CN114712321A - Diaminopyridine phosphate sustained-release tablet and preparation method thereof - Google Patents
Diaminopyridine phosphate sustained-release tablet and preparation method thereof Download PDFInfo
- Publication number
- CN114712321A CN114712321A CN202210424289.4A CN202210424289A CN114712321A CN 114712321 A CN114712321 A CN 114712321A CN 202210424289 A CN202210424289 A CN 202210424289A CN 114712321 A CN114712321 A CN 114712321A
- Authority
- CN
- China
- Prior art keywords
- sustained
- release
- diaminopyridine
- diaminopyridine phosphate
- release tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 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 85
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims description 23
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000013268 sustained release Methods 0.000 claims abstract description 13
- 239000012730 sustained-release form Substances 0.000 claims abstract description 13
- 239000000463 material Substances 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims description 49
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 34
- 239000008187 granular material Substances 0.000 claims description 31
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 239000011812 mixed powder Substances 0.000 claims description 28
- 239000003826 tablet 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
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 17
- 229920001249 ethyl cellulose Polymers 0.000 claims description 17
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 17
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 17
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 17
- 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 17
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 16
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 15
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 15
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 15
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 15
- 239000008101 lactose Substances 0.000 claims description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- 238000007908 dry granulation Methods 0.000 claims description 10
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 7
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 6
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 6
- 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 5
- 239000000945 filler Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 229920002125 Sokalan® Polymers 0.000 claims description 3
- 229960001631 carbomer Drugs 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 238000005469 granulation Methods 0.000 claims description 2
- 230000003179 granulation Effects 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940083542 sodium Drugs 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 8
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 14
- 238000012360 testing method Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 230000001276 controlling effect Effects 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000004677 Nylon Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 229920001778 nylon Polymers 0.000 description 6
- 238000005259 measurement Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000005550 wet granulation Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000007605 air drying Methods 0.000 description 3
- 238000007599 discharging Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000013265 extended release Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000028161 membrane depolarization Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- LOSIUHLAYNGOTD-UHFFFAOYSA-N 4-cyclopropyl-2h-triazole Chemical compound C1CC1C1=CNN=N1 LOSIUHLAYNGOTD-UHFFFAOYSA-N 0.000 description 1
- 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
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 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
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 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 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
- 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
- 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
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 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
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 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
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 230000036473 myasthenia Effects 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
- 229960001476 pentoxifylline Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 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
- 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
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 208000008732 thymoma Diseases 0.000 description 1
- 102000038650 voltage-gated calcium channel activity Human genes 0.000 description 1
- 108091023044 voltage-gated calcium channel activity Proteins 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
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
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, is readily soluble in water, and is sparingly soluble in solvents such as ethanol, methanol, and acetic acid. The pH of the 1% diaminopyridine phosphate aqueous solution was 4.4. Molecular formula C5H7N3·H3PO4Molecular weight 207.1, structural formula shown below:
diaminopyridine phosphate is a nonspecific voltage-gated potassium channel blocker. Channel blockade can cause depolarization of the presynaptic membrane, slowing or inhibiting repolarization. Depolarization leads to the opening of slow voltage-gated calcium channels, allowing calcium influx. The increase of intracellular calcium ion concentration can cause the release of the vesicle containing acetylcholine, promote neuromuscular transmission and signal transduction, recover muscular fiber contraction force and improve the symptoms of weak muscular strength of LEMS patients.
Currently, diaminopyridine phosphate is only available in the market as a quick release formulation, Firdapse, whose formula comprises diaminopyridine phosphate, microcrystalline cellulose, calcium stearate, colloidal silicon dioxide, and the peak plasma concentration can be reached 20 minutes to 1 hour after the quick release formulation is orally administered. Steady state is generally reached within 1 day after administration. After multiple administrations, diaminopyridine phosphate is not accumulated, only 3-aza-acetyldipyridine metabolite.
The diaminopyridine phosphate indication is the treatment of adult lambert-eaton myasthenia syndrome (LEMS). LEMS is more than 50-70 years old, and the ratio of male to female is 5: 1. In the European region, roughly 4-10 out of every 100 million people suffer from LEMS, and 1200-3100 people in the United states suffer from the disease. About 60% of patients have small cell lung cancer, and also have breast cancer, prostate cancer, gastric cancer, renal cancer, rectal cancer, lymphoma, acute leukemia, reticulosarcoma, etc., and some have thymoma. Worldwide LEMS incidence is about three parts per million. Based on 14 hundred million people in China and the incidence rate calculated by three parts per million, about 4200 LEMS patients exist in China, and the drug market potential is huge.
Disclosure of Invention
The diaminopyridine phosphate sustained-release tablet provided by the invention reduces the administration times, slows down the absorption rate, and controls the blood concentration within an effective blood concentration range, thereby reducing the side effect 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 a main component: the source of the diaminopyridine phosphate used in the present invention is not particularly limited, and commercially available products known to those skilled in the art may be used. In the present invention, the reagents and raw 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 of the present invention comprises the following components in parts by weight:
preferably, the filler is lactose, microcrystalline cellulose or a combination of the two, preferably in a weight ratio of 2: 1; or
The sustained-release material is one or more of hydroxypropyl methylcellulose, ethyl cellulose, sodium carboxymethylcellulose, carbomer and polyvinyl alcohol, preferably hydroxypropyl methylcellulose and ethyl cellulose in a weight ratio of 1: 1; or
The disintegrating agent is one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch, preferably croscarmellose sodium or low-substituted hydroxypropyl cellulose, and further preferably low-substituted hydroxypropyl cellulose; or
The lubricant is one or two of talcum powder and magnesium stearate, preferably magnesium stearate.
In some embodiments, the slow release tablet of diaminopyridine phosphate comprises an external part and an internal part, wherein the ratio of the external part to the internal part is 3:7-7:3, preferably 3: 7.
Preferably, the diaminopyridine phosphate sustained-release tablet of the present invention comprises the following components in parts by weight:
in some embodiments, the slow release tablet of diaminopyridine phosphate comprises a low-substituted hydroxypropylcellulose divided into an external part and an internal part, wherein the ratio of the external part to the internal part to the low-substituted hydroxypropylcellulose is 3:7-7:3, preferably, the ratio of the external part to the internal part to the 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 granules 1 for total mixing;
4) tabletting to obtain the slow release tablet of diaminopyridine phosphate.
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 granules 1 for total mixing;
4) tabletting to obtain the slow release tablet of diaminopyridine phosphate.
Preferably, in the method for preparing the diaminopyridine phosphate sustained-release tablets, the rotation speed of premixing in the step 1) is 5-15 r/min, and the premixing time is 5-15 min; or
Preferably, in the method for preparing the diaminopyridine phosphate sustained release tablet, the dry granulation feeding frequency in the step 2) is 5-10HZ, the tabletting frequency is 5-10HZ, and the granulation frequency is 5-10 HZ; or
Preferably, in the method for preparing the diaminopyridine phosphate sustained release tablet, the total mixing speed in the step 3) is 5-10 r/min, and the total mixing time is 5-10 min; or
Preferably, in the above method for preparing diaminopyridine phosphate sustained-release tablets, the tablet hardness in step 4) is 50-80N.
The invention also provides a diaminopyridine phosphate sustained-release tablet, wherein the prescription of each tablet is as follows (unit: mg):
the preparation method 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, rotating at 8 r/min, and premixing for 10min to obtain mixed powder 1;
2) performing dry granulation on the mixed powder 1, wherein the feeding frequency is 5HZ, the tabletting frequency is 5HZ, and the grading frequency is 5HZ to obtain granules 1;
3) respectively and sequentially adding the rest 30% of low-substituted hydroxypropylcellulose and magnesium stearate into the granules 1 for total mixing, wherein the total mixing speed is 8 r/min, and the mixing time is 5 min;
4) tabletting, and controlling the hardness to be 50-80N to prepare 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 adopts a mixed framework material consisting of two specific substances, namely hydroxypropyl methylcellulose and ethyl cellulose, in a weight ratio of 1:1 as a sustained-release material, and is prepared by a simple preparation process (after a mixture is obtained by premixing raw materials with a filling agent, the sustained-release material and part of disintegrant and performing dry granulation, the rest of the disintegrant and a lubricant are added for total mixed tabletting), so that the diaminopyridine phosphate sustained-release tablet not only has the function of regulating the release of the medicament and realizes a good sustained-release effect, but also has good product uniformity, so that the in-vitro release behavior reproducibility of the product is good, and the consistency of the product quality can be better ensured.
The diaminopyridine phosphate sustained-release tablet provided by the invention is simple in composition, simple and easy in preparation process, and in-vitro release degree experiment results show that the release degree of the pentoxifylline sustained-release tablet provided by the invention for 1h is 25-35%, the cumulative release degree for 6h is 55-65%, the cumulative release degree for 12h is about 90-93%, the cumulative release degree for 16h is more than 95%, no sudden release of the drug occurs for 1-6h, the drug is stably released for 6-12h, the drug is completely released in 16h, and a good sustained-release effect is shown. The result of the repeatability test of the release rate shows that the diaminopyridine phosphate sustained-release tablet has good uniformity in batches, the release rate has a smaller RSD value, and the product quality has good uniformity.
Drawings
FIG. 1 Release Profile of example 1 three batches
FIG. 2 Release Profile of comparative example 1
Detailed Description
In order to make the technical solution of the present invention more comprehensible to those skilled in the art, the present invention is further described below with reference to examples. It should be noted that the following embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art may obtain other embodiments without any inventive premise based on the embodiments of the present invention, and the embodiments are within the protection scope of the present invention.
EXAMPLE 1 preparation of diaminopyridine phosphate sustained Release tablets
Prescription (unit: mg)
The preparation process 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, rotating at 8 r/min, and premixing for 10min to obtain mixed powder 1;
2) performing dry granulation on the mixed powder 1, wherein the feeding frequency is 5HZ, the tabletting frequency is 5HZ, and the grading frequency is 5HZ to obtain granules 1;
3) respectively and sequentially adding the rest 30% of low-substituted hydroxypropyl cellulose and magnesium stearate into the granules 1 for total mixing, wherein the total mixing speed is 8 r/min, and the mixing time is 5 min;
4) tabletting, and controlling the hardness to be 50-80N to prepare the diaminopyridine phosphate sustained-release tablet.
EXAMPLE 2 preparation of diaminopyridine phosphate sustained Release tablets
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, rotating at 15 r/min, and premixing for 15 min to obtain mixed powder 1;
2) performing dry granulation on the mixed powder 1, wherein the feeding frequency is 10HZ, the tabletting frequency is 10HZ, and the grading frequency is 10HZ to obtain granules 1;
3) sequentially and respectively adding the rest 70% of low-substituted hydroxypropyl cellulose and magnesium stearate into the granules 1 for total mixing, wherein the total mixing speed is 15 r/min, and the mixing time is 5 min;
4) tabletting, and controlling the hardness to be 50-80N to prepare 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, hydroxypropyl methylcellulose, ethyl cellulose and 50% low-substituted hydroxypropyl cellulose into a mixing barrel, rotating at 15 r/min for 10min to obtain mixed powder 1;
2) performing dry granulation on the mixed powder 1, wherein the feeding frequency is 10HZ, the tabletting frequency is 10HZ, and the grading frequency is 10HZ to obtain granules 1;
3) respectively and sequentially adding the rest 50% of low-substituted hydroxypropyl cellulose and talcum powder into the granules 1 for total mixing, wherein the total mixing speed is 15 r/min, and the mixing time is 10min each;
4) tabletting, and controlling the hardness to be 50-80N to prepare 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, hydroxypropyl methylcellulose, polyvinyl alcohol and 70% of croscarmellose sodium into a mixing barrel, rotating at 15 revolutions per minute for 15 minutes to obtain mixed powder 1;
2) performing dry granulation on the mixed powder 1, wherein the feeding frequency is 10HZ, the tabletting frequency is 15HZ, and the grading frequency is 20HZ to obtain granules 1;
3) respectively and sequentially adding the rest 30% of croscarmellose sodium and magnesium stearate into the granules 1 for total mixing at a total mixing speed of 15 r/min for 10 min;
4) tabletting, and controlling the hardness to be 50-80N to prepare 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, ethyl cellulose, carbomer and 70% low-substituted hydroxypropyl cellulose into a mixing barrel, rotating at 20 r/min for 10min to obtain mixed powder 1;
2) performing dry granulation on the mixed powder 1, wherein the feeding frequency is 10HZ, the tabletting frequency is 10HZ, and the grading frequency is 15HZ to obtain granules 1;
3) adding the rest 30% of low-substituted hydroxypropyl cellulose and talcum powder into the granules 1, and mixing at a total mixing speed of 15 r/min for 10min each;
4) tabletting, and controlling the hardness to be 50-80N to prepare 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, hydroxypropyl methylcellulose and ethyl cellulose into a mixing barrel, rotating at the speed of 20 r/min, and premixing for 10min to obtain mixed powder 1;
2) performing wet granulation on the mixed powder 1, starting stirring at 200rpm, cutting at 1500rpm for 5 min; slowly adding 95% ethanol at constant speed for 1 min; 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, feeding into an oven, drying at 50-60 deg.C, air drying to room temperature, discharging, and granulating with 16 mesh nylon screen;
4) respectively and sequentially adding low-substituted hydroxypropyl cellulose and magnesium stearate into the granules 1 for total mixing, wherein the total mixing speed is 15 r/min, and the mixing time is 10min each;
5) tabletting, and controlling the hardness to be 50-80N to prepare 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, hydroxypropyl methylcellulose, ethyl cellulose and 70% low-substituted hydroxypropyl cellulose into a mixing barrel, rotating at 20 r/min, and premixing for 10min to obtain mixed powder 1;
2) carrying out wet granulation on the mixed powder 1, starting stirring at 200rpm, chopping at 1500rpm for 5 min; slowly adding 95% ethanol at constant speed for 1 min; 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, feeding into an oven, drying at 50-60 deg.C, air drying to room temperature, discharging, and granulating with 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 r/min, and the mixing time is 10min each;
4) tabletting, and controlling the hardness to be 50-80N to prepare 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, hydroxypropyl methylcellulose, ethyl cellulose and low-substituted hydroxypropyl cellulose into a mixing barrel, rotating at 20 r/min, and premixing for 10min to obtain mixed powder 1;
2) carrying out wet granulation on the mixed powder 1, starting stirring at 200rpm, chopping at 1500rpm for 5 min; slowly adding 95% ethanol at constant speed for 1 min; 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, feeding into an oven, drying at 50-60 deg.C, air drying to room temperature, discharging, and granulating with 16 mesh nylon screen;
4) putting the granules 1 into a mixer, adding magnesium stearate, and mixing at a total mixing speed of 15 r/min for 10 min;
4) tabletting, and controlling the hardness to be 50-80N to prepare the diaminopyridine phosphate sustained-release tablet.
Example 6 in vitro Release test
Samples of the diaminopyridine phosphate extended release oral tablets prepared in examples 1-5 and comparative examples 1-3 were taken and tested for their in vitro dissolution profile in hydrochloric acid solution at pH 1.0. The specific method comprises the following steps: according to the second method of 0391 in the general rule of the four parts of the Chinese pharmacopoeia 2015 edition, 900mL of hydrochloric acid (pH1.0) is used as a dissolution medium, 10mL of solution is taken at the rotating speed of 50r/min for 1h, 6h, 12h and 16h, the dissolution medium with the same volume and the same temperature is supplemented at the same time, the solution is filtered by a microporous membrane, the subsequent filtrate is taken as a test solution, the absorbance is measured at the wavelength of 230nm, and the cumulative dissolution amount of the medicine is calculated.
TABLE 1 results of testing the degree of Release of examples 1 to 5 and comparative examples 1 to 3
The results show that the diaminopyridine phosphate sustained-release tablet obtained by adopting dry granulation and internal and external processing of the disintegrant has good in-vitro sustained-release effect, and particularly, the active medicament is released more slowly after being released for 1 to 6 hours. In comparative examples 1 to 3 obtained by wet granulation, no matter whether the disintegrant was subjected to an internal-external addition method, an external addition method or an internal addition method, the burst release of the drug occurred at 6 hours, and the release of the drug was apparently not as stable as in examples 1 to 5 after 1 to 12 hours.
Example 7 in vitro Release reproducibility test
The release rates of the tablets of each three batches of the samples of example 1 and comparative example 1 were examined according to the in vitro release rate test method of example 6, and the results are as follows:
table 2 results of testing the degree of release of example 1
Table 3 results of testing release degree of comparative example 1
The results show that the diaminopyridine phosphate sustained-release tablet has better release reproducibility, the sustained-release effect is obviously better than that of a control product, and the quality uniformity is better.
Example 8 Release stability Studies
The samples of the invention example 1 and the comparative example 1 are taken and placed for 6 months under the conditions of 40 ℃ plus or minus 2 ℃ and 75% plus or minus 5% of relative humidity, and samples are taken at the end of 1, 2, 3 and 6 months respectively to examine the change condition of the release rate. The results are as follows:
table 4 accelerated release test results of example 1
| Degree of Release (%) | 1 hour | 6 hours | 12 hours | 16 hours |
| Day 0 | 27.86 | 59.01 | 93.20 | 97.12 |
| Accelerated for 1 month | 27.10 | 58.56 | 92.50 | 96.30 |
| Accelerated for 2 months | 27.32 | 60.12 | 94.49 | 97.20 |
| Accelerated for 3 months | 26.90 | 57.64 | 93.49 | 97.49 |
| Accelerated for 6 months | 28.03 | 52.69 | 93.54 | 98.19 |
Table 5 accelerated release test results of comparative example 1
| Degree of Release (%) | 1 hour | 6 hours | 12 hours | 16 hours |
| Day 0 | 46.37 | 90.31 | 95.36 | 96.24 |
| Accelerated for 1 month | 45.34 | 84.36 | 93.50 | 97.30 |
| Accelerated for 2 months | 42.19 | 93.18 | 97.94 | 99.20 |
| Accelerated for 3 months | 39.28 | 92.67 | 94.49 | 99.49 |
| Accelerated for 6 months | 36.39 | 87.26 | 90.54 | 92.19 |
The data show that the release rate of the diaminopyridine phosphate sustained-release tablet in example 1 is basically unchanged after the diaminopyridine phosphate sustained-release tablet is placed for 6 months under an accelerated condition, the stability is high, and the sustained-release effect is obvious. Comparative example 1 was inferior in stability, and the sustained-release effect was inferior to that of example 1.
Example 9 stability test examination
The samples of the sustained-release tablets in example 1 are taken for the examination of the influence factors of the appearance and the content.
(1) High-temperature test: a proper amount of the sample in the example 1 is spread in a culture dish and placed in a thermostat at 60 ℃ for 10 days, and samples are respectively taken for measurement on the 0 th day, the 5 th day and the 10 th day during the period, and the measurement results are shown in a table 5;
(2) high humidity test: taking a proper amount of the sample of the example 1, paving the sample in a culture dish, placing the sample for 10 days under the condition of 25 ℃ and 70% +/-5 ℃ relative humidity, and respectively taking samples for measurement on 0 day, 5 days and 10 days in the period, wherein the measurement results are shown in a table 5;
(3) strong light irradiation test: taking a proper amount of the sample of example 1, spreading the sample on a culture dish, placing the culture dish in a light cabinet, illuminating for 10 days under the condition of 4500Lx +/-500 Lx, and taking samples to measure on 0 th day, 5 th day and 10 th day respectively during the period, wherein the measurement results are shown in Table 5;
TABLE 6 stability of extended release tablets in example 1 under high temperature, high humidity and high light
TABLE 7 stability of comparative example 1 sustained release tablet at high temperature, high humidity and high light
The data show that after the diaminopyridine phosphate sustained-release tablet in example 1 is placed for 10 days under the condition of influencing factors, the properties, the content and the stability are basically unchanged, and the stability is high; the degradation products, related substances, are not obviously increased, and the related quality standard requirements (the limit of impurities is less than 2%) are met. Comparative example 1 is lowered in content and poor in stability after being left for 10 days under the condition of influencing factors; the degradation products, related substances, are obviously increased.
Claims (10)
1. The slow release tablet of diaminopyridine phosphate contains the following components by weight:
2. the diaminopyridine phosphate sustained-release tablet of claim 1, which comprises the following components in parts by weight:
3. diaminopyridine phosphate sustained-release tablets according to claim 1 or 2, characterised in that the filler is lactose, microcrystalline cellulose or a combination of the two, preferably in a weight ratio of 2:1, or
The sustained-release material is characterized in that the sustained-release material is one or more of hydroxypropyl methylcellulose, ethyl cellulose, sodium carboxymethyl cellulose, carbomer and polyvinyl alcohol, preferably the combination of hydroxypropyl methylcellulose and ethyl cellulose in a weight ratio of 1:1, or
The disintegrating agent is characterized by being one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch, preferably being croscarmellose sodium or low-substituted hydroxypropyl cellulose, and further preferably being low-substituted hydroxypropyl cellulose; or
The lubricant is one or two of talcum powder and magnesium stearate, preferably magnesium stearate.
4. Diaminopyridine phosphate sustained-release tablets according to any of claims 1 to 3, characterised in that the disintegrant is divided into an additional and an additional part, wherein the ratio of the additional and the additional disintegrant is from 3:7 to 7:3, preferably the ratio is 3: 7.
5. The diaminopyridine phosphate sustained-release tablet of claim 1, wherein the sustained-release tablet comprises the following components in parts by weight:
6. a diaminopyridine phosphate sustained-release tablet as in claim 5, wherein the low-substituted hydroxypropylcellulose is divided into an added part and an added part, wherein the ratio of the added and added low-substituted hydroxypropylcellulose is 3:7 to 7:3, preferably the ratio of the added and added low-substituted hydroxypropylcellulose is 3: 7.
7. A process for the preparation of diaminopyridine phosphate sustained release tablets as claimed in any of claims 1 to 4, comprising the steps of:
1) adding the diaminopyridine phosphate, the filler, the slow-release material and the disintegrating agent of the internal addition part into a mixing barrel, and premixing to obtain mixed powder 1;
2) dry granulating the mixed powder 1 to obtain granules 1;
3) adding an external part of disintegrant and lubricant into the granules 1 for total mixing;
4) tabletting to obtain the slow release tablet of diaminopyridine phosphate.
8. A process for preparing a diaminopyridine phosphate sustained-release tablet as defined in claim 5 or 6, which comprises the steps of:
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 granules 1 for total mixing;
4) tabletting to obtain the slow release tablet of diaminopyridine phosphate.
9. The process according to claim 7 or 8, wherein the rotation speed of the premixing in step 1) is 5 to 15 rpm and the premixing time is 5 to 15 minutes; or
In the step 2), the dry granulation feeding frequency is 5-10HZ, the tabletting frequency is 5-10HZ, and the granulation frequency is 5-10 HZ; or
In the step 3), the total mixing speed is 5-10 r/min, and the total mixing time is 5-10 min; or
The tablet hardness in the step 4) is 50-80N.
10. A diaminopyridine phosphate sustained release tablet comprises the following formula (unit: mg):
the preparation method 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, rotating at 8 r/min, and premixing for 10min 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 granulating frequency is 5HZ to obtain granules 1;
3) respectively and sequentially adding the rest 30% of low-substituted hydroxypropyl cellulose and magnesium stearate into the granules 1 for total mixing, wherein the total mixing speed is 8 r/min, and the mixing time is 5 min;
4) tabletting, and controlling the hardness to be 50-80N to prepare the diaminopyridine phosphate sustained-release tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210424289.4A CN114712321A (en) | 2022-04-22 | 2022-04-22 | Diaminopyridine phosphate sustained-release tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210424289.4A CN114712321A (en) | 2022-04-22 | 2022-04-22 | Diaminopyridine phosphate sustained-release tablet and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114712321A true CN114712321A (en) | 2022-07-08 |
Family
ID=82246125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210424289.4A Pending CN114712321A (en) | 2022-04-22 | 2022-04-22 | Diaminopyridine phosphate sustained-release tablet and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114712321A (en) |
Citations (5)
| 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 |
| US20040106651A1 (en) * | 2001-02-05 | 2004-06-03 | Francois Guyon | 3,4-diaminopyriding tartrate and phosphate, pharmaceutical compositions and uses thereof |
| WO2004082684A1 (en) * | 2003-03-17 | 2004-09-30 | Acorda Therapeutics | Stable oral formulations of aminopyridines and uses thereof |
| US20140255380A1 (en) * | 2011-06-30 | 2014-09-11 | Biomarin Pharmaceuticals, Inc. | Methods of administering 3, 4-diaminopyridine |
| WO2020212267A1 (en) * | 2019-04-18 | 2020-10-22 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Manufacturing process for amifampridine phosphate |
-
2022
- 2022-04-22 CN CN202210424289.4A patent/CN114712321A/en active Pending
Patent Citations (5)
| 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 |
| US20040106651A1 (en) * | 2001-02-05 | 2004-06-03 | Francois Guyon | 3,4-diaminopyriding tartrate and phosphate, pharmaceutical compositions and uses thereof |
| WO2004082684A1 (en) * | 2003-03-17 | 2004-09-30 | Acorda Therapeutics | Stable oral formulations of aminopyridines and uses thereof |
| US20140255380A1 (en) * | 2011-06-30 | 2014-09-11 | Biomarin Pharmaceuticals, Inc. | Methods of administering 3, 4-diaminopyridine |
| WO2020212267A1 (en) * | 2019-04-18 | 2020-10-22 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Manufacturing process for amifampridine phosphate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102836159A (en) | Dasatinib dispersoid, preparation method thereof and application thereof in tablets | |
| CN112022825A (en) | Alvatripopa maleate tablet and preparation method thereof | |
| CN111632036A (en) | Ticagrelor tablet and preparation method thereof | |
| CN105796519A (en) | Pramipexole dihydrochloride sustained-release tablet and preparation method thereof | |
| CN113795252B (en) | Pharmaceutical composition containing nitroquinoline, nitroquinoline oral solid tablet, preparation method and application thereof | |
| CN105853386B (en) | Tablet containing dapagliflozin propylene glycol hydrate and preparation method thereof | |
| CN105395506B (en) | A kind of clonidine hydrochloride sustained release tablets | |
| CN114712321A (en) | Diaminopyridine phosphate sustained-release tablet and preparation method thereof | |
| CN106038502A (en) | Ramelteon oral disintegrating tablets and preparation method thereof | |
| CN105030707B (en) | Method for preparing clotrimazole buccal tablets based on modified glucose whole powder direct compression method | |
| CN102688236B (en) | Candesartan cilexetil and amlodipine tablet composition and preparation method thereof | |
| CN114767648A (en) | Exemestane film-coated tablet and preparation method thereof | |
| CN112168796B (en) | Controlled-release drug sustained-release preparation of biphasic sustained-release system and preparation method thereof | |
| CN111643467B (en) | Nifedipine sustained release tablet and production process thereof | |
| CN114272219A (en) | Donepezil hydrochloride tablet and preparation method thereof | |
| CN110433163B (en) | Levamlodipine besylate composition and preparation method thereof | |
| CN113116892A (en) | Pharmaceutical composition containing repaglinide and preparation method thereof | |
| CN110833529A (en) | Terbinafine hydrochloride tablet and preparation method thereof | |
| CN109966256B (en) | Pramipexole sustained-release pharmaceutical composition, preparation method and application thereof | |
| CN111643473B (en) | Nifedipine sustained release tablet and preparation method thereof | |
| CN117241789A (en) | Pharmaceutical composition | |
| CN114177152A (en) | Digoxin micro tablet and preparation method thereof | |
| CN105596306A (en) | Sodium houttuyfonate tablets and preparation method thereof | |
| CN116157391A (en) | Pharmaceutical composition comprising EGFR inhibitor and preparation method thereof | |
| CN116173039A (en) | Pharmaceutical composition for treating irritable bowel syndrome and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |