gel, and placing four batches of samples each time; placing for 24 hours under the condition, wherein the humidity in the dryer is controlled within the range of 8-20% in the whole experimental process; taking out, putting into glass tubes (24 mm inner diameter, 200mm length) standing on wood board (2 cm thickness) one by one, freely dropping cylindrical weights (made of polytetrafluoroethylene, 22mm diameter, 20 g+ -0.1 g) from the glass tube opening, and recording the number of broken particles according to whether the hollow capsule is broken or not.
And (3) testing disintegration time limit: the disintegration time limit examination method of the general rule 0921 of the Chinese pharmacopoeia of 2020 edition is referred to, wherein an aqueous medium, pH1.2 hydrochloric acid, pH4.5 acetate and pH6.8 phosphate are used as mediums, and the disintegration time limit of the capsule is observed.
Dissolution observation test: the capsule is subjected to shell breaking in the dissolution process by adopting a spin basket method, the rotating speed is 100rmp, the temperature is 37.0+/-0.5 ℃, the content is amoxicillin, purified water, pH1.2 hydrochloric acid, pH4.5 acetate and pH6.8 phosphate are taken as dissolution media.
TABLE 1 results of friability test
| Sample of | Upper probability (%) | Friability (granule) |
| Example 1 | 99.5 | 2 |
| Example 2 | 99.5 | 1 |
| Example 3 | 99.9 | 0 |
| Example 4 | 99.9 | 0 |
| Example 5 | 99.9 | 0 |
| Example 6 | 99.9 | 0 |
| Example 7 | 99.9 | 0 |
| Example 8 | 99.9 | 0 |
| Comparative example 1 | 95.0 | 6 |
| Comparative example 2 | 95.0 | 5 |
| Comparative example 3 | 95.5 | 4 |
| Comparative example 4 | 95.0 | 4 |
| Comparative example 5 | 95.0 | 4 |
| Comparative example 6 | 85.0 | 10 |
| Comparative example 7 | 96.0 | 2 |
| Comparative example 8 | 83 | 5 |
| Comparative example 9 | 94.0 | 3 |
| Comparative example 10 | 80 | 15 |
Table 1 shows that the brittle fracture strength of example 1 is 0 to 2 grains/100 grains, and falls within the standard range. Examples 3-8 containing triethanolamine, xylitol and silicified microcrystalline cellulose have friability of 0, high strength and up-probability of 99.9%, which shows that the friability is reduced after adding triethanolamine, xylitol and silicified microcrystalline cellulose, the strength of the empty capsule is improved, and the up-probability of the empty capsule is increased. Comparative example 6 shows that increasing the viscosity of the dope reduces the strength and the upper probability of the empty capsules because the final film forming property of the empty capsules is poor and the yield is low by increasing the viscosities of hypromellose and the dope. Comparative examples 7 to 10: the addition of excess xylitol or silicified microcrystalline cellulose reduces the smoothness of the capsule and reduces the upper probability.
Table 2 time limit for disintegration of empty capsules
As can be seen from Table 2, the hollow capsules prepared in this example had an adjustable disintegration time of 2 '43' -20 '42' in purified water at pH7.0 and 3 '45' -19 '05' in aqueous hydrochloric acid at pH1.2, the adjustable disintegration time in aqueous solution of pH4.5 acetate is 4'32 "-19' 45", the adjustable disintegration time in aqueous solution of pH6.8 phosphate is 5'07 "-19' 08", and the greater the viscosity of hypromellose, the longer the disintegration time. The disintegration time period of examples 1 and 2 was longer than that of example 3, and the disintegration time period of the empty capsules in the purified water, pH1.2 hydrochloric acid, pH4.5 acetate and pH6.8 phosphate as dissolution medium was longer in comparative example 1 lacking the anti-potassium agent, indicating that the disintegration time period of the empty capsules could be shortened by increasing triethanolamine, xylitol and silicified microcrystalline cellulose, and the limitation of potassium ions on the disintegration time period of the empty capsules was reduced. Comparative example 6 has a significantly prolonged disintegration time compared with example 8 because the viscosity of hypromellose and the gum solution is increased, so that the water solubility of the empty capsule is deteriorated, resulting in a slow disintegration rate. Comparative examples 7 to 10: the dosage of xylitol is continuously increased, the disintegration time is not continuously reduced, and the limit value of xylitol dissolution is reached; since silicified microcrystalline cellulose itself is insoluble in water, the disintegration time can only be reduced to some extent by dissolution, and increasing the excess silicified microcrystalline cellulose increases the disintegration time instead.
In conclusion, the technical effect of adjusting the disintegration time limit is achieved by adjusting the viscosity of the hypromellose and the components of the triethanolamine, the xylitol and the silicified microcrystalline cellulose.
TABLE 3 drug dissolution time
Note that: the beginning indicates the time (min) for starting the crust breaking and the ending indicates the total time (min) for breaking.
Table 3 shows that the hollow capsules prepared in the embodiment of the invention have adjustable shell breaking time of 2-23min and dissolution time of 4-7min in purified water with pH of 7.0; the adjustable shell breaking time in the hydrochloric acid aqueous solution with the pH value of 1.2 is 3-25min, and the dissolution time is 2-8min; the adjustable shell breaking time in the aqueous solution of acetate with pH of 4.5 is 3-23min, and the dissolution time is 2-7min; the adjustable crust breaking time is 2-24min in phosphate aqueous solution with pH of 6.8, and the dissolution time is 3-8min; and the greater the viscosity of the hypromellose, the longer the drug dissolution time. The drug dissolution time period of examples 1 and 2 was longer than that of example 3, and the comparative example 1 lacking the anti-potassium agent, the drug dissolution time of the empty capsule in the purified water, the pH1.2 hydrochloric acid, the pH4.5 acetate and the pH6.8 phosphate as the dissolution medium was longer, indicating that the drug dissolution time can be shortened by increasing triethanolamine, xylitol and silicified microcrystalline cellulose, and the limit of potassium ions on the disintegration time of the empty capsule was reduced. Comparative example 6 is a significant increase in drug dissolution time as compared with example 8, because the viscosity of hypromellose and gum increases, and the water solubility of the empty capsules becomes poor. Comparative examples 7 to 10 show that the dissolution time is not continuously reduced by continuously increasing the amount of xylitol, and the limit of dissolution of xylitol is reached; since silicified microcrystalline cellulose itself is insoluble in water, the dissolution time can only be reduced to some extent by dissolution, and increasing the excess silicified microcrystalline cellulose increases the dissolution time instead.
In conclusion, the technical effect of adjusting the dissolution time limit of the medicine is achieved by adjusting the viscosity of the hypromellose and the components of the triethanolamine, the xylitol and the silicified microcrystalline cellulose.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (10)
1. A controlled release hypromellose empty capsule, characterized in that: the raw material components of the hollow capsule comprise hypromellose, a curing agent, potassium salt, sodium dodecyl sulfate, a solubilizer and triethanolamine.
2. A controlled release hypromellose empty capsule according to claim 1 wherein: the composition comprises the following components in parts by weight: comprises 15-25 parts of hydroxypropyl methylcellulose, 0.1-5 parts of curing agent, 0.1-3 parts of potassium salt, 0.1-5 parts of sodium dodecyl sulfate, 0.5-1 part of solubilizer and 0.5-1 part of triethanolamine.
3. A controlled release hypromellose empty capsule according to claim 2 wherein: also comprises 0.1-3 parts by weight of xylitol.
4. A controlled release hypromellose empty capsule according to claim 3 wherein: also comprises 0.1-3 parts by weight of silicified microcrystalline cellulose.
5. A controlled release hypromellose empty capsule according to claim 4 wherein: the silicified microcrystalline cellulose D90 is 100-300 μm and D50 is 50-100 μm.
6. A controlled release hypromellose empty capsule according to claim 1 wherein: the curing agent is one or a combination of more of carrageenan, xanthan gum and gellan gum.
7. A controlled release hypromellose empty capsule according to claim 1 wherein: the solubilizer is Tween 20.
8. A controlled release hypromellose empty capsule according to claim 1 wherein: the potassium salt is potassium acetate or potassium citrate.
9. A method for preparing a controlled release hypromellose hollow capsule according to claim 4, wherein: the method comprises the following steps:
s1, sol: adding hydroxypropyl methylcellulose and xylitol into purified water at 80-90 ℃, stirring for 30-60min, adding silicified microcrystalline cellulose, continuously stirring for 30-60min, adding 0.1-5 parts of curing agent, continuously stirring for 30-60min, cooling the glue solution, adding potassium salt, solubilizer, sodium dodecyl sulfate and potassium resisting agent, vacuumizing for 30-60min under stirring, maintaining the temperature of the glue solution at 50-60 ℃, and transferring the glue solution into a glue raising barrel for standby;
s2, heat preservation and color mixing: adding pigment into a glue raising barrel, stirring uniformly, and standing for 3-6h for standby;
s3, molding: dipping in glue at 50-60 deg.c and setting at 15-30 deg.c;
s4, drying: drying at 20-40deg.C;
s5, demolding, cutting and sleeving: and demolding the dried blank, and cutting and sleeving to obtain the hollow capsule after quality inspection is qualified.
10. A method for preparing a controlled release hypromellose hollow capsule according to claim 9, wherein: after defoaming, controlling the viscosity of the glue solution to 400-1500 mPa.s, and transferring the glue solution to a glue raising barrel.
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| CN202311594311.0A CN117398364A (en) | 2023-11-27 | 2023-11-27 | Controlled-release hydroxypropyl methylcellulose hollow capsule and preparation method thereof |
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