CN114053235A - Theophylline sustained release tablet and preparation method thereof - Google Patents
Theophylline sustained release tablet and preparation method thereof Download PDFInfo
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- CN114053235A CN114053235A CN202010791400.4A CN202010791400A CN114053235A CN 114053235 A CN114053235 A CN 114053235A CN 202010791400 A CN202010791400 A CN 202010791400A CN 114053235 A CN114053235 A CN 114053235A
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- Prior art keywords
- theophylline
- hexadecanol
- release tablet
- octadecanol
- sieving
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- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 title claims abstract description 418
- 229960000278 theophylline Drugs 0.000 title claims abstract description 207
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 95
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims abstract description 87
- 238000002156 mixing Methods 0.000 claims abstract description 59
- 239000000463 material Substances 0.000 claims abstract description 45
- 239000003826 tablet Substances 0.000 claims abstract description 35
- 239000000314 lubricant Substances 0.000 claims abstract description 24
- 239000000853 adhesive Substances 0.000 claims abstract description 8
- 230000001070 adhesive effect Effects 0.000 claims abstract description 8
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 120
- 239000000243 solution Substances 0.000 claims description 76
- 239000008187 granular material Substances 0.000 claims description 67
- 238000007873 sieving Methods 0.000 claims description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 34
- 238000001035 drying Methods 0.000 claims description 26
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 23
- 239000008116 calcium stearate Substances 0.000 claims description 23
- 235000013539 calcium stearate Nutrition 0.000 claims description 23
- 229940082500 cetostearyl alcohol Drugs 0.000 claims description 20
- 238000005469 granulation Methods 0.000 claims description 20
- 230000003179 granulation Effects 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 20
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 20
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 20
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 claims description 20
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 18
- 235000019359 magnesium stearate Nutrition 0.000 claims description 18
- 229940069328 povidone Drugs 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 13
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- 230000008569 process Effects 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 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 8
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 238000005550 wet granulation Methods 0.000 claims description 5
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 4
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 4
- 238000010298 pulverizing process Methods 0.000 claims description 3
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 229950005770 hyprolose Drugs 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 23
- 238000013268 sustained release Methods 0.000 abstract description 14
- 239000012730 sustained-release form Substances 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 8
- 238000002844 melting Methods 0.000 abstract description 2
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- 239000008213 purified water Substances 0.000 description 20
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- 238000013265 extended release Methods 0.000 description 10
- 208000006673 asthma Diseases 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
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- 239000008108 microcrystalline cellulose Substances 0.000 description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 description 6
- 239000001856 Ethyl cellulose Substances 0.000 description 5
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 235000019325 ethyl cellulose Nutrition 0.000 description 5
- 229920001249 ethyl cellulose Polymers 0.000 description 5
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 229960004674 theophylline anhydrous Drugs 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
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- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000007779 soft material Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- KMEBCRWKZZSRRT-UHFFFAOYSA-N 2-methyl-7h-purine Chemical compound CC1=NC=C2NC=NC2=N1 KMEBCRWKZZSRRT-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 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 description 1
- 238000002835 absorbance Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
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- 229960003767 alanine Drugs 0.000 description 1
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- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
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- 230000001684 chronic effect Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
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- 230000000857 drug effect Effects 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000003860 sleep quality Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a theophylline sustained release tablet and a preparation method thereof, wherein the theophylline sustained release tablet is prepared from the following raw and auxiliary materials in parts by weight: 100 parts of anhydrous theophylline, 5-13 parts of hexadecanol, 3-6 parts of an adhesive and 1-3 parts of a lubricant. The sustained-release theophylline tablet is prepared by taking a hexadecadecanol material as a sustained-release framework material, melting or dissolving the material in high-concentration ethanol, adding other auxiliary materials, fully mixing with theophylline, and granulating. The theophylline sustained release tablet has good 24-hour sustained release effect, the release degree of theophylline at 24-hour time point exceeds 85%, the theophylline is completely released, the bioavailability is high, and the repeatability in batches and among batches in the preparation process is better.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a theophylline sustained release tablet and a preparation method thereof.
Background
Bronchial asthma (short for asthma) is a common disease and frequently encountered disease. Currently, about 3 hundred million people suffer from global asthma and about 3000 million suffer from Chinese asthma. Asthma is an important disease affecting physical and mental health of people, and can be fatal if treatment is not timely and normative, the standardized treatment can well control the disease of nearly 80% of asthma patients, and the selection of a treatment mode which is easily accepted by the patients is an important method for timely and normative treatment of the patients.
Theophylline is a methylpurine medicine, has effects of tonifying heart, promoting urination, dilating coronary artery, relaxing bronchial smooth muscle and exciting central nervous system, and is mainly used for treating bronchial asthma, emphysema, bronchitis, and cardiac dyspnea. However, the therapeutic window of theophylline drugs is narrow, the therapeutic concentration is close to the toxic concentration, and the individual difference of patients is large, so the theophylline is prepared into a sustained-release preparation to reduce the fluctuation of blood concentration, avoid toxic action and reduce the administration times. Theophylline is taken as a representative medicine for treating asthma diseases, and the theophylline sustained-release tablet is a very effective medicine for stably treating asthma and also has a good treatment effect. At present, the existing theophylline sustained release tablet products in China are all theophylline sustained release tablet products with 12-hour release period, and no theophylline sustained release tablet products with 24-hour release period are on the market. The product with a 12-hour release period has the peak time of blood concentration of 4-7 hours, the blood concentration of theophylline in vivo can be maintained within a treatment range (5-20 g/ml) for 12 hours, and the product is required to be taken 1-2 tablets/time and 2 times/day every day according to the specification, and is orally taken in the morning and before sleeping to maintain the treatment effect. For patients with chronic symptoms, the product has the advantages of quick release, high peak value of blood concentration, short peak reaching time, higher probability of adverse reaction of the bodies of the patients and poorer compliance. The theophylline sustained release tablet with 24-hour drug release period is taken 1 time after supper every day according to the specification of Japanese reference preparation (UNICON Tab.100), and the nighttime sleep quality is not affected, especially the onset from nighttime to early morning. For patients with acute symptoms, the difference is not obvious, and the product has slow peak reaching time and can improve the compliance of the patients.
Chinese patent publication No. CN10755088A provides a theophylline sustained release tablet releasing drug for 24 hours, wherein the matrix material used is mainly cellulose, and cellulose is a material swelling in water, and encapsulates theophylline, thereby achieving the purpose of sustained release, but it cannot form a spatial structure with a network, so that the release of theophylline is not complete.
Disclosure of Invention
Based on the theophylline sustained release tablet, the theophylline sustained release tablet with 24-hour drug release period has good 24-hour sustained release effect, the release degree of the theophylline at the 24-hour time point exceeds 85%, the theophylline is completely released, and the bioavailability is high.
The specific technical scheme is as follows:
a theophylline sustained release tablet is prepared from the following raw and auxiliary materials in parts by weight:
in some of these embodiments, the cetostearyl alcohol is present in an amount of 6 to 12 parts by weight.
In some of these embodiments, the cetostearyl alcohol is present in an amount of 9 to 11 parts by weight.
In some embodiments, the content of the hexadecanol and the octadecanol is 20% to 50% and 50% to 80% respectively, based on 100% of the hexadecanol and the octadecanol.
In some embodiments, the content of the hexadecanol and the octadecanol is 25 to 35 percent and 65 to 75 percent, respectively, based on 100 percent of the hexadecanol and the octadecanol.
In some embodiments, the ratio of hexadecanol in the hexadecanol is 30% and the ratio of octadecanol in the hexadecanol is 70%, based on the content of the hexadecanol and the octadecanol being 100%.
In some of these embodiments, the binder is one or more of povidone, hydroxyethyl cellulose, hypromellose, and hyprolose.
In some embodiments, the lubricant is one or more of calcium stearate, magnesium stearate, and talc.
In some of the embodiments, the binder is povidone with a weight part of 4.5 to 5.5 parts; the lubricant is calcium stearate and accounts for 1.5-2.5 parts by weight.
The invention also provides a preparation method of the theophylline sustained release tablet.
The specific technical scheme is as follows:
the preparation method of the theophylline sustained release tablet comprises the following steps:
putting the anhydrous theophylline into granulation equipment, spraying ethanol water solution of hexadecanol and octadecanol and water solution of the binding agent in sequence, granulating, drying and sieving the obtained wet granules, adding the lubricant, uniformly mixing and tabletting to obtain the theophylline sustained release tablet; or,
the preparation method of the theophylline sustained release tablet comprises the following steps:
adding the anhydrous theophylline and the hexadecanol into wet granulation equipment, uniformly mixing, heating to melt the hexadecanol and the octadecanol, fully mixing with the anhydrous theophylline, cooling, adding the aqueous solution of the binding agent, granulating, drying and sieving the obtained wet granules, adding the lubricating agent, uniformly mixing and tabletting to obtain the theophylline sustained release tablet; or,
the preparation method of the theophylline sustained release tablet comprises the following steps:
adding anhydrous theophylline and hexadecanol into a granulating device, uniformly mixing, spraying the aqueous solution of the adhesive, granulating, heating, keeping the temperature for a certain time to melt the hexadecanol and the octadecanol, fully mixing with the anhydrous theophylline, continuously heating to dry the obtained granules, sieving the obtained dry granules, adding the lubricant, uniformly mixing, and tabletting to obtain the theophylline sustained release tablet.
In some embodiments, the preparation method of the theophylline sustained release tablet comprises the following steps:
(1) crushing the anhydrous theophylline and then sieving for later use; sieving the lubricant for later use;
(2) pulverizing the cetostearyl alcohol and sieving for later use; or dissolving the hexadecanol and the octadecanol with an ethanol water solution to be used as a solution A for later use;
(3) dissolving the adhesive by water to obtain solution B for later use;
(4) granulating and tabletting;
the granulating and tabletting method comprises any one of the following steps:
method A, comprising the steps of: putting the crushed and sieved anhydrous theophylline into granulation equipment, spraying the solution A and the solution B in sequence, granulating, drying and sieving the obtained wet granules, adding a sieved lubricant, uniformly mixing and tabletting to obtain the theophylline sustained release tablet;
the method B comprises the following steps:
adding the crushed and sieved anhydrous theophylline and hexadecanol into wet granulation equipment, uniformly mixing, heating to melt the hexadecanol and the octadecanol, fully mixing with the anhydrous theophylline, cooling, adding the solution B, granulating, drying and sieving the obtained wet granules, adding a sieved lubricant, uniformly mixing and tabletting to obtain the theophylline sustained release tablet;
method C, comprising the steps of:
adding the crushed and sieved anhydrous theophylline and the hexadecanol into a granulating device, uniformly mixing, spraying the solution B, granulating, heating and keeping the temperature for a certain time to melt the hexadecanol and the octadecanol and fully mix with the anhydrous theophylline, continuously heating to dry the obtained granules, sieving the obtained dry granules, adding the sieved lubricant, uniformly mixing and tabletting to obtain the theophylline sustained release tablet.
In some embodiments, the anhydrous theophylline is crushed and sieved to pass through a 60-100-mesh sieve in the step (1); and sieving the lubricant to pass through a sieve of 30-50 meshes.
In some embodiments, the cetostearyl alcohol is crushed and sieved to pass through a sieve of 80-100 meshes in the step (2); the mass concentration of the hexadecanol and octadecanol in the solution A is 5-15%; the concentration of the ethanol water solution is 85-98%.
In some embodiments, the mass concentration of the binder in the solution B in the step (3) is 5% to 15%.
In some of the embodiments, the temperature of the granulation is 35-45 ℃ in method A.
In some embodiments, in the method B, the heating temperature is 50 ℃ to 65 ℃, the heating time is 10 to 30/min, and the temperature reduction is to be 40 ℃ ± 5 ℃.
In some of the embodiments, in method C, the temperature of the granulation is 35-45 ℃; the temperature is increased and kept constant for a certain time, the temperature is 45-55 ℃, and the time is 8-15 minutes; the temperature is continuously increased to 60-65 ℃.
In some of these embodiments, the granulating and tableting steps are performed by drying the granules to a moisture content of less than 3% and sieving by a 14 mesh sieve.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention takes a certain amount of hexadecanol and octadecanol as the sustained-release framework material, and can prepare the theophylline into the theophylline sustained-release tablet with 24-hour drug release period by matching with a certain amount of adhesive and lubricant. The theophylline sustained release tablet obviously delays the dissolution of theophylline, can well control the release of the theophylline, has longer stability in the dissolution release process, has a sustained release period of 24 hours, has good reproducibility of the release rate, has the release rate of more than 85 percent in the 24 th hour, is completely released, and has high bioavailability.
(2) The theophylline sustained release tablet takes the hexadecadecanol as the sustained release skeleton material, so that the proportion of the auxiliary materials in the prescription is small, and good controlled release effect can be achieved only by mixing and granulating a small amount of the skeleton material, the auxiliary materials and the theophylline, the drug content in the theophylline sustained release tablet is improved, the production cost is reduced, and the obtained theophylline sustained release tablet has better uniformity and batch reproducibility when being released.
(3) The effective components of the theophylline sustained release tablet prepared by the invention are consistent with the external dissolution of theophylline sustained release tablets produced by Nichi-Iko Pharmaceutical Co. The theophylline sustained release tablet is designed into a once-a-day administration mode, is favorable for improving the administration compliance of patients, overcomes the defects of inconvenience and high concentration fluctuation caused by multiple administrations, and provides convenience for the patients.
(4) The common technique for preparing the theophylline sustained release tablet at present comprises high-speed wet granulation, coating of a sustained release film coating layer and the like, and then mixing with certain auxiliary materials to be pressed into tablets; the commonly used sustained-release framework material is cellulose derivative, such as ethyl cellulose, hydroxypropyl methyl cellulose and the like, the characteristic of the sustained-release framework material is insoluble in water, the production process needs ethanol with higher concentration for granulation, certain potential safety hazard exists, the cleaning is inconvenient, certain requirements on production equipment and environment are met, and organic solvent residue may exist. The theophylline sustained-release tablet is granulated by taking the hexadecanol and octadecanol as sustained-release framework materials, so that granules can be prepared according to the traditional wet process in the granulating process, and the hexadecanol and octadecanol as the framework materials can be fully melted and then contacted and mixed with the theophylline uniformly by a heating and melting mode, thereby avoiding using an organic solvent in the production process, not only avoiding potential safety hazards caused by using the organic solvent in the production process, but also avoiding the risk of organic solvent residue in the obtained product; and the production process and the production equipment are simple, the repeatability in and among batches in the preparation process is good, the repeatability is high, the continuous production can be realized, and the method is suitable for industrial amplification.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusions. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to only those steps or modules listed, but may alternatively include other steps not listed or inherent to such process, method, article, or device.
The "plurality" referred to in the present invention means two or more. "and/or" describes the association relationship of the associated objects, meaning that there may be three relationships, e.g., a and/or B, which may mean: a exists alone, A and B exist simultaneously, and B exists alone. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
In the following examples, the ratio of cetostearyl alcohol in parentheses means the mass ratio of cetostearyl alcohol to cetostearyl alcohol, for example, "cetostearyl alcohol (2: 8)" means: the mass ratio of the hexadecanol to the octadecanol in the hexadecanol is 2:8, wherein the content of the hexadecanol is 100%.
EXAMPLE 124 preparation of theophylline extended release tablets with an hour Release period
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained release tablet (100mg) and proportion thereof
| Name of raw and auxiliary materials | Dosage per gram |
| Anhydrous theophylline | 100 |
| Hexadecanol (3:7) | 10 |
| Hydroxypropyl methylcellulose | 6 |
| Talcum powder | 2 |
| Magnesium stearate | 1 |
| 95% ethanol | Proper amount of |
| Purified water | Proper amount of |
Secondly, the preparation method comprises the following steps:
(1) crushing anhydrous theophylline and sieving with a 80-mesh sieve; sieving pulvis Talci and magnesium stearate with 40 mesh sieve;
(2) preparing the hexadecanol and octadecanol into a solution with the mass concentration of 12% by using an ethanol water solution with the mass concentration of 95% as a solution A for later use; preparing hydroxypropyl methylcellulose into a solution with the mass concentration of 5% by using purified water, and using the solution as a solution B for later use;
(3) adding anhydrous theophylline into a one-step granulator, normally fluidizing and preheating to 40 deg.C, spraying solution A, mixing with theophylline, and spraying solution B to granulate to obtain wet granules;
(4) drying the wet granules until the water content is less than 3%, collecting granules, sieving the obtained dry granules with a 14-mesh sieve, adding talcum powder and magnesium stearate, uniformly mixing, and tabletting to obtain the theophylline sustained-release tablet with the hardness of 3 kg-4 kg.
EXAMPLE preparation of theophylline extended Release tablets with a Release period of 224 hours
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained release tablet (100mg) and proportion thereof
| Name of raw and auxiliary materials | Dosage per gram |
| Anhydrous theophylline | 100 |
| Hexadecanol (3:7) | 10 |
| Hydroxypropyl cellulose | 5 |
| Magnesium stearate | 2 |
| Purified water | Proper amount of |
Secondly, the preparation method comprises the following steps:
(1) crushing anhydrous theophylline and hexadecanol, and sieving with 80 mesh sieve; sieving magnesium stearate with 40 mesh sieve;
(2) preparing hydroxypropyl cellulose into a solution with the mass concentration of 10% by using purified water, and using the solution as a solution B for later use;
(3) adding anhydrous theophylline and cetostearyl alcohol into a one-step granulator to ensure that the materials are normally fluidized and preheated to 40 ℃, uniformly mixing, and spraying the solution B for granulation;
(4) after the liquid spraying is finished, heating to 50 ℃, keeping the temperature constant for 10 minutes (so as to melt the hexadecanol and the octadecanol and fully mix with the theophylline), continuously heating to 60 ℃, until the moisture of the obtained granules is less than 3%, collecting the granules, sieving the obtained dry granules with a 14-mesh sieve, adding the magnesium stearate, uniformly mixing and tabletting, and measuring the hardness of the tablets to be between 3kg and 4kg, thus obtaining the theophylline sustained release tablets.
EXAMPLE 324 preparation of theophylline extended release tablets with an hour Release cycle
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained release tablet (100mg) and proportion thereof
| Name of raw and auxiliary materials | Dosage per gram |
| Anhydrous theophylline | 100 |
| Hexadecanol (3:7) | 10 |
| Povidone | 4 |
| Hydroxyethyl cellulose | 2 |
| Talcum powder | 2 |
| Magnesium stearate | 1 |
| Purified water | Proper amount of |
Secondly, the preparation method comprises the following steps:
(1) crushing anhydrous theophylline and hexadecanol, and sieving with 80 mesh sieve; sieving pulvis Talci and magnesium stearate with 40 mesh sieve;
(2) preparing povidone into a solution with the mass concentration of 8% by using purified water, and using the solution as B1 solution for later use; preparing hydroxyethyl cellulose into a solution with the mass concentration of 5% by using purified water, and using the solution as B2 solution for later use;
(3) adding anhydrous theophylline and cetostearyl alcohol into a wet granulator, and premixing for 3 minutes; then setting the temperature of the wet granulator to 55 ℃, setting the rotating speed of a bottom paddle to 250 revolutions and the rotating speed of a side paddle to 1000 revolutions, mixing anhydrous theophylline and cetostearyl alcohol in the wet granulator for 20 minutes (so that the cetostearyl alcohol is melted and fully mixed with the theophylline), cooling to 40 +/-5 ℃, adding B1 liquid for granulation, and continuing adding B2 liquid for granulation to obtain wet granules;
(4) and (3) putting the wet granules into a fluidized bed, drying until the water content is less than 3%, collecting granules, sieving the obtained dry granules with a 14-mesh sieve, adding talcum powder and magnesium stearate, uniformly mixing, and tabletting to obtain the theophylline sustained-release tablets with the hardness of 3 kg-4 kg.
EXAMPLE 424 preparation of extended release theophylline tablets with an hour Release cycle
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained release tablet (100mg) and proportion thereof
| Name of raw and auxiliary materials | Dosage per gram |
| Anhydrous theophylline | 100 |
| Hexadecanol (2:8) | 10 |
| Hydroxypropyl cellulose | 6 |
| Magnesium stearate | 3 |
| Purified water | Proper amount of |
Secondly, the preparation method comprises the following steps:
(1) crushing anhydrous theophylline and hexadecanol, and sieving with 80 mesh sieve; sieving magnesium stearate with 40 mesh sieve;
(2) preparing hydroxypropyl cellulose into a solution with the mass concentration of 7% by using purified water, and using the solution as a solution B for later use;
(3) adding anhydrous theophylline and cetostearyl alcohol into a wet granulator, premixing for 3 minutes, setting the temperature of the wet granulator to be 50 ℃, setting the rotating speed of a bottom paddle to be 250 revolutions, setting the rotating speed of a side paddle to be 1000 revolutions, mixing the anhydrous theophylline and the cetostearyl alcohol in the wet granulator for 20 minutes (so that the cetostearyl alcohol is melted and fully mixed with the theophylline), cooling to 40 +/-5 ℃, and adding liquid B for granulation to obtain wet granules;
(4) and (3) putting the wet granules into a fluidized bed, drying until the water content is less than 3%, collecting granules, sieving the obtained dry granules with a 14-mesh sieve, adding magnesium stearate, uniformly mixing, and tabletting to obtain the theophylline sustained-release tablets with the hardness of 3 kg-4 kg.
EXAMPLE 524 preparation of extended release theophylline tablets with an extended release period of 524 hours
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained release tablet (100mg) and proportion thereof
| Name of raw and auxiliary materials | Dosage per gram |
| Theophylline anhydrous | 100 |
| Hexadecanol (5:5) | 10 |
| Povidone | 5 |
| Calcium stearate | 2 |
| Purified water | Proper amount of |
Secondly, the preparation method comprises the following steps:
(1) crushing anhydrous theophylline and hexadecanol, and sieving with 80 mesh sieve; sieving calcium stearate with 40 mesh sieve;
(2) preparing solution with mass concentration of 10% from povidone by using purified water, and using the solution as solution B for later use;
(3) anhydrous theophylline and hexadecanol are added into a wet granulator and premixed for 3 minutes; then setting the temperature of the wet granulator to be 60 ℃, setting the rotating speed of a bottom paddle to be 250 revolutions and the rotating speed of a side paddle to be 1000 revolutions, mixing anhydrous theophylline and hexadecadecyl alcohol in the wet granulator for 20 minutes (so that the hexadecadecyl alcohol is melted and fully mixed with the theophylline), cooling to 40 +/-5 ℃, adding the liquid B for granulation, and obtaining wet granules;
(4) and (3) putting the wet granules into a fluidized bed, drying until the water content is less than 3%, collecting granules, sieving the obtained dry granules with a 14-mesh sieve, adding calcium stearate, uniformly mixing, tabletting, and measuring the hardness of the tablets to be between 3kg and 4kg to obtain the theophylline sustained-release tablets.
EXAMPLE preparation of theophylline extended Release tablets with a Release period of 624 hours
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained release tablet (100mg) and proportion thereof
| Name of raw and auxiliary materials | Dosage per gram |
| Theophylline anhydrous | 100 |
| Hexadecanol (2:8) | 10 |
| Povidone | 5 |
| Calcium stearate | 2 |
| Purified water | Proper amount of |
Secondly, the preparation method comprises the following steps:
(1) crushing anhydrous theophylline and hexadecanol, and sieving with 80 mesh sieve; sieving calcium stearate with 40 mesh sieve;
(2) preparing solution with mass concentration of 10% from povidone by using purified water, and using the solution as solution B for later use;
(3) anhydrous theophylline and hexadecanol are added into a wet granulator and premixed for 3 minutes; then setting the temperature of the wet granulator to be 60 ℃, setting the rotating speed of a bottom paddle to be 250 revolutions and the rotating speed of a side paddle to be 1000 revolutions, mixing anhydrous theophylline and hexadecadecyl alcohol in the wet granulator for 20 minutes (so that the hexadecadecyl alcohol is melted and fully mixed with the theophylline), cooling to 40 +/-5 ℃, adding the liquid B for granulation, and obtaining wet granules;
(4) and (3) putting the wet granules into a fluidized bed, drying until the water content is less than 3%, collecting granules, sieving the obtained dry granules with a 14-mesh sieve, adding calcium stearate, uniformly mixing, tabletting, and measuring the hardness of the tablets to be between 3kg and 4kg to obtain the theophylline sustained-release tablets.
EXAMPLE 724 preparation of extended release theophylline tablets with an hour Release cycle
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained release tablet (100mg) and proportion thereof
| Name of raw and auxiliary materials | Dosage per gram |
| Theophylline anhydrous | 100 |
| Hexadecanol (3:7) | 10 |
| Povidone | 5 |
| Calcium stearate | 2 |
| Purified water | Proper amount of |
Secondly, the preparation method comprises the following steps:
(1) crushing anhydrous theophylline and hexadecanol, and sieving with 80 mesh sieve; sieving calcium stearate with 40 mesh sieve;
(2) preparing solution with mass concentration of 10% from povidone by using purified water, and using the solution as solution B for later use;
(3) anhydrous theophylline and hexadecanol are added into a wet granulator and premixed for 3 minutes; then setting the temperature of the wet granulator to be 60 ℃, setting the rotating speed of a bottom paddle to be 250 revolutions and the rotating speed of a side paddle to be 1000 revolutions, mixing anhydrous theophylline and hexadecadecyl alcohol in the wet granulator for 20 minutes (so that the hexadecadecyl alcohol is melted and fully mixed with the theophylline), cooling to 40 +/-5 ℃, adding the liquid B for granulation, and obtaining wet granules;
(4) and (3) putting the wet granules into a fluidized bed, drying until the water content is less than 3%, collecting granules, sieving the obtained dry granules with a 14-mesh sieve, adding calcium stearate, uniformly mixing, tabletting, and measuring the hardness of the tablets to be between 3kg and 4kg to obtain the theophylline sustained-release tablets.
EXAMPLE 824 preparation of extended release theophylline tablets with an hourly Release period
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained release tablet (100mg) and proportion thereof
Secondly, the preparation method comprises the following steps:
(1) crushing anhydrous theophylline and hexadecanol, and sieving with 80 mesh sieve; sieving calcium stearate with 40 mesh sieve;
(2) preparing solution with mass concentration of 10% from povidone by using purified water, and using the solution as solution B for later use;
(3) anhydrous theophylline and hexadecanol are added into a wet granulator and premixed for 3 minutes; then setting the temperature of the wet granulator to be 60 ℃, setting the rotating speed of a bottom paddle to be 250 revolutions and the rotating speed of a side paddle to be 1000 revolutions, mixing anhydrous theophylline and hexadecadecyl alcohol in the wet granulator for 20 minutes (so that the hexadecadecyl alcohol is melted and fully mixed with the theophylline), cooling to 40 +/-5 ℃, adding the liquid B for granulation, and obtaining wet granules;
(4) and (3) putting the wet granules into a fluidized bed, drying until the water content is less than 3%, collecting granules, sieving the obtained dry granules with a 14-mesh sieve, adding calcium stearate, uniformly mixing, tabletting, and measuring the hardness of the tablets to be between 3kg and 4kg to obtain the theophylline sustained-release tablets.
EXAMPLE preparation of sustained-Release theophylline tablets with a Release period of 924 hours
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained release tablet (100mg) and proportion thereof
Secondly, the preparation method comprises the following steps:
(1) crushing anhydrous theophylline and hexadecanol, and sieving with 80 mesh sieve; sieving calcium stearate with 40 mesh sieve;
(2) preparing solution with mass concentration of 10% from povidone by using purified water, and using the solution as solution B for later use;
(3) anhydrous theophylline and hexadecanol are added into a wet granulator and premixed for 3 minutes; then setting the temperature of the wet granulator to be 60 ℃, setting the rotating speed of a bottom paddle to be 250 revolutions and the rotating speed of a side paddle to be 1000 revolutions, mixing anhydrous theophylline and hexadecadecyl alcohol in the wet granulator for 20 minutes (so that the hexadecadecyl alcohol is melted and fully mixed with the theophylline), cooling to 40 +/-5 ℃, adding the liquid B for granulation, and obtaining wet granules;
(4) and (3) putting the wet granules into a fluidized bed, drying until the water content is less than 3%, collecting granules, sieving the obtained dry granules with a 14-mesh sieve, adding calcium stearate, uniformly mixing, tabletting, and measuring the hardness of the tablets to be between 3kg and 4kg to obtain the theophylline sustained-release tablets.
Comparative example 1 theophylline sustained-release tablet prepared by conventional wet process
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained-release tablet and proportion thereof
Secondly, the preparation method comprises the following steps:
(1) dissolving 4g of polyvinylpyrrolidone in an ethanol solution to prepare an alcohol solution with the mass concentration of 8%;
(2) placing the sieved theophylline, the rest polyvinylpyrrolidone, the L-alanine, the alginic acid and the lactose in a wet granulator, setting the rotating speed of a bottom paddle to be 250 revolutions and the rotating speed of a side paddle to be 1000 revolutions, mixing for 3 minutes, adding the solution obtained in the step (1), and fully mixing for 2 minutes to obtain a soft material;
(3) putting the wet granules into a fluidized bed, drying until the water content is less than 3%, collecting the granules, sieving the obtained dry granules with a 14-mesh sieve, adding a lubricating glidant magnesium stearate to obtain mixed powder, adding all the mixed powder into a multiphase motion mixer, mixing and pressing into tablets, and measuring the hardness of the tablets to be between 3kg and 4 kg;
(4) sieving talcum powder, mixing, adding into ethanol solution containing sodium carboxymethylcellulose and propylene glycol, stirring, grinding, and making into coating solution with mass concentration of 12%;
(5) and (3) adding the plain tablets into a nonporous coating pot, setting the air inlet temperature to be 70-80 ℃, preheating the plain tablets, adding the coating liquid for coating, and controlling the material temperature to be 40 +/-5 ℃ in the coating process to obtain the theophylline sustained release tablets.
Comparative example 2
The experiment was repeated according to the experimental conditions in example 1 of patent CN 107550880A.
The prescription composition is as follows:
200g of theophylline, 24g of microcrystalline cellulose, 12g of ethyl cellulose and 4g of magnesium stearate which are 240g in total, and 1000 theophylline tablets can be theoretically prepared into the 24-hour sustained release tablet.
Wherein: the microcrystalline cellulose is domestic common microcrystalline cellulose.
The preparation method comprises the following steps:
(1) pulverizing theophylline, sieving with 80 mesh sieve, sieving microcrystalline cellulose with 120 mesh sieve, and sieving magnesium stearate with 60 mesh sieve;
(2) calculating the actual material demand according to the batch and the prescription composition, and weighing theophylline, microcrystalline cellulose and ethyl cellulose;
(3) dissolving weighed ethyl cellulose with 95% ethanol to be used as a binder, wherein the concentration (w/w) of the ethyl cellulose is 20%;
(4) adding weighed theophylline and microcrystalline cellulose into a wet granulator, uniformly mixing, adding an adhesive to prepare a soft material, and then granulating with a 20-mesh sieve;
(5) drying the intermediate product obtained in the step (4) by using a boiling drying granulator, setting the drying temperature to be 60 ℃, and finishing the drying when the drying weight loss of the granules is 2.0%;
(6) straightening the intermediate product obtained in the step (5) by using a 1.5mm screen;
(7) weighing the intermediate product obtained in the step (6), and weighing magnesium stearate according to the prescription proportion;
(8) adding the weighed materials in the step (7) into a mixer, and uniformly mixing;
(9) and (3) adding the intermediate product obtained in the step (8) into a tabletting machine for tabletting to obtain the theophylline sustained release tablet for 24 hours, wherein the diameter of a circular mould is 9.5mm, and the average hardness of the tablet is 78N.
Comparative example 3
This comparative example differs from example 5 in that hexadecanol is used instead of hexadecanol.
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained release tablet (100mg) and proportion thereof
Secondly, the preparation method comprises the following steps:
(1) crushing anhydrous theophylline and hexadecanol, and sieving with 80 mesh sieve; sieving calcium stearate with 40 mesh sieve;
(2) preparing solution with mass concentration of 10% from povidone by using purified water, and using the solution as solution B for later use;
(3) adding theophylline and hexadecanol into a wet granulator without water, and mixing for 3 minutes; setting the temperature of a wet granulator to be 60 ℃, setting the rotating speed of a bottom paddle to be 250 revolutions and the rotating speed of a side paddle to be 1000 revolutions, mixing anhydrous theophylline and hexadecanol in the wet granulator for 20 minutes (so that the hexadecanol is melted and fully mixed with the theophylline), cooling to 40 +/-5 ℃, and adding the liquid B for granulation to obtain wet granules;
(4) and (3) putting the wet granules into a fluidized bed, drying until the water content is less than 3%, collecting granules, sieving the obtained dry granules with a 14-mesh sieve, adding calcium stearate, uniformly mixing, tabletting, and measuring the hardness of the tablets to be between 3kg and 4kg to obtain the theophylline sustained-release tablets.
Comparative example 4
This comparative example differs from example 5 in that cetostearyl alcohol is replaced by stearyl alcohol.
Firstly, weighing the following components in parts by weight:
raw and auxiliary materials of theophylline sustained release tablet (100mg) and proportion thereof
| Name of raw and auxiliary materials | Dosage per gram |
| Theophylline anhydrous | 100 |
| Octadecanol | 10 |
| Povidone | 6 |
| Calcium stearate | 1 |
| Purified water | Proper amount of |
Secondly, the preparation method comprises the following steps:
(1) crushing anhydrous theophylline and octadecanol, and sieving with a 80-mesh sieve; sieving calcium stearate with 40 mesh sieve;
(2) preparing solution with mass concentration of 10% from povidone by using purified water, and using the solution as solution B for later use;
(3) anhydrous adding theophylline and octadecanol into a wet granulator and mixing for 3 minutes; setting the temperature of a wet granulator to be 60 ℃, setting the rotating speed of a bottom paddle to be 250 revolutions and the rotating speed of a side paddle to be 1000 revolutions, mixing anhydrous theophylline and octadecanol in the wet granulator for 20 minutes (so that octadecanol is melted and fully mixed with theophylline), cooling to 40 +/-5 ℃, adding the solution B for granulation, and obtaining wet granules;
(4) and (3) putting the wet granules into a fluidized bed, drying until the water content is less than 3%, collecting granules, sieving the obtained dry granules with a 14-mesh sieve, adding calcium stearate, uniformly mixing, tabletting, and measuring the hardness of the tablets to be between 3kg and 4kg to obtain the theophylline sustained-release tablets.
The release rate of the theophylline sustained release tablets prepared in the examples and comparative examples of the present invention was tested according to the dissolution method provided in "quality information of pharmaceutical products for medical use in japan" (2011 edition), and the specific method was as follows:
taking the product, performing dissolution test (paddle method), using 900ml of water as solvent, rotating at 100 rpm, operating according to the method, filtering appropriate amount of solution, simultaneously supplementing medium with the same temperature and volume, discarding at least 10ml of primary filtrate, precisely taking appropriate amount of subsequent filtrate, diluting with water to obtain solution containing 11 μ g per 1ml, and using as sample solution. And accurately weighing 0.022g of theophylline control product which is dried at 105 ℃ for 4 hours, placing the theophylline control product in a 100ml measuring flask, adding water to dissolve the theophylline control product and dilute the theophylline control product to the scale, shaking up, accurately weighing 5ml, placing the theophylline control product in the 100ml measuring flask, adding water to dilute the theophylline control product to the scale, and shaking up to obtain a control solution. And (3) irradiating the two solutions by an ultraviolet-visible spectrophotometry, respectively measuring the absorbance at the wavelength of 271nm, and calculating the dissolution amount of each tablet, wherein the dissolution amount of each tablet of the product in 4 hours, 8 hours and 24 hours is respectively 15-45%, 35-65% and more than 70% of the marked amount.
The test results are shown in table 1.
Wherein, the reference preparation is:
| trade name | UNICON |
| Name of English | Theophylline Sustained-release Tablets |
| Specification of | 0.1g |
| Holder | Nichi-Iko Pharmaceutical Co.,Ltd |
TABLE 1 Release Rate results for theophylline extended release tablets
According to the data in the table 1, the theophylline sustained release tablet prepared by the invention has good dissolution fitting degree with a reference preparation, the release degree reaches more than 85% in 24 hours, and the RSD value of the dissolution degree at each time point is less than 4%. The invention creatively uses the hexadecanol and the octadecanol as the sustained-release framework material and uses a small amount of auxiliary materials to prepare the theophylline sustained-release tablet with 24-hour release period. The skeleton material can be fully and uniformly mixed with theophylline in the granulation process, so that the obtained theophylline sustained release tablet has better uniformity and batch reproducibility when being released, the production process is controllable, and the obtained theophylline sustained release tablet can stably exert the drug effect for 24 hours. The release effect of the obtained theophylline sustained release tablet can be further improved by further controlling the dosage of the hexadecanol and the octadecanol and the proportion of the hexadecanol and the octadecanol in the hexadecanol and the octadecanol, and further preferably matching the binder and the lubricant. Wherein, the dosage of the hexadecanol and the octadecanol is 10 parts, the mass ratio of the hexadecanol and the octadecanol in the hexadecanol and the octadecanol is 3:7, the binding agent is 5 parts of povidone, and the lubricating agent is 2 parts of calcium stearate, so that the prepared theophylline sustained release tablet has the best release effect.
In comparative example 1, according to the conventional wet process, the release rate of the prepared theophylline sustained release tablet meets the standard of Chinese pharmacopoeia, but the theophylline sustained release tablet is a product with a 12-hour release period, and the release rate in 8 hours reaches 66%.
In comparative example 2, the theophylline sustained release tablet prepared according to the prescription and process provided in CN107550880A has a tendency of slow drug release within 24 hours, and meets the japanese standard, but the dissolution is incomplete, and the dissolution rate within 24 hours is less than 80%, which may be caused by the prescription using cellulose as a matrix material, and insufficient dissolution due to lack of sufficient mesh channels in the tablet core.
In comparative example 3, when hexadecanol was used instead of hexadecanol and the tablet weight was equivalent, the dissolution fit of the theophylline sustained release tablet prepared using hexadecanol was lower than that of the reference preparation, and f2 was less than 50, indicating that the requirement of 24-hour drug release cannot be satisfied by using hexadecanol alone.
In the comparative example 4, octadecanol is used instead of hexadecanol, and because octadecanol has stronger thickening performance than hexadecanol, and is easy to agglomerate in the granulation process, the content uniformity of the prepared theophylline sustained release tablet is poorer, the dissolution rate is reduced more, the release of theophylline is incomplete within 24 hours, and the preparation requirement of 24-hour release is not met.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The theophylline sustained release tablet is characterized by being prepared from the following raw and auxiliary materials in parts by weight:
2. the theophylline sustained-release tablet according to claim 1, wherein the amount of the cetostearyl alcohol is 6 to 12 parts by weight, and more preferably 9 to 11 parts by weight.
3. The theophylline sustained-release tablet according to any one of claims 1 to 2, wherein the proportion of hexadecanol and octadecanol in the hexadecanol and octadecanol tablet is 20% to 50% and 50% to 80%, respectively, based on the content of the hexadecanol and the octadecanol tablet as 100%.
4. The theophylline sustained-release tablet of claim 3, wherein the proportion of hexadecanol and octadecanol in the hexadecanol and octadecanol sustained-release tablet is 25-35% and 65-75%, respectively, based on the content of the hexadecanol and the octadecanol being 100%.
5. The theophylline sustained-release tablet of claim 4, wherein the proportion of hexadecanol and octadecanol in the hexadecanol and octadecanol tablet is 30% and 70%, respectively, based on the content of the hexadecanol and octadecanol tablet being 100%.
6. The theophylline sustained release tablet of any one of claims 1-2, wherein the binder is one or more of povidone, hydroxyethyl cellulose, hypromellose and hyprolose; and/or the presence of a gas in the gas,
the lubricant is one or more of calcium stearate, magnesium stearate and talcum powder.
7. The theophylline sustained-release tablet according to claim 6, wherein the binder is povidone 4.5-5.5 parts by weight; the lubricant is calcium stearate and accounts for 1.5-2.5 parts by weight.
8. The process for preparing a theophylline sustained release tablet as claimed in any one of claims 1 to 7, comprising the steps of:
putting the anhydrous theophylline into granulation equipment, spraying ethanol water solution of hexadecanol and octadecanol and water solution of the binding agent in sequence, granulating, drying and sieving the obtained wet granules, adding the lubricant, uniformly mixing and tabletting to obtain the theophylline sustained release tablet; or,
the preparation method of the theophylline sustained release tablet comprises the following steps:
adding the anhydrous theophylline and the hexadecanol into wet granulation equipment, uniformly mixing, heating to melt the hexadecanol and the octadecanol, fully mixing with the anhydrous theophylline, cooling, adding the aqueous solution of the binding agent, granulating, drying and sieving the obtained wet granules, adding the lubricating agent, uniformly mixing and tabletting to obtain the theophylline sustained release tablet; or,
the preparation method of the theophylline sustained release tablet comprises the following steps:
adding anhydrous theophylline and hexadecanol into a granulating device, uniformly mixing, spraying the aqueous solution of the adhesive, granulating, heating, keeping the temperature for a certain time to melt the hexadecanol and the octadecanol, fully mixing with the anhydrous theophylline, continuously heating to dry the obtained granules, sieving the obtained dry granules, adding the lubricant, uniformly mixing, and tabletting to obtain the theophylline sustained release tablet.
9. The method for preparing the theophylline sustained release tablet according to claim 8, comprising the steps of:
(1) crushing the anhydrous theophylline and then sieving for later use; sieving the lubricant for later use;
(2) pulverizing the cetostearyl alcohol and sieving for later use; or dissolving the hexadecanol and the octadecanol with an ethanol water solution to be used as a solution A for later use;
(3) dissolving the adhesive by water to obtain solution B for later use;
(4) granulating and tabletting;
the granulating and tabletting method comprises any one of the following steps:
method A, comprising the steps of: putting the crushed and sieved anhydrous theophylline into granulation equipment, spraying the solution A and the solution B in sequence, granulating, drying and sieving the obtained wet granules, adding a sieved lubricant, uniformly mixing and tabletting to obtain the theophylline sustained release tablet;
the method B comprises the following steps:
adding the crushed and sieved anhydrous theophylline and hexadecanol into wet granulation equipment, uniformly mixing, heating to melt the hexadecanol and the octadecanol, fully mixing with the anhydrous theophylline, cooling, adding the solution B, granulating, drying and sieving the obtained wet granules, adding a sieved lubricant, uniformly mixing and tabletting to obtain the theophylline sustained release tablet;
method C, comprising the steps of:
adding the crushed and sieved anhydrous theophylline and the hexadecanol into a granulating device, uniformly mixing, spraying the solution B, granulating, heating and keeping the temperature for a certain time to melt the hexadecanol and the octadecanol and fully mix with the anhydrous theophylline, continuously heating to dry the obtained granules, sieving the obtained dry granules, adding the sieved lubricant, uniformly mixing and tabletting to obtain the theophylline sustained release tablet.
10. The process for producing a theophylline sustained-release tablet according to claim 9,
crushing the anhydrous theophylline and sieving the crushed anhydrous theophylline to obtain a powder with a 60-100-mesh sieve; sieving the lubricant to pass through a sieve of 30-50 meshes; and/or the presence of a gas in the gas,
crushing the cetostearyl alcohol and sieving the crushed cetostearyl alcohol to pass through a sieve of 80-100 meshes; the mass concentration of the hexadecanol and octadecanol in the solution A is 5-15%; the concentration of the ethanol water solution is 85-98%; and/or the presence of a gas in the gas,
in the step (3), the mass concentration of the adhesive in the liquid B is 5-15%; and/or the presence of a gas in the gas,
in the method A, the granulating temperature is 35-45 ℃; and/or the presence of a gas in the gas,
in the method B, the heating temperature is 50-65 ℃, the heating time is 10-30/min, and the temperature is reduced to 40 +/-5 ℃; and/or the presence of a gas in the gas,
in the method C, the granulating temperature is 35-45 ℃; the temperature is increased and kept constant for a certain time, the temperature is 45-55 ℃, and the time is 8-15 minutes; the continuous heating is to heat up to 60-65 ℃; and/or the presence of a gas in the gas,
in the steps of granulating and tabletting, the drying is to dry the granules until the moisture content is less than 3 percent, and the sieving is to pass through a 14-mesh sieve.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5091189A (en) * | 1988-06-02 | 1992-02-25 | Euroceltique S.A. | Controlled release dosage forms having a defined water content |
| CN108721238A (en) * | 2017-04-17 | 2018-11-02 | 上海葆隆生物科技有限公司 | A kind of lithium carbonate sustained release tablets |
| CN109700777A (en) * | 2019-02-27 | 2019-05-03 | 中国药科大学 | A kind of pH dependent form drug hydrophobic framework sustained release tablets and preparation method thereof |
| CN111450069A (en) * | 2020-04-02 | 2020-07-28 | 南京致中生物科技有限公司 | Metformin hydrochloride oral sustained-release tablet and preparation method thereof |
-
2020
- 2020-08-07 CN CN202010791400.4A patent/CN114053235B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5091189A (en) * | 1988-06-02 | 1992-02-25 | Euroceltique S.A. | Controlled release dosage forms having a defined water content |
| CN108721238A (en) * | 2017-04-17 | 2018-11-02 | 上海葆隆生物科技有限公司 | A kind of lithium carbonate sustained release tablets |
| CN109700777A (en) * | 2019-02-27 | 2019-05-03 | 中国药科大学 | A kind of pH dependent form drug hydrophobic framework sustained release tablets and preparation method thereof |
| CN111450069A (en) * | 2020-04-02 | 2020-07-28 | 南京致中生物科技有限公司 | Metformin hydrochloride oral sustained-release tablet and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 李丹 等: "基于QbD理念对蜡骨架缓释片的优化", 《沈阳药科大学学报》 * |
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