CN114712321B - Diaminopyridine phosphate sustained release tablet and preparation method thereof - Google Patents
Diaminopyridine phosphate sustained release tablet and preparation method thereof Download PDFInfo
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- CN114712321B CN114712321B CN202210424289.4A CN202210424289A CN114712321B CN 114712321 B CN114712321 B CN 114712321B CN 202210424289 A CN202210424289 A CN 202210424289A CN 114712321 B CN114712321 B CN 114712321B
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- diaminopyridine phosphate
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- PZOSJXSJAYQXCR-UHFFFAOYSA-N phosphoric acid;pyridine-2,3-diamine Chemical compound OP(O)(O)=O.NC1=CC=CN=C1N PZOSJXSJAYQXCR-UHFFFAOYSA-N 0.000 title claims abstract description 77
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims description 21
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000000463 material Substances 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims description 51
- 239000008187 granular material Substances 0.000 claims description 33
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- 239000011812 mixed powder Substances 0.000 claims description 26
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 22
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 20
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 20
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 20
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 18
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 18
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 18
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 18
- 239000001856 Ethyl cellulose Substances 0.000 claims description 17
- 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 17
- 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 17
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 17
- 229920001249 ethyl cellulose Polymers 0.000 claims description 17
- 239000008101 lactose Substances 0.000 claims description 16
- 229960003943 hypromellose Drugs 0.000 claims description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims description 13
- 239000003826 tablet Substances 0.000 claims description 11
- 239000002245 particle Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 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 5
- 239000000945 filler Substances 0.000 claims description 4
- 238000007908 dry granulation Methods 0.000 claims description 3
- 239000000314 lubricant Substances 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 abstract description 11
- 239000012730 sustained-release form Substances 0.000 abstract description 11
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- 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 5
- 238000005259 measurement Methods 0.000 description 5
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- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 4
- 229960001681 croscarmellose sodium Drugs 0.000 description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 4
- 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 description 4
- 229960001476 pentoxifylline Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
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- 229910001424 calcium ion Inorganic materials 0.000 description 2
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- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
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- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 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 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 102000003734 Voltage-Gated Potassium Channels Human genes 0.000 description 1
- 108090000013 Voltage-Gated Potassium Channels Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- OYTKINVCDFNREN-UHFFFAOYSA-N amifampridine Chemical compound NC1=CC=NC=C1N OYTKINVCDFNREN-UHFFFAOYSA-N 0.000 description 1
- 229960004012 amifampridine Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 208000016334 muscle symptom Diseases 0.000 description 1
- 210000001087 myotubule Anatomy 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229940125422 potassium channel blocker Drugs 0.000 description 1
- 239000003450 potassium channel blocker Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002336 repolarization Effects 0.000 description 1
- 210000001995 reticulocyte Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000015424 sodium Nutrition 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
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the technical field of pharmaceutical preparations and discloses a diaminopyridine phosphate sustained release tablet. The diaminopyridine phosphate sustained release tablet disclosed by the invention has the advantages of few types of auxiliary materials, simple prescription process, good sustained release effect, good drug release reproducibility, high product stability and the like.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a diaminopyridine phosphate sustained release tablet and a preparation method thereof.
Background
Diaminopyridine phosphate is a white crystalline powder, readily soluble in water, and slightly soluble in solvents such as ethanol, methanol, and acetic acid. The pH of the 1% aqueous diaminopyridine phosphate solution was 4.4. The molecular formula is C 5H7N3·H3PO4, the molecular weight is 207.1, and the structural formula is shown as follows:
Diaminopyridine phosphate is a nonspecific voltage-gated potassium channel blocker. Channel blockade can cause depolarization of the presynaptic membrane, slowing or inhibiting repolarization. Depolarization results in slow voltage-gated opening of calcium ion channels, allowing calcium ion influx. The increase of the intracellular calcium ion concentration can cause the release of vesicles containing acetylcholine, promote the transmission of neuromuscular, signal transduction, recover the contractility of muscle fibers and improve the weak muscle symptoms of LEMS patients.
Currently, diaminopyridine phosphate has only been available in commercial formulations in immediate release formulations, firdapse, and the formulation includes diaminopyridine phosphate, microcrystalline cellulose, calcium stearate, colloidal silicon dioxide, and plasma peak concentrations ranging from 20 minutes to 1 hour after oral immediate release formulation. Steady state is typically achieved within 1 day after administration. After multiple doses, diaminopyridine phosphate did not accumulate, only 3-nitrogen-acetyldiaminopyridine metabolites accumulated.
Diaminopyridine phosphate indications are the treatment of adult lambert-eaton muscle weakness syndrome (LEMS). LEMS onset is more than 50-70 years old, and the ratio of men and women is 5:1. In the European region, approximately 4-10 out of every 100 tens of thousands have LEMS, and 1200-3100 in the United states are afflicted with this disease. About 60% of patients have small cell lung cancer in combination, and also have breast cancer, prostate cancer, gastric cancer, renal cancer, rectal cancer, lymphoma, acute leukemia, reticulocyte sarcoma, etc., with individual breast tumors in combination. Global LEMS incidence is approximately three parts per million. Calculated by 14 hundred million people in China, the incidence rate is three parts per million, and about 4200 LEMS patients in China have huge market potential.
Disclosure of Invention
The diaminopyridine phosphate sustained release tablet provided by the invention reduces the administration frequency and slows down the absorption rate, so that the blood concentration is controlled within an effective blood concentration range, thereby reducing side effects and improving the compliance of patients. The diaminopyridine phosphate sustained release tablet provided by the invention has the advantages of good sustained release effect, good drug release reproducibility, high product stability and high bioavailability; and the diaminopyridine phosphate sustained release tablet provided by the invention has the advantages of few types of auxiliary materials, simple prescription process and low cost.
In the invention, the diaminopyridine phosphate is used as a main component: the source of the diaminopyridine phosphate is not particularly limited in the present invention, and commercially available products known to those skilled in the art may be used. In the present invention, the reagents and materials used are commercially available.
The invention provides a diaminopyridine phosphate sustained release tablet which comprises the following components in parts by weight:
preferably, the diaminopyridine phosphate sustained release tablet comprises the following components in parts by weight:
preferably, the filler is lactose, microcrystalline cellulose or a combination of the lactose and microcrystalline cellulose, and the weight ratio of the lactose to the microcrystalline cellulose is 2:1; or (b)
The slow release material is one or more of hypromellose, ethylcellulose, sodium carboxymethylcellulose, carbomer and polyvinyl alcohol, preferably hypromellose and ethylcellulose, and the weight ratio is 1:1; or (b)
The disintegrating agent is one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch, preferably, the disintegrating agent is the croscarmellose sodium or the low-substituted hydroxypropyl cellulose, and further preferably, the disintegrating agent is the low-substituted hydroxypropyl cellulose; or (b)
The lubricant is one or two of talcum powder and magnesium stearate, preferably magnesium stearate.
In some embodiments, the diaminopyridine phosphate sustained release tablet is divided into an external and an internal part, wherein the ratio of the external and the internal part of the disintegrant is 3:7 to 7:3, preferably the ratio is 3:7.
Preferably, the diaminopyridine phosphate sustained release tablet comprises the following components in parts by weight:
In some embodiments, the diaminopyridine phosphate sustained release tablet is divided into an external and an internal addition part, wherein the ratio of the external and the internal addition low-substituted hydroxypropylcellulose is 3:7-7:3, preferably the ratio of the external and the internal addition low-substituted hydroxypropylcellulose is 3:7.
The invention provides a preparation method of the diaminopyridine phosphate sustained release tablet, which comprises the following steps:
1) Adding lactose, microcrystalline cellulose, diaminopyridine phosphate, hydroxypropyl methylcellulose, ethyl cellulose and 70% low-substituted hydroxypropyl cellulose into a mixing barrel, and premixing to obtain mixed powder 1;
2) Dry granulating the mixed powder 1 to obtain granules 1;
3) Adding the rest 30% of low-substituted hydroxypropyl cellulose and magnesium stearate into the granule 1 for total mixing;
4) Tabletting to obtain diaminopyridine phosphate sustained release tablet.
The invention also provides a method for preparing the diaminopyridine phosphate sustained release tablet, which comprises the following steps:
1) Adding lactose, microcrystalline cellulose, diaminopyridine phosphate, hydroxypropyl methylcellulose, ethyl cellulose and 70% low-substituted hydroxypropyl cellulose into a mixing barrel, and premixing to obtain mixed powder 1;
2) Dry granulating the mixed powder 1 to obtain granules 1;
3) Adding the rest 30% of low-substituted hydroxypropyl cellulose and magnesium stearate into the granule 1 for total mixing;
4) Tabletting to obtain diaminopyridine phosphate sustained release tablet.
Preferably, in the method for preparing the diaminopyridine phosphate sustained release tablet, the speed of premixing in the step 1) is 5-15 rpm, and the premixing time is 5-15 min; or (b)
Preferably, in the method for preparing the diaminopyridine phosphate sustained release tablet, in the step 2), the feeding frequency of the dry granulation is 5-10HZ, the tabletting frequency is 5-10HZ, and the granule finishing frequency is 5-10HZ; or (b)
Preferably, in the method for preparing the diaminopyridine phosphate sustained release tablet, in the step 3), the total mixing rotating speed is 5-10 revolutions per minute, and the total mixing time is 5-10 minutes; or (b)
Preferably, in the method for preparing the diaminopyridine phosphate sustained release tablet, the hardness of the tablet in the step 4) is 50-80N.
The invention also provides a diaminopyridine phosphate sustained release tablet, each tablet has the following prescription (unit: mg):
The preparation method comprises the following steps:
1) Adding lactose, microcrystalline cellulose, diaminopyridine phosphate, hypromellose, ethyl cellulose and 70% low-substituted hypromellose into a mixing barrel, and premixing for 10 min at a rotation speed of 8 rpm to obtain mixed powder 1;
2) Dry granulating the mixed powder 1, wherein the feeding frequency is 5HZ, the tabletting frequency is 5HZ, and the granule finishing frequency is 5HZ to obtain granules 1;
3) Adding the rest 30% of low-substituted hydroxypropyl cellulose and magnesium stearate into the particles 1 in sequence respectively for total mixing, wherein the total mixing rotating speed is 8 revolutions per minute, and the mixing time is 5 minutes;
4) Tabletting, controlling the hardness at 50-80N, and preparing the diaminopyridine phosphate sustained release tablet.
The diaminopyridine phosphate sustained release tablet provided by the invention adopts a skeleton preparation technology. The diaminopyridine phosphate sustained-release tablet is prepared from a mixed framework material consisting of two specific substances, namely hydroxypropyl methylcellulose and ethylcellulose in a weight ratio of 1:1, and is used as a sustained-release material together, and after a mixture is obtained by premixing raw materials, a filler, the sustained-release material and part of disintegrating agents and granulating by a dry method, the rest of disintegrating agents and the rest of lubricating agents are added to form a total mixed tablet, so that the effect of regulating the release of the medicine is achieved, a good sustained-release effect is realized, and the uniformity of the diaminopyridine phosphate sustained-release tablet is better, so that the reproducibility of the in-vitro release behavior of the product is good, and the consistency of the product quality is ensured.
The diaminopyridine phosphate sustained release tablet provided by the invention has the advantages that the composition is simple, the preparation process is simple and easy to implement, the in vitro release degree experiment result shows that the release degree of the pentoxifylline sustained release tablet provided by the invention is 25-35% in 1h, the accumulated release degree of the pentoxifylline sustained release tablet is 55-65% in 6h, the accumulated release degree of the pentoxifylline sustained release tablet is about 90-93% in 12h, the accumulated release degree of the pentoxifylline sustained release tablet in 16h is more than 95%, the medicine is not suddenly released in 1-6h, the medicine is stably released in 6-12h, the medicine is completely released in 16h, and a good sustained release effect is shown. The release degree reproducibility test result shows that the diaminopyridine phosphate sustained release tablet has good in-batch uniformity, the release degree has smaller RSD value, and the product quality uniformity is good.
Drawings
FIG. 1 Release profile for three samples of example 1
FIG. 2 Release profile for comparative example 1 three samples
Detailed Description
In order that those skilled in the art will better understand the present invention, the technical scheme of the present invention will be further described with reference to the following examples. It should be noted that the implementations described below are only some embodiments, but not all embodiments, of the present invention, and other embodiments obtained by those skilled in the art without making any creative effort based on the embodiments of the present invention are all within the protection scope of the present invention.
EXAMPLE 1 preparation of diaminopyridine phosphate sustained release tablet
Prescription (Unit: mg)
The preparation process comprises the following steps:
1) Adding lactose, microcrystalline cellulose, diaminopyridine phosphate, hypromellose, ethyl cellulose and 70% low-substituted hypromellose into a mixing barrel, and premixing for 10 min at a rotation speed of 8 rpm to obtain mixed powder 1;
2) Dry granulating the mixed powder 1, wherein the feeding frequency is 5HZ, the tabletting frequency is 5HZ, and the granule finishing frequency is 5HZ to obtain granules 1;
3) Adding the rest 30% of low-substituted hydroxypropyl cellulose and magnesium stearate into the particles 1 in sequence respectively for total mixing, wherein the total mixing rotating speed is 8 revolutions per minute, and the mixing time is 5 minutes;
4) Tabletting, controlling the hardness at 50-80N, and preparing the diaminopyridine phosphate sustained release tablet.
EXAMPLE 2 preparation of diaminopyridine phosphate sustained release tablet
Prescription (unit: mg):
the preparation process comprises the following steps:
1) Adding lactose, diaminopyridine phosphate, hydroxypropyl methylcellulose, ethyl cellulose and 30% low-substituted hydroxypropyl cellulose into a mixing barrel, and pre-mixing for 15 minutes at a rotating speed of 15 revolutions per minute to obtain mixed powder 1;
2) Dry granulating the mixed powder 1, wherein the feeding frequency is 10HZ, the tabletting frequency is 10HZ, and the granule finishing frequency is 10HZ to obtain granules 1;
3) Adding the rest 70% of low-substituted hydroxypropyl cellulose and magnesium stearate into the particles 1 respectively in sequence for total mixing, wherein the total mixing rotating speed is 15 revolutions per minute, and the mixing time is 5 minutes;
4) Tabletting, controlling the hardness at 50-80N, and preparing the diaminopyridine phosphate sustained release tablet.
EXAMPLE 3 preparation of diaminopyridine phosphate sustained release tablets of the present invention
Prescription (unit: mg):
the preparation process comprises the following steps:
1) Adding lactose, microcrystalline cellulose, diaminopyridine phosphate, hypromellose, ethyl cellulose and 50% low-substituted hyprolose into a mixing barrel, and premixing for 10 min at 15 rpm to obtain mixed powder 1;
2) Dry granulating the mixed powder 1, wherein the feeding frequency is 10HZ, the tabletting frequency is 10HZ, and the granule finishing frequency is 10HZ to obtain granules 1;
3) Adding the rest 50% of low-substituted hydroxypropyl cellulose and talcum powder into the granules 1 in sequence respectively for total mixing, wherein the total mixing rotating speed is 15 revolutions per minute, and the mixing time is 10 minutes respectively;
4) Tabletting, controlling the hardness at 50-80N, and preparing the diaminopyridine phosphate sustained release tablet.
EXAMPLE 4 preparation of diaminopyridine phosphate sustained release tablets of the present invention
Prescription (unit: mg):
the preparation process comprises the following steps:
1) Adding lactose, microcrystalline cellulose, diaminopyridine phosphate, hypromellose, polyvinyl alcohol and 70% of croscarmellose sodium into a mixing barrel, and premixing for 15 minutes at a rotating speed of 15 revolutions per minute to obtain mixed powder 1;
2) Dry granulating the mixed powder 1, wherein the feeding frequency is 10HZ, the tabletting frequency is 15HZ, and the granule finishing frequency is 20HZ to obtain granules 1;
3) Sequentially adding the rest 30% of croscarmellose sodium and magnesium stearate into the particles 1 respectively for total mixing, wherein the total mixing rotating speed is 15 revolutions per minute, and the mixing time is 10 minutes;
4) Tabletting, controlling the hardness at 50-80N, and preparing the diaminopyridine phosphate sustained release tablet.
EXAMPLE 5 preparation of diaminopyridine phosphate sustained release tablets of the present invention
Prescription (unit: mg):
the preparation process comprises the following steps:
1) Adding microcrystalline cellulose, diaminopyridine phosphate, ethylcellulose, carbomer and 70% low-substituted hydroxypropyl cellulose into a mixing barrel, and premixing for 10 minutes at a rotating speed of 20 revolutions per minute to obtain mixed powder 1;
2) Dry granulating the mixed powder 1, wherein the feeding frequency is 10HZ, the tabletting frequency is 10HZ, and the granule finishing frequency is 15HZ to obtain granules 1;
3) Adding the rest 30% low-substituted hydroxypropyl cellulose and talcum powder into the granule 1 for total mixing, wherein the total mixing speed is 15 rpm, and the mixing time is 10min each;
4) Tabletting, controlling the hardness at 50-80N, and preparing the diaminopyridine phosphate sustained release tablet.
Comparative example 1
A diaminopyridine phosphate sustained release tablet has a tablet specification of 10mg, and the feeding information of each tablet is as follows (unit: mg):
the preparation process comprises the following steps:
1) Adding lactose, microcrystalline cellulose, diaminopyridine phosphate, hypromellose and ethyl cellulose into a mixing barrel at a rotating speed of 20 rpm for 10 minutes to obtain mixed powder 1;
2) Wet granulating the mixed powder 1, starting stirring at 200rpm, cutting at 1500rpm for 5min; slowly adding 95% ethanol at constant speed for 1min; granulating with 18 mesh nylon screen to obtain granule 1;
3) Placing the granules 1 in a drying tray with the thickness of 2-3cm, sending into a drying oven, drying at 50-60 ℃, airing the dried granules to room temperature, discharging, and granulating with a 16-mesh nylon screen;
4) Respectively and sequentially adding low-substituted hydroxypropyl cellulose and magnesium stearate into the particles 1 for total mixing, wherein the total mixing rotating speed is 15 revolutions per minute, and the mixing time is 10 minutes respectively;
5) Tabletting, controlling the hardness at 50-80N, and preparing the diaminopyridine phosphate sustained release tablet.
Comparative example 2
A diaminopyridine phosphate sustained release tablet has a tablet specification of 10mg, and the feeding information of each tablet is as follows (unit: mg):
the preparation process comprises the following steps:
1) Adding lactose, microcrystalline cellulose, diaminopyridine phosphate, hypromellose, ethyl cellulose and 70% low-substituted hypromellose into a mixing barrel, and premixing for 10 min at 20 rpm to obtain mixed powder 1;
2) Wet granulating the mixed powder 1, starting stirring at 200rpm, cutting at 1500rpm for 5min; slowly adding 95% ethanol at constant speed for 1min; granulating with 18 mesh nylon screen to obtain granule 1;
3) Placing the granules 1 in a drying tray with the thickness of 2-3cm, sending into a drying oven, drying at 50-60 ℃, airing the dried granules to room temperature, discharging, and granulating with a 16-mesh nylon screen;
4) Putting the granules 1 into a mixer, respectively and sequentially adding 30% of low-substituted hydroxypropyl cellulose and talcum powder for total mixing, wherein the total mixing speed is 15 revolutions per minute, and the mixing time is 10 minutes respectively;
4) Tabletting, controlling the hardness at 50-80N, and preparing the diaminopyridine phosphate sustained release tablet.
Comparative example 3
A diaminopyridine phosphate sustained release tablet has a tablet specification of 10mg, and the feeding information of each tablet is as follows (unit: mg):
the preparation process comprises the following steps:
1) Adding lactose, microcrystalline cellulose, diaminopyridine phosphate, hypromellose, ethyl cellulose and low-substituted hyprolose into a mixing barrel, and premixing for 10 minutes at a rotating speed of 20 revolutions per minute to obtain mixed powder 1;
2) Wet granulating the mixed powder 1, starting stirring at 200rpm, cutting at 1500rpm for 5min; slowly adding 95% ethanol at constant speed for 1min; granulating with 18 mesh nylon screen to obtain granule 1;
3) Placing the granules 1 in a drying tray with the thickness of 2-3cm, sending into a drying oven, drying at 50-60 ℃, airing the dried granules to room temperature, discharging, and granulating with a 16-mesh nylon screen;
4) Putting the particles 1 into a mixer, adding magnesium stearate for total mixing, wherein the total mixing rotating speed is 15 revolutions per minute, and the mixing time is 10 minutes respectively;
4) Tabletting, controlling the hardness at 50-80N, and preparing the diaminopyridine phosphate sustained release tablet.
Example 6 in vitro Release test
Samples of the diaminopyridine phosphate sustained release oral tablets prepared in examples 1 to 5 and comparative examples 1 to 3 were taken and their in vitro dissolution profiles in a hydrochloric acid solution at pH1.0 were determined. The specific method comprises the following steps: according to the second method of the four general rules 0391 of the 2015 edition of Chinese pharmacopoeia, 900mL of hydrochloric acid (pH 1.0) is used as a dissolution medium, the rotating speed is 50r/min, 10mL of solution is taken at 1h, 6h, 12h and 16h, the dissolution medium with the same temperature and the same volume is supplemented at the same time, the solution is filtered by a microporous filter membrane, the subsequent filtrate is taken as a solution of a test sample, the absorbance is measured at the wavelength of 230nm, and the accumulated dissolution amount of the medicine is calculated.
TABLE 1 Release test results for examples 1-5 and comparative examples 1-3
The results show that the diaminopyridine phosphate sustained release tablet obtained by adopting the dry granulation and the internal and external processing technology of the disintegrating agent has good in-vitro sustained release effect, and particularly releases the active drug more gradually within 1-6 hours. In contrast, comparative examples 1 to 3 obtained by wet granulation showed drug burst at 6 hours, and drug release for 1 to 12 hours was significantly less stable than examples 1 to 5, regardless of whether the disintegrant was added internally or externally or internally.
Example 7 in vitro release reproducibility test
The three batches of samples of example 1 and comparative example 1 were examined for tablet release according to the in vitro release assay of example 6, respectively, and the results were as follows:
TABLE 2 Release test results for example 1
TABLE 3 Release test results for comparative example 1
The results show that the diaminopyridine phosphate sustained release tablet has better reproducibility of release degree, obviously better sustained release effect than a control product and better quality uniformity.
Example 8 stability of Release test
Samples of inventive example 1 and comparative example 1 were taken and left for 6 months at a temperature of 40.+ -. 2 ℃ and a relative humidity of 75%.+ -. 5%, and were sampled at the end of each of 1 st, 2 nd, 3 rd and 6 th months, respectively, to examine the change in release rate. The results were as follows:
TABLE 4 results of Release acceleration test of example 1
| Degree of Release (%) | 1 Hour | For 6 hours | For 12 hours | 16 Hours |
| Day 0 | 27.86 | 59.01 | 93.20 | 97.12 |
| Accelerating for 1 month | 27.10 | 58.56 | 92.50 | 96.30 |
| Accelerating for 2 months | 27.32 | 60.12 | 94.49 | 97.20 |
| Accelerating for 3 months | 26.90 | 57.64 | 93.49 | 97.49 |
| Accelerating for 6 months | 28.03 | 52.69 | 93.54 | 98.19 |
TABLE 5 results of Release acceleration test of comparative example 1
| Degree of Release (%) | 1 Hour | For 6 hours | For 12 hours | 16 Hours |
| Day 0 | 46.37 | 90.31 | 95.36 | 96.24 |
| Accelerating for 1 month | 45.34 | 84.36 | 93.50 | 97.30 |
| Accelerating for 2 months | 42.19 | 93.18 | 97.94 | 99.20 |
| Accelerating for 3 months | 39.28 | 92.67 | 94.49 | 99.49 |
| Accelerating for 6 months | 36.39 | 87.26 | 90.54 | 92.19 |
The data show that the diaminopyridine phosphate sustained release tablet of the invention has basically no change in release degree, higher stability and remarkable sustained release effect after being placed for 6 months under the acceleration condition in the embodiment 1. Comparative example 1 has poor stability and a lower sustained release effect than example 1.
Example 9 stability test investigation
The appearance and content of the sustained release tablet sample of example 1 were examined for factors affecting the appearance and content.
(1) High temperature test: taking a proper amount of the sample in the embodiment 1, spreading the sample in a culture dish, placing the culture dish in an incubator at 60 ℃ for 10 days, and taking samples for measurement respectively on the 0 th day, the 5 th day and the 10 th day of the period, wherein the measurement results are shown in Table 5;
(2) High humidity test: spreading the sample of example 1 in a culture dish, standing at 25deg.C with relative humidity of 70% + -5deg.C for 10 days, and measuring at 0 day, 5 day and 10 day respectively, with the measurement results shown in Table 5;
(3) Strong light irradiation test: taking a proper amount of the sample in the embodiment 1, spreading the sample in a culture dish, placing the culture dish in a light cabinet, and irradiating the culture dish for 10 days under the condition of 4500 Lx+/-500 Lx, and taking samples for measurement respectively on the 0 th day, the 5 th day and the 10 th day of the period, wherein the measurement results are shown in Table 5;
TABLE 6 stability of the sustained release tablets of example 1 under high temperature, high humidity and strong light
TABLE 7 stability of comparative example 1 sustained release tablets under high temperature, high humidity and strong light
The data show that the diaminopyridine phosphate sustained release tablet of the invention has the characteristics, the content and the stability which are basically unchanged after being placed for 10 days under the condition of influencing factors and has high stability; the degradation products-related substances are not obviously increased, and the requirements of related quality standards (the impurity limit is below 2%) are met. The comparative example 1 has reduced content and poor stability after being placed for 10 days under the condition of influencing factors; its degradation products, related substances, are significantly increased.
Claims (4)
1. The diaminopyridine phosphate sustained release tablet is characterized by comprising the following components in parts by weight:
Wherein the filler is a combination of lactose and microcrystalline cellulose, and the weight ratio of the filler to the microcrystalline cellulose is 2:1; the slow release material is a combination of hypromellose and ethylcellulose, and the weight ratio of the slow release material to the ethylcellulose is 1:1; the disintegrating agent is low-substituted hydroxypropyl cellulose and is divided into an external adding part and an internal adding part, wherein the ratio of the external adding part to the internal adding part is 3:7; the lubricant is magnesium stearate.
2. The diaminopyridine phosphate sustained release tablet according to claim 1, wherein the sustained release tablet comprises the following components in parts by weight:
3. The method for preparing a diaminopyridine phosphate sustained release tablet according to any one of claims 1 to 2, comprising the steps of:
1) Adding lactose, microcrystalline cellulose, diaminopyridine phosphate, hydroxypropyl methylcellulose, ethyl cellulose and low-substituted hydroxypropyl cellulose into a mixing barrel, and premixing to obtain mixed powder 1;
2) Dry granulating the mixed powder 1 to obtain granules 1;
3) Adding additional low-substituted hydroxypropyl cellulose and magnesium stearate into the particles 1 for total mixing;
4) Tabletting to obtain diaminopyridine phosphate sustained release tablets;
Wherein, the speed of premixing in the step 1) is 5-15 rpm, and the premixing time is 5-15 min; in the step 2), the feeding frequency of the dry granulation is 5-10HZ, the tabletting frequency is 5-10HZ, and the granule finishing frequency is 5-10HZ; the total mixing rotating speed in the step 3) is 5-10 revolutions per minute, and the total mixing time is 5-10 minutes; the tablet hardness in the step 4) is 50-80N.
4. A diaminopyridine phosphate sustained release tablet comprises the following prescription in mg:
The preparation method comprises the following steps:
1) Adding lactose, microcrystalline cellulose, diaminopyridine phosphate, hypromellose, ethyl cellulose and internally-added low-substituted hypromellose into a mixing barrel, and premixing for 10 minutes at a rotating speed of 8 rpm to obtain mixed powder 1;
2) Dry granulating the mixed powder 1, wherein the feeding frequency is 5HZ, the tabletting frequency is 5HZ, and the granule finishing frequency is 5HZ to obtain granules 1;
3) Adding externally added low-substituted hydroxypropyl cellulose and magnesium stearate into the particles 1 in sequence to carry out total mixing, wherein the total mixing rotating speed is 8 revolutions per minute, and the mixing time is 5 minutes;
4) Tabletting, controlling the hardness at 50-80N, and preparing the diaminopyridine phosphate sustained release tablet.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5370879A (en) * | 1990-02-11 | 1994-12-06 | Elan Corporation, Plc | Formulations and their use in the treatment of neurological diseases |
| WO2004082684A1 (en) * | 2003-03-17 | 2004-09-30 | Acorda Therapeutics | Stable oral formulations of aminopyridines and uses thereof |
| WO2020212267A1 (en) * | 2019-04-18 | 2020-10-22 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Manufacturing process for amifampridine phosphate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2820423B1 (en) * | 2001-02-05 | 2005-12-02 | Assist Publ Hopitaux De Paris | 3,4-DIAMINOPYRIDINE TARTRATE AND PHOSPHATE, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF |
| US10793893B2 (en) * | 2011-06-30 | 2020-10-06 | Serb Sa | Methods of administering 3,4-diaminopyridine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5370879A (en) * | 1990-02-11 | 1994-12-06 | Elan Corporation, Plc | Formulations and their use in the treatment of neurological diseases |
| WO2004082684A1 (en) * | 2003-03-17 | 2004-09-30 | Acorda Therapeutics | Stable oral formulations of aminopyridines and uses thereof |
| WO2020212267A1 (en) * | 2019-04-18 | 2020-10-22 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Manufacturing process for amifampridine phosphate |
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