CN109864971B - Granules of lamotrigine solid dispersion and preparation method thereof - Google Patents
Granules of lamotrigine solid dispersion and preparation method thereof Download PDFInfo
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- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 title claims abstract description 86
- 229960001848 lamotrigine Drugs 0.000 title claims abstract description 84
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 58
- 239000008187 granular material Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 16
- 239000000314 lubricant Substances 0.000 claims abstract description 13
- 239000000945 filler Substances 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 239000011230 binding agent Substances 0.000 claims abstract description 7
- 239000007884 disintegrant Substances 0.000 claims abstract description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 11
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 11
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 11
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000000796 flavoring agent Substances 0.000 claims description 7
- 235000013355 food flavoring agent Nutrition 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- 239000000853 adhesive Substances 0.000 claims description 5
- 230000001070 adhesive effect Effects 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229940069328 povidone Drugs 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical group OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 229940085605 saccharin sodium Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 9
- 239000000654 additive Substances 0.000 abstract description 5
- 235000019640 taste Nutrition 0.000 abstract description 5
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000008184 oral solid dosage form Substances 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000008213 purified water Substances 0.000 description 15
- 239000002994 raw material Substances 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 9
- 229920002678 cellulose Polymers 0.000 description 8
- 239000001913 cellulose Substances 0.000 description 8
- 235000010980 cellulose Nutrition 0.000 description 8
- 206010010904 Convulsion Diseases 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 238000007865 diluting Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 238000007873 sieving Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 238000010008 shearing Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KXJGSNRAQWDDJT-UHFFFAOYSA-N 1-acetyl-5-bromo-2h-indol-3-one Chemical compound BrC1=CC=C2N(C(=O)C)CC(=O)C2=C1 KXJGSNRAQWDDJT-UHFFFAOYSA-N 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- 229920003086 cellulose ether Polymers 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000013022 formulation composition Substances 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 229960003943 hypromellose Drugs 0.000 description 3
- -1 i.e. Polymers 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000007779 soft material Substances 0.000 description 3
- 238000000527 sonication Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 208000019505 Deglutition disease Diseases 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000001037 epileptic effect Effects 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 238000009474 hot melt extrusion Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000009210 therapy by ultrasound Methods 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- 208000033001 Complex partial seizures Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 201000006792 Lennox-Gastaut syndrome Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- OMRYJSVAHRNTGC-UHFFFAOYSA-N benzene triazine Chemical compound C1=CC=CC=C1.C1=CN=NN=C1 OMRYJSVAHRNTGC-UHFFFAOYSA-N 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 229940072170 lamictal Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229940095353 oral granules Drugs 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention relates to granules of lamotrigine solid dispersion and a preparation method thereof, belonging to the field of pharmaceutical preparations. The invention provides granules of lamotrigine solid dispersion, which are mainly prepared from lamotrigine solid dispersion and pharmaceutically acceptable additives, wherein the lamotrigine solid dispersion is prepared from an active drug lamotrigine and a pharmaceutically acceptable water-soluble carrier; the additives include filler, binder, disintegrant, lubricant and correctant. The solubility of the granules prepared by the invention is increased by about 30%, the solubility and bioavailability of lamotrigine are improved, and compared with other oral solid dosage forms, the granules have the advantages of quick absorption, quick effect, convenience in taking, good taste and the like. The preparation method of the granules provided by the invention has the advantages of simple process and stable preparation quality, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to granules of lamotrigine solid dispersion and a preparation method thereof.
Background
Dysphagia caused by choking fear (fear of choking) is common in all age groups, and dysphagia caused by epileptic attacks is common, which seriously hinders the efficacy of oral preparations. In the case of epileptic patients, the primary therapeutic goal is to maintain adequate antiepileptic levels and prevent subsequent seizures. Therefore, increased compliance with the dosing regimen is essential to maintain therapeutic blood levels.
Lamotrigine, chemical name 3, 5-diamino-6- (2, 3-dichlorophenyl) -1, 2, 4-triazine, molecular formula C9H7N5Cl2Molecular weight is 256.09, and the compound is a wide-spectrum antiepileptic drug of benzene triazine. Its indications include the simple partGeneralized seizures, complex partial seizures, secondary generalized tonic-clonic seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome, among others.
The antiepileptic drug containing lamotrigine which was first used clinically was marketed under the trade name LAMICTAL by GSKTMThe general tablet of (1). To date, various oral formulations containing lamotrigine have been marketed, including plain tablets, orally disintegrating tablets, chewable dispersible tablets and sustained release tablets. In clinical administration, the oral preparations are found to have poor administration compliance, difficult administration dosage control, poor curative effect caused by too small dosage and serious side effects such as rash caused by too much dosage.
Since lamotrigine is very slightly soluble in the aqueous phase (about 0.17mg/mL at 25 ℃ and about 0.57mg/mL at 37 ℃), there is a need to improve the solubility of lamotrigine in the aqueous phase using a formulation technique to prepare an oral granule for convenient administration in order to achieve the desired therapeutic effect while at the same time improving the administration compliance, avoiding or reducing the occurrence of side effects.
Disclosure of Invention
The invention aims to provide granules of lamotrigine solid dispersion on the basis of the prior art, improve the solubility and bioavailability of lamotrigine and solve the problem of low solubility of lamotrigine in an aqueous phase.
Another object of the present invention is to provide a lamotrigine solid dispersion.
The technical scheme of the invention is as follows:
a granule of lamotrigine solid dispersion is mainly prepared from lamotrigine solid dispersion and pharmaceutically acceptable additives, wherein the lamotrigine solid dispersion is prepared from an active drug lamotrigine and a pharmaceutically acceptable water-soluble carrier; the additives include filler, binder, disintegrant, lubricant and correctant.
The water-soluble carrier adopted by the invention comprises but is not limited to one or more of polyethylene glycol, povidone, poloxamer, organic acid, urea or cellulose derivatives.
Compared with the prior art, the lamotrigine solid dispersion granule provided by the invention is mainly prepared from lamotrigine solid dispersion and pharmaceutically acceptable additives, solves the problem of low solubility of lamotrigine in a water phase under the coordination of other conditions, improves the solubility and bioavailability of lamotrigine, and has the advantages of quick absorption, quick effect, convenience in taking, good taste and the like. Compared with the same amount of lamotrigine, the solubility of the granules of the lamotrigine solid dispersion prepared by the invention is increased by about 30%.
Any organic acid which does not affect the effect of the present invention may be used in the present invention, for example: citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid. In a preferred embodiment, the organic acid used in the present invention is fumaric acid.
The cellulose derivatives employed according to the invention are predominantly cellulose ethers, for example: methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cyanoethyl cellulose, hydroxypropyl methyl cellulose. In a preferred embodiment, the cellulose derivative is hydroxypropyl methylcellulose, i.e., hypromellose.
The weight ratio of active drug lamotrigine to water-soluble carrier in the lamotrigine solid dispersion provided by the invention is 1: 1-1: 10, preferably 1: 3-1: 7; more preferably 1: 5.
The granules of the lamotrigine solid dispersion prepared by the invention are characterized in that the filler is one or more of calcium carbonate, microcrystalline cellulose or starch.
In a further preferred embodiment, the binder is povidone.
Further, the disintegrating agent is low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium or a combination thereof.
Further, the lubricant is magnesium stearate.
Further, the corrigent is saccharin sodium, essence or a combination thereof.
The granules of the lamotrigine solid dispersion prepared by the invention comprise the following components in parts by weight: 110-130 parts of lamotrigine solid dispersion, 36-52 parts of filler, 20-40 parts of disintegrating agent, 3-6 parts of adhesive, 0.4-4 parts of flavoring agent and 1.0-6 parts of lubricant.
The granules of the lamotrigine solid dispersion prepared by the invention comprise the following components in parts by weight: 115-125 parts of lamotrigine solid dispersion, 40-48 parts of filler, 20-30 parts of disintegrating agent, 4-6 parts of adhesive, 1-3 parts of flavoring agent and 2-4 parts of lubricant.
The granules of the lamotrigine solid dispersion prepared by the invention comprise 120 parts of lamotrigine solid dispersion, 45-46 parts of filler, 23-25 parts of disintegrant, 5-6 parts of adhesive, 2 parts of flavoring agent and 3 parts of lubricant.
A preparation method of granules of lamotrigine solid dispersion mainly comprises the following steps:
adding the internally added raw and auxiliary materials into a wet mixing granulator, starting stirring for 3r/s, simultaneously shearing for 15r/s, mixing for five minutes, starting stirring for 3r/s and shearing for 20r/s simultaneously, adding water to prepare a soft material, timing for 4 minutes, discharging, sieving with a 24-mesh sieve for granulation, drying in an oven until the moisture content is less than 5%, sieving with a 24-mesh sieve for granulation, transferring into a hopper mixer, adding a lubricant with a formula amount, and mixing for 10 minutes at a speed of 15r/s, thereby obtaining the granules of the lamotrigine solid dispersion.
The lamotrigine solid dispersion is prepared from an active drug lamotrigine and a pharmaceutically acceptable water-soluble carrier, wherein the weight ratio of the active drug lamotrigine to the water-soluble carrier is 1: 1-1: 10; preferably 1:3 to 1: 7; more preferably 1: 5. Wherein the water-soluble carrier is one or more of polyethylene glycol, polyvidone, poloxamer, organic acid, urea or cellulose derivatives.
In lamotrigine solid dispersions, the cellulose derivatives are predominantly cellulose ethers, for example: methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cyanoethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. In a preferred embodiment, the cellulose derivative is hydroxypropyl methylcellulose, i.e., hypromellose.
In lamotrigine solid dispersions, the cellulose derivatives are predominantly cellulose ethers, for example: methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cyanoethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. In a preferred embodiment, the cellulose derivative is hydroxypropyl methylcellulose, i.e., hypromellose.
The lamotrigine solid dispersion provided by the invention is prepared by a hot-melt extrusion method. The hot-melt extrusion method is a method for preparing a solid dispersion by heating equipment to be above the glass transition temperature of a carrier to soften the carrier, so that a medicine is fully fused with the carrier, and extruding and cooling the mixture by a screw of a machine.
Methods of increasing drug solubility include physical modifications such as solid dispersions, nanoparticles, co-crystals; chemical modification such as salt formation or prodrug formation; carrier systems such as inclusion complexes, polymeric micelles, amphiphilic polymers, microemulsions; solvent compositions such as solubilizers, cosolvents, and wetting agents, and the like, are varied.
The solid dispersion can increase the solubility of insoluble active pharmaceutical ingredients, improve the stability of the medicament and reduce toxic and side effects. The medicine is highly dispersed in the solid matrix, so that the specific surface area of the medicine is increased, the dissolution rate of the medicine is accelerated, and the bioavailability of the medicine is improved.
The solid dispersion technology can effectively improve the solubility of the active pharmaceutical ingredient and improve the bioavailability of the active pharmaceutical ingredient. The medicine is prepared into granules, and has the advantages of quick absorption, quick effect, convenient taking, good taste and the like.
By adopting the technical scheme of the invention, the advantages are as follows:
compared with the same amount of lamotrigine, the solubility of the granules prepared by the invention is increased by about 30%, and the solubility and bioavailability of lamotrigine are improved.
The granules of lamotrigine solid dispersion provided by the invention can be used for oral granules, and compared with other oral solid dosage forms, the granules have the advantages of quick absorption, quick effect, convenience in taking, good taste and the like.
The preparation method of the granules provided by the invention has the advantages of simple process and stable preparation quality, and is suitable for industrial production.
Detailed Description
The granules of lamotrigine solid dispersions of the present invention are further illustrated by the following examples, which are not intended to limit the invention in any way. Variations and modifications may be effected by one skilled in the art without departing from the spirit and scope of the invention. All such modifications and variations are intended to be included herein within the scope of this disclosure.
The components and the amounts of lamotrigine solid dispersions provided by the present invention are shown in table 1.
TABLE 1 solid Dispersion formula composition
The above examples 1 to 6 were prepared as follows:
the preparation method of the lamotrigine solid dispersion provided by the invention comprises the following steps: in the amount of the formulation described in Table 1 for each example, it was fed into a hot-melt extruder, and the barrel temperature was set to 140 ℃ to 175 ℃ and the screw rotation speed was set to 60 rpm to 90rpm, whereby a molded body of a solid dispersion was obtained. The obtained molded body was pulverized in a ball mill, and then the pulverized product was sieved, and the sieved product was collected, thereby obtaining a solid dispersion powder.
The components and the amounts of the granules of lamotrigine solid dispersion provided by the present invention are shown in table 2.
TABLE 2 granular formulation composition
The above examples 7 to 9 were prepared according to the following method:
the preparation method of the granules of the lamotrigine solid dispersion provided by the invention comprises the following steps: adding the internally added raw and auxiliary materials into a wet mixing granulator, starting stirring for 3r/s, simultaneously shearing for 15r/s, mixing for five minutes, starting stirring for 3r/s and shearing for 20r/s simultaneously, adding water to prepare a soft material, timing for 4 minutes, discharging, sieving with a 24-mesh sieve for granulation, drying in an oven until the moisture content is less than 5%, sieving with a 24-mesh sieve for granulation, transferring into a hopper mixer, adding a lubricant with a formula amount, and mixing for 10 minutes at a speed of 15r/s, thereby obtaining the granules of the lamotrigine solid dispersion.
The formulation compositions of the granules of lamotrigine solid dispersion example 7, comparative example 1, comparative example 2, comparative example 3 and comparative example 4 provided by the present invention are shown in table 3, and the preparation methods of comparative examples 1 to 3 refer to example 7.
TABLE 3 granular formulation composition
Compared with example 7, the granule prepared in comparative example 1 is not added with flavoring agent, has unacceptable taste, hardly shields the bitterness of the raw material medicine, and has poor oral administration compliance.
Compared with example 7, the granules prepared in comparative example 2, which did not contain magnesium stearate as a lubricant, absorbed moisture and agglomerated in a large amount during long-term storage, and thus were not easy to store.
In contrast to example 7, the granules prepared in comparative example 3 were not added with povidone as a binder, resulting in the preparation of granules in which the majority of fine powder was present, and which did not have the properties that the granules had.
Compared with example 7, the binder is added in excess in comparative example 4, which causes the obstruction of soft material sieving and granulating to be larger, and the dried granules are harder, thus being inconvenient for granule finishing through a screen and difficult for operation of the process.
Example 10: the analysis and comparison method comprises the following steps: solubility studies were conducted.
Preparing a reference substance solution: accurately weighing about 20mg of lamotrigine raw material, placing the lamotrigine raw material in a 10mL volumetric flask, adding 6mL of purified water, dissolving the lamotrigine raw material by ultrasonic treatment for 15 minutes, cooling the lamotrigine raw material to room temperature, adding the purified water to a constant volume of 10mL, and shaking up. Filtering with 0.45 μm filter membrane, placing 1mL of filtrate in 100mL volumetric flask, adding purified water for dilution, diluting to constant volume, and shaking up to obtain the final product.
Preparing a test solution: about 200mg of the granules (example 7) (about equivalent to 20mg of the raw material containing lamotrigine) was precisely weighed, placed in a 10mL volumetric flask, added with 6mL of purified water, dissolved by sonication for 15 minutes, cooled to room temperature, added with purified water to a constant volume of 10mL, and shaken up. Filtering with 0.45 μm filter membrane, placing 1mL of filtrate in 100mL volumetric flask, adding purified water for dilution, diluting to constant volume, and shaking up to obtain the final product.
And (3) detecting the absorbance by adopting an ultraviolet-visible spectrophotometer at the wavelength of 306nm, wherein the measured result shows that the solubility of the test sample is about 30 percent higher than that of the reference sample.
| Sample name | Sample weighing (mg) | Absorbance of the solution |
| Reference 1 | 20.05 | 0.460 |
| Control 2 | 20.00 | 0.456 |
| Control 3 | 20.07 | 0.462 |
| Sample 1 (example 7) | 200.10 | 0.596 |
| Sample 2 (example 7) | 200.01 | 0.590 |
| Sample 3 (example 7) | 200.03 | 0.591 |
Example 11: the analysis and comparison method comprises the following steps: solubility studies were conducted.
Preparing a raw material solution of lamotrigine: accurately weighing about 20mg of lamotrigine raw material, placing the lamotrigine raw material in a 10mL volumetric flask, adding 6mL of purified water, dissolving the lamotrigine raw material by ultrasonic treatment for 15 minutes, cooling the lamotrigine raw material to room temperature, adding the purified water to a constant volume of 10mL, and shaking up. Filtering with 0.45 μm filter membrane, placing 1mL of filtrate in 100mL volumetric flask, adding purified water for dilution, diluting to constant volume, and shaking up to obtain the final product.
Preparing a lamotrigine solid dispersion solution: about 120mg of lamotrigine solid dispersion (example 6) (about equivalent to 20mg of lamotrigine-containing raw material) was precisely weighed, placed in a 10mL volumetric flask, added with 6mL of purified water, dissolved by sonication for 15 minutes, cooled to room temperature, added with purified water to a constant volume of 10mL, and shaken up. Filtering with 0.45 μm filter membrane, placing 1mL of filtrate in 100mL volumetric flask, adding purified water for dilution, diluting to constant volume, and shaking up to obtain the final product.
Preparing a granule solution of the lamotrigine solid dispersion: about 200mg (about equivalent to 20mg of lamotrigine-containing raw material) of granules of lamotrigine solid dispersion (example 9) was precisely weighed, placed in a 10mL volumetric flask, added with 6mL of purified water, dissolved by sonication for 15 minutes, cooled to room temperature, added with purified water to a constant volume of 10mL, and shaken up. Filtering with 0.45 μm filter membrane, placing 1mL of filtrate in 100mL volumetric flask, adding purified water for dilution, diluting to constant volume, and shaking up to obtain the final product.
And (3) detecting the absorbance by using an ultraviolet-visible spectrophotometer at the wavelength of 306nm, wherein the detection result shows that the solubility of the lamotrigine solid dispersion and the solubility of the granules are equivalent, and the solubilities of the lamotrigine solid dispersion and the granules are about 30% higher than that of the lamotrigine raw material.
Claims (3)
1. The granules of the lamotrigine solid dispersion are characterized by being mainly prepared from the lamotrigine solid dispersion, a filling agent, a binding agent, a disintegrating agent, a lubricating agent and a flavoring agent, and comprising the following components in parts by weight: 115-125 parts of lamotrigine solid dispersion, 40-48 parts of filler, 20-30 parts of disintegrating agent, 4-6 parts of adhesive, 1-3 parts of flavoring agent and 2-4 parts of lubricant; the lamotrigine solid dispersion is prepared from an active drug lamotrigine and hydroxypropyl methylcellulose, wherein the weight ratio of the active drug lamotrigine to the hydroxypropyl methylcellulose is 1: 5; the filler is starch; the binder is povidone; the disintegrant is low-substituted hydroxypropyl cellulose and/or carboxymethyl starch sodium; the lubricant is magnesium stearate; the correctant is saccharin sodium and/or essence.
2. Granules of lamotrigine solid dispersions according to claim 1, characterized in that they comprise the following components in parts by weight: 120 parts of lamotrigine solid dispersion, 45-46 parts of filler, 23-25 parts of disintegrant, 5-6 parts of adhesive, 2 parts of flavoring agent and 3 parts of lubricant.
3. Granules of lamotrigine solid dispersions according to claim 2, characterized in that they comprise the following components in parts by weight: 120 parts of lamotrigine solid dispersion, 46 parts of starch, 15 parts of low-substituted hydroxypropyl cellulose, 8 parts of carboxymethyl starch sodium, 6 parts of povidone, 1 part of saccharin sodium, 1 part of essence and 3 parts of magnesium stearate.
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