CN117815192A - Phloroglucinol sustained release tablet and preparation method thereof - Google Patents
Phloroglucinol sustained release tablet and preparation method thereof Download PDFInfo
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- CN117815192A CN117815192A CN202211201585.4A CN202211201585A CN117815192A CN 117815192 A CN117815192 A CN 117815192A CN 202211201585 A CN202211201585 A CN 202211201585A CN 117815192 A CN117815192 A CN 117815192A
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- phloroglucinol
- cellulose
- sustained release
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- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 title claims abstract description 93
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 title claims abstract description 93
- 229960001553 phloroglucinol Drugs 0.000 title claims abstract description 93
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title abstract description 31
- 239000000463 material Substances 0.000 claims abstract description 82
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 239000000314 lubricant Substances 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 239000000853 adhesive Substances 0.000 claims abstract description 9
- 230000001070 adhesive effect Effects 0.000 claims abstract description 9
- 238000005550 wet granulation Methods 0.000 claims abstract description 9
- 239000000945 filler Substances 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims description 59
- 239000002245 particle Substances 0.000 claims description 49
- 239000008187 granular material Substances 0.000 claims description 33
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 31
- 238000001035 drying Methods 0.000 claims description 28
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 24
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 24
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 23
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 23
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 23
- 239000001856 Ethyl cellulose Substances 0.000 claims description 21
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 21
- 229920001249 ethyl cellulose Polymers 0.000 claims description 21
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 21
- 239000003826 tablet Substances 0.000 claims description 20
- 239000011159 matrix material Substances 0.000 claims description 19
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 18
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 18
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 16
- 229960003943 hypromellose Drugs 0.000 claims description 15
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 14
- 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 11
- 239000008101 lactose Substances 0.000 claims description 11
- 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 10
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 10
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 10
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 10
- 238000013268 sustained release Methods 0.000 claims description 10
- 239000012730 sustained-release form Substances 0.000 claims description 10
- 239000004925 Acrylic resin Substances 0.000 claims description 8
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 8
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 8
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 8
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 8
- 229920000609 methyl cellulose Polymers 0.000 claims description 8
- 239000001923 methylcellulose Substances 0.000 claims description 8
- 235000010981 methylcellulose Nutrition 0.000 claims description 8
- 229920000178 Acrylic resin Polymers 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 229920002301 cellulose acetate Polymers 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 239000004698 Polyethylene Substances 0.000 claims description 6
- 239000005038 ethylene vinyl acetate Substances 0.000 claims description 6
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 claims description 6
- -1 polyethylene Polymers 0.000 claims description 6
- 229920000573 polyethylene Polymers 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 229940069328 povidone Drugs 0.000 claims description 4
- 229910021487 silica fume Inorganic materials 0.000 claims description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000008119 colloidal silica Substances 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
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000011812 mixed powder Substances 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 12
- 238000005469 granulation Methods 0.000 abstract description 5
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- 238000003756 stirring Methods 0.000 description 26
- 230000000052 comparative effect Effects 0.000 description 21
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- 239000000499 gel Substances 0.000 description 15
- 238000007873 sieving Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000005303 weighing Methods 0.000 description 14
- 238000005520 cutting process Methods 0.000 description 13
- 239000008213 purified water Substances 0.000 description 13
- 229910001220 stainless steel Inorganic materials 0.000 description 13
- 239000010935 stainless steel Substances 0.000 description 13
- 229960004667 ethyl cellulose Drugs 0.000 description 10
- 229950005770 hyprolose Drugs 0.000 description 8
- 230000001133 acceleration Effects 0.000 description 7
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 6
- 229960001375 lactose Drugs 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000007547 defect Effects 0.000 description 5
- 239000003405 delayed action preparation Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 210000002460 smooth muscle Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 4
- 238000011161 development Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000001078 anti-cholinergic effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000002048 spasmolytic effect Effects 0.000 description 2
- YEQBHMVRNHTCPJ-UHFFFAOYSA-N 2-methylprop-2-enoic acid;3-oxobutanoic acid Chemical compound CC(=C)C(O)=O.CC(=O)CC(O)=O YEQBHMVRNHTCPJ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 206010038419 Renal colic Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
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- 229940111202 pepsin Drugs 0.000 description 1
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- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a phloroglucinol sustained release tablet and a preparation method thereof. The phloroglucinol sustained release tablet is prepared by adopting a semi-dry wet granulation (auxiliary material granulation) process and comprises a therapeutically effective amount of phloroglucinol, a pharmaceutically acceptable framework material, an adhesive, a filler, a lubricant and the like. The content of phloroglucinol is 20.0% -50.0%, the content of insoluble framework material is 25.0% -56.0% and the content of hydrophilic gel framework material is 5.0% -55.0% by weight of the total weight of the preparation. The phloroglucinol provided by the invention has the advantages that the phloroglucinol can realize long-acting and stable release in different pH media from the integral effect, and the raw material medicines are basically not degraded in the preparation and storage processes, so that the quality is stable; simple process steps, low cost, convenient administration for patients and suitability for commercial production and popularization.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, relates to a high-stability slow-release solid oral preparation, and in particular relates to a phloroglucinol slow-release tablet and a preparation method thereof.
Background
The slow release preparation refers to a preparation in which oral medicines are released slowly in a prescribed solvent at a non-constant speed as required, and the number of times of daily administration is reduced at least once or the interval between administrations is prolonged compared with the corresponding ordinary preparation. Compared with the sustained release preparation, the sustained release preparation can release the medicine more accurately and more uniformly, so that the blood concentration is more stable, and the toxic and side effects are reduced. For patients needing to take medicines for a long time, the slow release preparation can reduce the taking times and improve the compliance of the patients.
The phloroglucinol is a clinically common smooth muscle antispasmodic drug, can directly act on smooth muscle of gastrointestinal tract and genitourinary tract, relieve smooth muscle spasm, and is suitable for acute spasmodic pain, acute spasmodic urethra, bladder, renal colic, gynecological spasmodic pain and the like caused by digestive system and biliary tract dysfunction. Compared with other smooth muscle spasmolytics, the phloroglucinol has the characteristics of no anticholinergic effect, and can relieve smooth muscle spasticity without generating a series of anticholinergic side effects. The phloroglucinol can not cause symptoms such as hypotension, heart rate acceleration, arrhythmia and the like, has no influence on cardiovascular functions, and has wide application in the clinical spasmolytic and analgesic fields.
At present, the clinical common dosage forms of phloroglucinol are injection and orally disintegrating tablets, and the injection has the defects of short administration frequency, harsh use conditions and the like, so that the patient compliance is poor; the phloroglucinol orally disintegrating tablet has the advantages of rapid disintegration and dissolution, good taste, and the phloroglucinol preparation has the advantages of rapid onset of action, high safety and wide indication, but is biological in generalThe half-life period is short, the administration times are high (2 tablets are orally taken by an adult for 2-3 times a day), the pain can not be continuously relieved, and the existing dosage forms have the technical defect of being difficult to deal with the persistent spasmodic pain. The development of a once-a-day sustained release formulation not only improves patient compliance, but also reduces drug C in the blood max Reducing or avoiding side effects associated with dosage and increasing the efficacy of the drug by extending its effective concentration in the plasma has significant advantages. Therefore, the development of the phloroglucinol sustained release preparation for prolonging the acting time of the medicine is urgently needed in clinic.
The phloroglucinol has larger clinical dosage (320 mg-480mg of the adult daily) and better water solubility, and is difficult to maintain stable slow release by the prior conventional technology, thus seriously affecting the in vivo curative effect; in addition, the phloroglucinol raw material has the characteristics of poor stability and sensitivity to light and damp heat, and is easy to generate process impurities in the preparation process, thereby influencing the product quality.
At present, no literature report on a phloroglucinol sustained release preparation exists, and in the prior art (such as patent CN113616607A, CN 105560202B), when hydrophilic gel matrix materials such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and a combination thereof are adopted to prepare a sustained release tablet, the dosage of the matrix materials is large, the early release speed of the prepared gel matrix sustained release tablet is relatively high, and burst release is easy to cause; in addition, the raw materials are easily soluble, the clinical administration specification is large, and when the hydrophilic gel framework material is used as the slow-release framework material, the release speed is difficult to control, the slow-release time is short, and the effect is poor. The existing slow release technology aims at the defect of the effective framework slow release material of large-scale high-water-solubility active ingredients, and development by research and development personnel is urgently needed.
Analyzing the above various techniques has certain defects, and a stable and long-acting phloroglucinol sustained release preparation cannot be prepared; therefore, the phloroglucinol sustained release tablet which is simple and controllable in preparation process, long-acting in release speed and stable is developed, and has remarkable advantages in pharmaceutical quality and market prospect. The invention adopts a combined framework material which takes an insoluble framework material as a main material and a hydrophilic gel framework material as an auxiliary material, and prepares the phloroglucinol sustained release tablet which can be stably stored and has no burst release and sustained release through a semi-dry wet granulation (auxiliary material granulation) process.
Disclosure of Invention
In view of the requirements of clinical medication and the defects of the prior art, the invention aims to provide the phloroglucinol sustained release tablet which has no burst release, slow release and high stability;
the invention also aims to provide a preparation method of the phloroglucinol sustained release tablet which has low production cost, no abrupt release, slow release and high stability in clinic.
The method for solving the problems comprises the following steps:
the inventors of the present invention have conducted intensive studies in order to develop a stable sustained-release composition free of burst release and sustained release, which can be stored for a long period of time, and have found that a combination matrix material comprising an insoluble matrix material as a main component and a hydrophilic gel matrix material as an auxiliary component can be used, by means of a semi-dry wet granulation (auxiliary material granulation) process and controlling the particle size of the raw materials, a sustained-release tablet of phloroglucinol can be stored more stably and released in a sustained manner free of burst release, and the dissolution profile can be maintained stably during stability, thereby completing the present invention.
The phloroglucinol sustained release tablet comprises the following components in percentage by weight based on the total weight:
phloroglucinol 20.0-50.0%,
25.0 to 56.0 percent of insoluble framework material,
5.0 to 50.0 percent of hydrophilic gel framework material,
and the sum of the weight percentages of all the components is 100 percent;
the insoluble framework material is selected from ethyl cellulose, cellulose acetate, acrylic resin, ethylene-vinyl acetate copolymer, polyethylene, crosslinked polyvinylpyrrolidone or a combination thereof;
the hydrophilic gel skeleton material is selected from hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone or a combination thereof.
As a preferable mode of the invention, the phloroglucinol sustained release tablet comprises the following components in percentage by weight based on the total weight:
phloroglucinol: 20.0% -50.0%,
insoluble matrix material: 25.0% -56.0%,
hydrophilic gel matrix material: 5.0% -50.0%,
and (2) an adhesive: 5.0 to 50.0 percent,
and the sum of the weight percentages of all the components is 100 percent;
the insoluble framework material is selected from ethyl cellulose, cellulose acetate, acrylic resins (such as acetoacetate methacrylate, polymethacrylic resin, polyacrylic resin IV, ammonium polymethacrylate and the like), ethylene-vinyl acetate copolymer, polyethylene, crosslinked polyvinylpyrrolidone and combinations thereof;
the hydrophilic gel framework material is selected from hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone or a combination thereof;
the binder is selected from sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, povidone or a combination thereof.
As a preferable mode of the invention, the phloroglucinol sustained release tablet comprises the following components in percentage by weight based on the total weight:
phloroglucinol: 20.0% -50.0%,
insoluble matrix material: 25.0% -56.0%,
hydrophilic gel matrix material: 5.0 to 43.5.0 percent,
and (2) an adhesive: 5.0% -50.0%,
filler: 6.0% -25.0%,
and (3) a lubricant: 0.5% -2.5%,
and the sum of the weight percentages of all the components is 100 percent;
the insoluble framework material is selected from ethyl cellulose, cellulose acetate, acrylic resin, ethylene-vinyl acetate copolymer, polyethylene, crosslinked polyvinylpyrrolidone and a combination thereof;
the hydrophilic gel framework material is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone and a combination thereof;
the adhesive is selected from sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, povidone or a combination thereof;
the filler is selected from microcrystalline cellulose, lactose, starch, mannitol or a combination thereof;
the lubricant is selected from colloidal silica, silica fume, magnesium stearate, talcum powder or a combination thereof.
As a preferable mode of the invention, the phloroglucinol sustained release tablet comprises the following components in percentage by weight:
phloroglucinol: 20.0% -50.0%,
insoluble matrix material: 27.0% -45.0%,
hydrophilic gel matrix material: 5.0% -25.0%,
and (2) an adhesive: 5.0% -25.0%,
filler: 8.0% -22.0%,
and (3) a lubricant: 0.5% -2.0%,
and the sum of the weight percentages of all the components is 100 percent.
As a further preferred aspect of the present invention, the insoluble framework material is ethylcellulose; the hydrophilic gel framework material is hydroxypropyl methylcellulose.
The invention relates to a method for preparing a phloroglucinol sustained release tablet, which is prepared by adopting a semi-dry wet granulation process, and comprises the following specific steps:
a. uniformly mixing auxiliary materials with the prescription amount in a wet granulator, wherein the auxiliary materials are the rest components except the phloroglucinol and the lubricant which are main medicines in the prescription;
b. placing the mixed powder prepared in the step a into wet granulation machine to prepare wet granules;
c. drying the wet granules obtained in step b and finishing the granules;
d. after finishing, uniformly mixing auxiliary material particles and main medicine phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules;
e. d, uniformly mixing the dry particles prepared in the step with a lubricant;
f. tabletting.
As a preferred embodiment of the present invention, the particle diameter D10 of the raw material is 60 to 230. Mu.m, and the D90 is 320 to 550. Mu.m.
As a preferred embodiment of the present invention, the particle diameter D10 of the raw material is 110 to 200. Mu.m, and the D90 is 380 to 490. Mu.m.
The invention has the main advantages that:
1) The inventor researches in the realization process, and discovers that the slow release effect is extremely outstanding by adopting a combined framework material taking an insoluble framework material as a main and a hydrophilic gel framework as an auxiliary, and the slow release duration and the clinical curative effect of the large-scale high-solubility medicament phloroglucinol are obviously prolonged.
2) Furthermore, the inventors found that stable release of phloroglucinol can be maintained without burst release when the particle diameter D10 of the raw material is controlled to 60 to 230 μm and the D90 is controlled to 320 to 550. Mu.m.
3) Furthermore, a large number of process comparison experiments show that the preparation method adopts a semi-dry wet granulation (auxiliary material granulation) process, can effectively reduce the generation of process impurities and greatly improve the stability of the product; meanwhile, the requirements on process conditions and equipment are simple, and the production cost is low.
Drawings
FIG. 1 dissolution profile of phloroglucinol sustained release tablets (examples 1-7 and comparative examples 1-7)
FIG. 2 dissolution profile of phloroglucinol sustained release tablets (examples 1-7 before and after acceleration)
FIG. 3 dissolution profile of phloroglucinol sustained release tablets (comparative examples 1-7 before and after acceleration)
FIG. 4 dissolution profile of phloroglucinol sustained release tablets (examples 1-7 and comparative examples 1-7 accelerated)
Detailed Description
The above-described aspects of the present invention will be described in further detail by way of examples, which should not be construed as limiting the scope of the above-described subject matter of the present invention to the following examples.
Example 1
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 150 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 425 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing hypromellose, hyprolose, ethylcellulose and lactose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, uniformly mixing auxiliary material particles and phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules; uniformly mixing the prepared dry particles with magnesium stearate; tabletting.
Example 2
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 150 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 425 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose and microcrystalline cellulose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, uniformly mixing auxiliary material particles and phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules; mixing the obtained dry particles with magnesium stearate and silica gel micropowder; tabletting.
Example 3
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 150 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 425 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing hypromellose, hyprolose, ethylcellulose, polyvinylpyrrolidone and lactose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, uniformly mixing auxiliary material particles and phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules; uniformly mixing the prepared dry particles with magnesium stearate; tabletting.
Example 4
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 60 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 320 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing hypromellose, hyprolose, ethylcellulose and lactose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, uniformly mixing auxiliary material particles and phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules; uniformly mixing the prepared dry particles with magnesium stearate; tabletting.
Example 5
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 230 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 550 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing hypromellose, hyprolose, ethylcellulose and lactose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, uniformly mixing auxiliary material particles and phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules; uniformly mixing the prepared dry particles with magnesium stearate; tabletting.
Example 6
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 150 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 425 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing cellulose acetate, hypromellose and lactose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, uniformly mixing auxiliary material particles and phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules; uniformly mixing the prepared dry particles with magnesium stearate; tabletting.
Example 7
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 150 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 425 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, acrylic resin and microcrystalline cellulose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, uniformly mixing auxiliary material particles and phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules; mixing the obtained dry particles with magnesium stearate and silica gel micropowder; tabletting.
Comparative example 1
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 150 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 425 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing hypromellose, hyprolose, ethylcellulose and lactose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, uniformly mixing auxiliary material particles and phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules; uniformly mixing the prepared dry particles with magnesium stearate; tabletting.
Comparative example 2
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 150 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 425 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose and microcrystalline cellulose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. Uniformly mixing auxiliary material particles and phloroglucinol after finishing, and putting the mixture into a dry granulator to prepare a dry (the feeding speed is 25rpm, the rotation speed of a press roll is 4.0rpm, the primary finishing speed is 100rpm, the secondary finishing speed is 200rpm, and the press roll pressure is 30-33 KN); mixing the obtained dry particles with magnesium stearate and silica gel micropowder; tabletting.
Comparative example 3
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 150 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 425 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing hypromellose, hyprolose, ethylcellulose, polyvinylpyrrolidone and lactose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, uniformly mixing auxiliary material particles and phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules; uniformly mixing the prepared dry particles with magnesium stearate; tabletting.
Comparative example 4
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 40 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 250 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing hypromellose, hyprolose, ethylcellulose and lactose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, uniformly mixing auxiliary material particles and phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules; uniformly mixing the prepared dry particles with magnesium stearate; tabletting.
Comparative example 5
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the particle diameter D10 is controlled to be 255 mu m plus or minus 10 mu m, and the D90 is controlled to be 580 mu m plus or minus 10 mu m.
2. Preparation method
Weighing auxiliary materials, and uniformly mixing hypromellose, hyprolose, ethylcellulose and lactose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the granulated auxiliary material particles at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, uniformly mixing auxiliary material particles and phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules; uniformly mixing the prepared dry particles with magnesium stearate; tabletting.
Comparative example 6
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 150 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 425 mu m plus or minus 10 mu m.
2. Preparation method
Weighing raw materials and auxiliary materials, and uniformly mixing phloroglucinol, hypromellose, hydroxypropyl cellulose, ethylcellulose and microcrystalline cellulose by using a wet granulator; stirring, adding purified water while stirring, cutting, mixing for 4-5min, and granulating with 20 mesh stainless steel screen; drying the wet granules after granulation at 60 ℃ for 2 hours; and (5) drying and sieving with a 20-mesh sieve to obtain granules. After finishing, mixing with magnesium stearate and micro silica gel uniformly; tabletting.
Comparative example 7
1. Prescription composition
Totaling 1000 tablets
The phloroglucinol is crushed, and the grain diameter D10 is controlled to be 150 mu m plus or minus 10 mu m, and the grain diameter D90 is controlled to be 425 mu m plus or minus 10 mu m.
2. Preparation method
Weighing raw materials and auxiliary materials, and uniformly mixing phloroglucinol, hypromellose, hydroxypropyl cellulose, ethylcellulose and microcrystalline cellulose; granulating by using a dry granulating machine; sieving with 20 mesh sieve, and granulating. After finishing, mixing with magnesium stearate and micro silica gel uniformly; tabletting.
Effect example 1
The samples prepared in examples 1 to 7 were subjected to in vitro dissolution behavior studies to examine the dissolution curves of the samples in examples 1 to 7 and comparative examples 1 to 7 under different pH media such as pH1.0, pH4.5 and pH6.8, and the specific methods are as follows:
release detection device: LOGAN ADRIII-7 reciprocating cylinder digestion instrument
0-1h, taking 300mL of hydrochloric acid solution with pH of 1.0 and pepsin solution as a release medium; 1-2h, 300mL acetate solution with pH of 4.5 is used as a release medium; 2-12h, and taking phosphate solution with pH value of 6.8 as a release medium.
Travel: 10cm, reciprocation speed: 30dpm, temperature 37 ℃, screen mesh number up and down: 40 mesh; taking a proper amount of solution at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h respectively, filtering, and taking the subsequent filtrate as a sample solution.
The results are shown in FIG. 1.
Effect example 2
Quality comparison study during acceleration test of inventive examples with comparative examples
According to the embodiment of the invention and the comparative example, the products are packaged according to the packaging form of the products on the market, and the products are subjected to comparative research on the items such as appearance characters, related substances, content measurement, dissolution curves and the like of the samples after 6 months of examination on the stability sample retention under the acceleration condition of 75% +/-5% RH at 40+/-2 ℃.
The test results are as follows:
table 1 results of comparative tests before and after the acceleration test of examples and comparative examples
From the above results, it is clear that the phloroglucinol sustained release tablet prepared in examples 1 to 7 of the present invention can maintain stable release of phloroglucinol without abrupt release when the particle size distribution D10 of phloroglucinol is controlled to be 60 to 230 μm and the D90 of phloroglucinol is controlled to be 320 to 550 μm, and the dissolution end point is reached for about 12 hours; through accelerated test investigation, the appearance and the related substances are basically unchanged, and the dissolution curve can be kept stable and free from abrupt release. While the insoluble framework material or the hydrophilic gel framework material adopted in the comparative examples 1-3 is not in the required range, the particle size of the raw material phloroglucinol in the comparative examples 4-5 is not controlled in the required range, and the raw material phloroglucinol is dissolved out in a dissolution curve of 0 day, namely, the dissolution is too fast, the slow and stable release cannot be kept, and the dissolution end point is reached within 2 hours basically; after 6 months of acceleration, it was shown that (1) the relevant substances increased, especially for both comparative examples 3,4 out of limit; (2) the dissolution curve speed is increased, the release shows abrupt release behavior, and the dissolution is basically completed within 1-2h, and the end point is reached; in particular, comparative example 4 had a dissolution rate exceeding 85% at 1 hour. Comparative examples 6 to 7 use the formulation of the claims, but the preparation process of semi-dry wet granulation is not used, and the sustained release phloroglucinol tablet with long-time slow release and good stability cannot be prepared.
The result shows that the phloroglucinol sustained release tablet prepared by the invention has extremely outstanding sustained release effect, and remarkably prolongs the sustained release duration and clinical curative effect of the large-scale high-solubility drug phloroglucinol; the stability is good, and the generation of impurities can be effectively reduced; the dissolution performance is stable in the stability process, and the transportation and the preservation of the product are more facilitated.
Claims (8)
1. The phloroglucinol sustained release tablet is characterized by comprising the following components in percentage by weight in total:
phloroglucinol 20.0-50.0%,
25.0 to 56.0 percent of insoluble framework material,
5.0 to 50.0 percent of hydrophilic gel framework material,
and the sum of the weight percentages of all the components is 100 percent;
the insoluble framework material is selected from ethyl cellulose, cellulose acetate, acrylic resin, ethylene-vinyl acetate copolymer, polyethylene, crosslinked polyvinylpyrrolidone or a combination thereof;
the hydrophilic gel skeleton material is selected from hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone or a combination thereof.
2. The phloroglucinol sustained release tablet of claim 1, comprising the following components by weight percent based on total weight:
phloroglucinol: 20.0% -50.0%,
insoluble matrix material: 25.0% -56.0%,
hydrophilic gel matrix material: 5.0% -50.0%,
and (2) an adhesive: 5.0 to 50.0 percent,
and the sum of the weight percentages of all the components is 100 percent;
the insoluble framework material is selected from ethyl cellulose, cellulose acetate, acrylic resin, ethylene-vinyl acetate copolymer, polyethylene, crosslinked polyvinylpyrrolidone or a combination thereof;
the hydrophilic gel framework material is selected from hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone or a combination thereof;
the binder is selected from sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, povidone or a combination thereof.
3. The phloroglucinol sustained release tablet of claim 1, comprising the following components in weight percent based on total weight:
phloroglucinol: 20.0% -50.0%,
insoluble matrix material: 25.0% -56.0%,
hydrophilic gel matrix material: 5.0% -43.5%,
and (2) an adhesive: 5.0% -50.0%,
filler: 6.0% -25.0%,
and (3) a lubricant: 0.5% -2.5%,
and the sum of the weight percentages of all the components is 100 percent;
the insoluble framework material is selected from ethyl cellulose, cellulose acetate, acrylic resin, ethylene-vinyl acetate copolymer, polyethylene, crosslinked polyvinylpyrrolidone and a combination thereof;
the hydrophilic gel framework material is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone and a combination thereof;
the adhesive is selected from sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, povidone or a combination thereof;
the filler is selected from microcrystalline cellulose, lactose, starch, mannitol or a combination thereof;
the lubricant is selected from colloidal silica, silica fume, magnesium stearate, talcum powder or a combination thereof.
4. The phloroglucinol sustained release tablet of claim 1, comprising the following components in weight percent:
phloroglucinol: 20.0% -50.0%,
insoluble matrix material: 27.0% -45.0%,
hydrophilic gel matrix material: 5.0% -25.0%,
and (2) an adhesive: 5.0% -25.0%,
filler: 8.0% -22.0%,
and (3) a lubricant: 0.5% -2.0%,
and the sum of the weight percentages of all the components is 100 percent.
5. The sustained release phloroglucinol tablet of any of claims 1-4, wherein the insoluble matrix material is ethylcellulose; the hydrophilic gel framework material is hydroxypropyl methylcellulose.
6. A method for preparing the phloroglucinol sustained release tablet according to any one of claims 1-4, which is characterized by adopting a semi-dry wet granulation process, and comprises the following specific steps:
a. uniformly mixing auxiliary materials with the prescription amount in a wet granulator, wherein the auxiliary materials are the rest components except the phloroglucinol and the lubricant which are main medicines in the prescription;
b. placing the mixed powder prepared in the step a into wet granulation machine to prepare wet granules;
c. drying the wet granules obtained in step b and finishing the granules;
d. after finishing, uniformly mixing auxiliary material particles and raw material medicine phloroglucinol, and putting the mixture into a dry granulator to prepare dry granules;
e. d, uniformly mixing the dry particles prepared in the step with a lubricant;
f. tabletting.
7. The method of sustained release phloroglucinol tablet of claim 6, wherein the bulk drug is crushed, the particle size D10 is controlled to be 60-230 μm, and the D90 is controlled to be 320-550 μm.
8. The method of sustained release phloroglucinol tablet of claim 7, wherein the raw materials are crushed, the particle diameter D10 is controlled to be 110-200 μm, and the D90 is controlled to be 380-490 μm.
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| CN202211201585.4A CN117815192A (en) | 2022-09-29 | 2022-09-29 | Phloroglucinol sustained release tablet and preparation method thereof |
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