CN110613689A - Orally disintegrating tablet containing amphiphilic polymer-pregabalin compound - Google Patents
Orally disintegrating tablet containing amphiphilic polymer-pregabalin compound Download PDFInfo
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- CN110613689A CN110613689A CN201810628319.7A CN201810628319A CN110613689A CN 110613689 A CN110613689 A CN 110613689A CN 201810628319 A CN201810628319 A CN 201810628319A CN 110613689 A CN110613689 A CN 110613689A
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- Prior art keywords
- pregabalin
- amphiphilic polymer
- orally disintegrating
- disintegrating tablet
- amphiphilic
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- 229960001233 pregabalin Drugs 0.000 title claims abstract description 55
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 35
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims abstract description 35
- 229940079593 drug Drugs 0.000 claims abstract description 32
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 239000000693 micelle Substances 0.000 claims description 45
- 239000000843 powder Substances 0.000 claims description 38
- 229920000642 polymer Polymers 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000004108 freeze drying Methods 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000007853 buffer solution Substances 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000012528 membrane Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 238000002390 rotary evaporation Methods 0.000 claims description 12
- 230000036571 hydration Effects 0.000 claims description 11
- 238000006703 hydration reaction Methods 0.000 claims description 11
- 239000002861 polymer material Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 8
- 238000007907 direct compression Methods 0.000 claims description 7
- 238000001338 self-assembly Methods 0.000 claims description 5
- 238000000935 solvent evaporation Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- -1 Polyethylene Polymers 0.000 claims 1
- 239000004698 Polyethylene Substances 0.000 claims 1
- 239000008366 buffered solution Substances 0.000 claims 1
- 239000008176 lyophilized powder Substances 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 229920000573 polyethylene Polymers 0.000 claims 1
- 239000012266 salt solution Substances 0.000 claims 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 22
- 239000003826 tablet Substances 0.000 description 15
- 238000002156 mixing Methods 0.000 description 13
- 108010011485 Aspartame Proteins 0.000 description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 11
- 239000000605 aspartame Substances 0.000 description 11
- 235000010357 aspartame Nutrition 0.000 description 11
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 11
- 229960003438 aspartame Drugs 0.000 description 11
- 235000019359 magnesium stearate Nutrition 0.000 description 11
- 239000008108 microcrystalline cellulose Substances 0.000 description 11
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 description 11
- 238000003825 pressing Methods 0.000 description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 10
- 229930195725 Mannitol Natural products 0.000 description 10
- 229920000876 geopolymer Polymers 0.000 description 10
- 239000000594 mannitol Substances 0.000 description 10
- 235000010355 mannitol Nutrition 0.000 description 10
- 229960001855 mannitol Drugs 0.000 description 10
- 229920002472 Starch Polymers 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 229940083542 sodium Drugs 0.000 description 6
- 235000015424 sodium Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 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 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 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 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 150000003951 lactams Chemical class 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229960001375 lactose Drugs 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 229940009697 lyrica Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
The application provides an orally disintegrating tablet containing an amphiphilic polymer-pregabalin compound and a preparation method thereof. The practice of the present application is to improve the stability and compressibility of pregabalin and to increase patient compliance with medication.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly relates to an orally disintegrating tablet containing an amphiphilic polymer-pregabalin compound and a preparation method thereof.
Background
Pregabalin is a novel gamma-aminobutyric acid (GABA) receptor agonist having the formula C8H17NO2Molecular weight 159.23, is a white crystalline powder, easily soluble in water, alkaline and acidic aqueous solutions, and is specifically referred to herein as pregabalinS-pregabalin. Pregabalin was successfully developed by the company pfeiffe and is used clinically mainly for the treatment of peripheral neuralgia and adjuvant treatment of focal partial seizures, as well as for the treatment of pain and anxiety such as postherpetic neuralgia.
Pregabalin is currently marketed in several countries and regions, and the marketed dosage forms are mainly capsules and oral solutions (trade name "lereca", LYRICA)®). However, the preparation process of the pregabalin preparation has the following difficulties: (1) the pregabalin has primary amino and carboxyl in molecules, so that the pregabalin is easy to undergo intramolecular condensation to generate lactam, and the moist heat effect and filler auxiliary materials can accelerate the pregabalin to undergo intramolecular cyclization to generate lactam impurities. In addition, chinese patent CN02806750.9 shows that maillard reaction occurs between lactose and pregabalin, resulting in a lactose complex with multiple degradation products. (2) The pregabalin raw material is crystalline powder particles, has poor compressibility and flowability, and cannot meet the requirements of conventional powder direct compression or dry granulation. Meanwhile, the taking method of the lerecan comprises the following steps: the initial dose is 75mg each time, 2 times daily; or 50mg each time, three times daily. Can be increased to 150 mg per time within one week according to therapeutic effect and tolerance, and 2 times daily. The conventional capsule which is taken frequently is difficult for old patients and patients taking various medicines at the same time, and on the basis, the development of a novel pregabalin dosage form which is safe, reliable, stable in curative effect and convenient to take is very important.
Orally disintegrating tablets are tablets which can be swallowed to achieve the effect in the stomach by means of swallowing after the tablets are placed on the tongue surface and rapidly dissolved or disintegrated in saliva without water or a small amount of water or chewing. Compared with the common tablet, the orally disintegrating tablet has the advantages of quick response, high bioavailability, convenient taking, low first-pass effect and the like, and is more suitable for the old, children and patients in special environments with dysphagia or inconvenient drinking and the like.
Therefore, the application provides an orally disintegrating tablet containing an amphiphilic polymer-pregabalin compound and a preparation method thereof, pregabalin and amphiphilic polymer materials with different molecular weights are prepared into polymer micelles by a self-assembly solvent evaporation method, the micelles are freeze-dried by a freeze-drying technology to obtain freeze-dried powder, and the orally disintegrating tablet is prepared by a powder direct compression process. The method can remarkably improve stability and compressibility of pregabalin, and improve drug compliance of patients.
Disclosure of Invention
Direct compression of the powder is to self-compress the drug powder and appropriate excipients into tablets without granulation (wet or dry) after sieving and mixing the drug powder and the excipients, respectively. Because the process is simple, granulation and drying are not needed, energy and time are saved, the stability of the medicine is protected, the dissolution rate of the medicine is improved, the industrial automation degree is high, and the like, the method is increasingly adopted by pharmaceutical enterprises of various countries. Due to the existence of amino and carboxyl in the molecules of pregabalin, under the damp and hot conditions or the action of fillers and other auxiliary materials, intramolecular condensation is easy to occur to generate lactam, the stability is poor, and the compressibility and the fluidity are poor.
Based on this, the object of the present application is to provide an orally disintegrating tablet containing an amphiphilic polymer-pregabalin complex and a method for preparing the same. The method effectively isolates the raw material medicines from the auxiliary materials, improves the stability of the raw material medicines and improves the fluidity at the same time. And freeze-drying the micelle to obtain freeze-dried powder, and finally preparing the orally disintegrating tablet by adopting a direct powder tabletting process.
The purpose of the application is solved by the following scheme:
an orally disintegrating tablet containing an amphiphilic polymer-pregabalin complex, which consists of 25 to 50 percent of the amphiphilic polymer-pregabalin complex and 50 to 75 percent of other pharmaceutically acceptable auxiliary materials.
According to the present application, the amphiphilic polymeric material is PEG-DSPE.
According to the application, the molecular weight of the amphiphilic polymer material is 1000-6000.
Further, the molecular weight of the amphiphilic polymer material is 3000-5000.
According to the application, the weight ratio of the pregabalin to the amphiphilic polymer material is 1:0.5-1: 5.
Further, the weight ratio of the pregabalin to the amphiphilic polymer material is 1:1-1: 3.
According to the application, the preparation method of the orally disintegrating tablet comprises the following steps: the pregabalin and the amphiphilic polymer are prepared into micelles by adopting a self-assembly solvent evaporation method, the micelles are freeze-dried by adopting a freeze-drying technology to obtain freeze-dried powder, and then the freeze-dried powder is prepared into the orally disintegrating tablet by adopting a powder direct compression process.
According to the application, the preparation method of the polymer micelle solid preparation is a self-assembly solvent evaporation method, and comprises the following specific steps:
(1) fully dissolving the amphiphilic polymer and pregabalin in an organic solvent, and removing the organic solvent by reduced pressure rotary evaporation in an eggplant-shaped bottle at a proper temperature to obtain a uniform film.
(2) Adding preheated buffer solution into the uniform film, and rotating and hydrating in a water bath.
(3) And (3) granulating the obtained polymer micelle through a microporous filter membrane, and freeze-drying the filtrate through a freeze dryer to obtain drug-loaded polymer micelle powder.
According to the application, in the preparation process of the amphiphilic polymer-pregabalin compound, the added organic solvent comprises one or a mixed solvent of ethanol and chloroform.
According to the application, in the preparation process of the amphiphilic polymer-pregabalin compound, the added buffer salt solution is selected from phosphate buffer solution with the pH value of 6.8-7.4.
Detailed Description
For a better understanding of the present invention, the present invention and advantages and benefits thereof will be described and illustrated in detail below by way of examples and experimental data of the present invention, which are not intended to limit the present invention.
Example 1
The preparation process comprises the following steps:
fully dissolving PEG1000-DSPE and pregabalin in a prescription amount in ethanol, performing reduced pressure rotary evaporation in an eggplant-shaped bottle for 1h to remove an organic solvent to obtain a uniform film, adding a buffer solution preheated at 37 ℃, performing rotary hydration in a water bath kettle at 37 ℃, granulating the obtained geopolymer micelle through a 0.45-micron microporous filter membrane, and freeze-drying the filtrate through a freeze dryer to obtain drug-loaded polymer micelle powder.
The prepared drug-loaded polymer micelle powder is uniformly mixed with spray-dried mannitol, microcrystalline cellulose, sodium carboxymethyl starch and aspartame according to the prescription amount in sequence. And adding magnesium stearate in the prescribed amount into the mixture, uniformly mixing, and pressing into tablets with the hardness of 25N-40N.
Example 2
The preparation process comprises the following steps:
fully dissolving PEG6000-DSPE and pregabalin in a prescription amount in ethanol, performing reduced pressure rotary evaporation in an eggplant-shaped bottle for 1h to remove an organic solvent to obtain a uniform film, adding a buffer solution preheated at 37 ℃, performing rotary hydration in a water bath kettle at 37 ℃, granulating the obtained geopolymer micelle through a 0.45-micron microporous filter membrane, and freeze-drying the filtrate through a freeze dryer to obtain drug-loaded polymer micelle powder.
The prepared drug-loaded polymer micelle powder is uniformly mixed with spray-dried mannitol, microcrystalline cellulose, sodium carboxymethyl starch and aspartame according to the prescription amount in sequence. And adding magnesium stearate in the prescribed amount into the mixture, uniformly mixing, and pressing into tablets with the hardness of 25N-40N.
Example 3
The preparation process comprises the following steps:
fully dissolving PEG3000-DSPE and pregabalin in a prescription amount in ethanol, performing reduced pressure rotary evaporation in an eggplant-shaped bottle for 1h to remove an organic solvent to obtain a uniform film, adding a buffer solution preheated at 37 ℃, performing rotary hydration in a water bath kettle at 37 ℃, granulating the obtained geopolymer micelle through a 0.45-micron microporous filter membrane, and freeze-drying the filtrate through a freeze dryer to obtain drug-loaded polymer micelle powder.
The prepared drug-loaded polymer micelle powder is uniformly mixed with spray-dried mannitol, microcrystalline cellulose, sodium carboxymethyl starch and aspartame according to the prescription amount in sequence. And adding magnesium stearate in the prescribed amount into the mixture, uniformly mixing, and pressing into tablets with the hardness of 25N-40N.
Example 4
The preparation process comprises the following steps:
fully dissolving PEG3000-DSPE and pregabalin in a prescription amount in ethanol, performing reduced pressure rotary evaporation in an eggplant-shaped bottle for 1h to remove an organic solvent to obtain a uniform film, adding a buffer solution preheated at 37 ℃, performing rotary hydration in a water bath kettle at 37 ℃, granulating the obtained geopolymer micelle through a 0.45-micron microporous filter membrane, and freeze-drying the filtrate through a freeze dryer to obtain drug-loaded polymer micelle powder.
The prepared drug-loaded polymer micelle powder is uniformly mixed with spray-dried mannitol, microcrystalline cellulose, sodium carboxymethyl starch and aspartame according to the prescription amount in sequence. And adding magnesium stearate in the prescribed amount into the mixture, uniformly mixing, and pressing into tablets with the hardness of 25N-40N.
Example 5
The preparation process comprises the following steps:
fully dissolving PEG3000-DSPE and pregabalin in a prescription amount in ethanol, performing reduced pressure rotary evaporation in an eggplant-shaped bottle for 1h to remove an organic solvent to obtain a uniform film, adding a buffer solution preheated at 37 ℃, performing rotary hydration in a water bath kettle at 37 ℃, granulating the obtained geopolymer micelle through a 0.45-micron microporous filter membrane, and freeze-drying the filtrate through a freeze dryer to obtain drug-loaded polymer micelle powder.
The prepared drug-loaded polymer micelle powder is uniformly mixed with spray-dried mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and aspartame according to the prescription amount in sequence. And adding magnesium stearate in the prescribed amount into the mixture, uniformly mixing, and pressing into tablets with the hardness of 25N-40N.
Example 6
The preparation process comprises the following steps:
fully dissolving PEG3000-DSPE and pregabalin in a prescription amount in ethanol, performing reduced pressure rotary evaporation in an eggplant-shaped bottle for 1h to remove an organic solvent to obtain a uniform film, adding a buffer solution preheated at 37 ℃, performing rotary hydration in a water bath kettle at 37 ℃, granulating the obtained geopolymer micelle through a 0.45-micron microporous filter membrane, and freeze-drying the filtrate through a freeze dryer to obtain drug-loaded polymer micelle powder.
The prepared drug-loaded polymer micelle powder is uniformly mixed with spray-dried mannitol, microcrystalline cellulose, croscarmellose sodium and aspartame according to the prescription amount in sequence. And adding magnesium stearate in the prescribed amount into the mixture, uniformly mixing, and pressing into tablets with the hardness of 25N-40N.
Example 7
The preparation process comprises the following steps:
fully dissolving PEG5000-DSPE and pregabalin in a prescription amount in ethanol, performing reduced pressure rotary evaporation in an eggplant-shaped bottle for 1h to remove an organic solvent to obtain a uniform film, adding a buffer solution preheated at 37 ℃, performing rotary hydration in a water bath kettle at 37 ℃, granulating the obtained geopolymer micelle through a 0.45-micron microporous filter membrane, and freeze-drying the filtrate through a freeze dryer to obtain drug-loaded polymer micelle powder.
The prepared drug-loaded polymer micelle powder is uniformly mixed with spray-dried mannitol, microcrystalline cellulose, sodium carboxymethyl starch and aspartame according to the prescription amount in sequence. And adding magnesium stearate in the prescribed amount into the mixture, uniformly mixing, and pressing into tablets with the hardness of 25N-40N.
Example 8
The preparation process comprises the following steps:
fully dissolving PEG5000-DSPE and pregabalin in a prescription amount in ethanol, performing reduced pressure rotary evaporation in an eggplant-shaped bottle for 1h to remove an organic solvent to obtain a uniform film, adding a buffer solution preheated at 37 ℃, performing rotary hydration in a water bath kettle at 37 ℃, granulating the obtained geopolymer micelle through a 0.45-micron microporous filter membrane, and freeze-drying the filtrate through a freeze dryer to obtain drug-loaded polymer micelle powder.
The prepared drug-loaded polymer micelle powder is uniformly mixed with spray-dried mannitol, microcrystalline cellulose, sodium carboxymethyl starch and aspartame according to the prescription amount in sequence. And adding magnesium stearate in the prescribed amount into the mixture, uniformly mixing, and pressing into tablets with the hardness of 25N-40N.
Example 9
The preparation process comprises the following steps:
fully dissolving PEG5000-DSPE and pregabalin in a prescription amount in ethanol, performing reduced pressure rotary evaporation in an eggplant-shaped bottle for 1h to remove an organic solvent to obtain a uniform film, adding a buffer solution preheated at 37 ℃, performing rotary hydration in a water bath kettle at 37 ℃, granulating the obtained geopolymer micelle through a 0.45-micron microporous filter membrane, and freeze-drying the filtrate through a freeze dryer to obtain drug-loaded polymer micelle powder.
The prepared drug-loaded polymer micelle powder is uniformly mixed with spray-dried mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and aspartame according to the prescription amount in sequence. And adding magnesium stearate in the prescribed amount into the mixture, uniformly mixing, and pressing into tablets with the hardness of 25N-40N.
Example 10
The preparation process comprises the following steps:
fully dissolving PEG5000-DSPE and pregabalin in a prescription amount in ethanol, performing reduced pressure rotary evaporation in an eggplant-shaped bottle for 1h to remove an organic solvent to obtain a uniform film, adding a buffer solution preheated at 37 ℃, performing rotary hydration in a water bath kettle at 37 ℃, granulating the obtained geopolymer micelle through a 0.45-micron microporous filter membrane, and freeze-drying the filtrate through a freeze dryer to obtain drug-loaded polymer micelle powder.
The prepared drug-loaded polymer micelle powder is uniformly mixed with spray-dried mannitol, microcrystalline cellulose, croscarmellose sodium and aspartame according to the prescription amount in sequence. And adding magnesium stearate in the prescribed amount into the mixture, uniformly mixing, and pressing into tablets with the hardness of 25N-40N.
Comparative example 1
The preparation process comprises the following steps:
mixing pregabalin with prescription dose of spray-dried lactose, microcrystalline cellulose, croscarmellose sodium and aspartame in turn. And adding magnesium stearate in the prescribed amount into the mixture, uniformly mixing, and pressing into tablets with the hardness of 15N-25N.
TABLE 1 influence factor test results
Results and conclusions of the experiment
(1) As shown in the results of the influencing factor tests of examples 1 to 10, the orally disintegrating tablets containing the amphiphilic polymer-pregabalin compound have no obvious increase in the maximum unknown single impurities and total impurities after being placed in the influencing factor test (high temperature 60 ℃, high humidity 92.5% and illumination) for 10 days; in contrast, in comparative example 1, the raw material drug is not prepared into the polymer micelle, and the sample prepared by directly adopting the powder direct compression technology has the related substances obviously increased after being placed for 10 days of the influencing factor test.
(2) Examples 1-10 orally disintegrating tablets were prepared from amphiphilic polymer-pregabalin complex, with hardness ranging from 25N to 40N and still having room for compression on the basis of ensuring acceptable disintegration times; in comparative example 1, the bulk drug is not prepared into the polymer micelle, and the sample is directly prepared by adopting the powder direct compression technology, the hardness range of the orally disintegrating tablet is 15N-25N, and the tabletting equipment has obvious abrasion sound and poor compressibility.
In conclusion, the stability and compressibility of the raw material medicine are obviously improved by adopting the amphiphilic polymer material to perform inclusion on the pregabalin.
Claims (10)
1. An orally disintegrating tablet containing an amphiphilic polymer-pregabalin compound, which consists of 25 to 50 percent of the amphiphilic polymer-pregabalin compound and 50 to 75 percent of other pharmaceutically acceptable auxiliary materials.
2. The orally disintegrating tablet of claim 1, wherein the amphiphilic polymer material is Polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE).
3. The amphiphilic polymeric material of claim 2 having a molecular weight of 1000-6000.
4. The amphiphilic polymeric material of claim 2 having a molecular weight of 3000-5000.
5. The orally disintegrating tablet comprising an amphiphilic polymer-pregabalin complex according to claim 1, characterized in that the weight ratio of pregabalin to amphiphilic polymer material is 1:0.5-1: 5.
6. The orally disintegrating tablet comprising an amphiphilic polymer-pregabalin complex according to claim 5, characterized in that the weight ratio of pregabalin to amphiphilic polymer material is 1:1 to 1: 3.
7. The orally disintegrating tablet comprising an amphiphilic polymer-pregabalin complex according to claim 1, which is prepared by forming the pregabalin and the amphiphilic polymer into micelles by a self-assembly solvent evaporation method, lyophilizing the micelles to obtain a lyophilized powder by a freeze-drying technique, and then forming the orally disintegrating tablet by a powder direct compression process.
8. The amphiphilic polymer-pregabalin complex according to claim 7, wherein the preparation method of the polymeric micelle solid preparation is a self-assembly solvent evaporation method, and the specific steps are as follows:
fully dissolving amphiphilic polymer and pregabalin in an organic solvent, performing reduced pressure rotary evaporation to remove the organic solvent in an eggplant-shaped bottle at a proper temperature to obtain a uniform film, adding a preheated buffer solution into the uniform film, performing rotary hydration in a water bath kettle, granulating the obtained polymer micelle through a microporous filter membrane, and freeze-drying the filtrate through a freeze-dryer to obtain drug-loaded polymer micelle powder.
9. The amphiphilic polymer-pregabalin complex according to claim 8, wherein the added organic solvent includes one or a mixture of ethanol and chloroform.
10. Amphiphilic polymer-pregabalin complex according to claim 8, characterized in that the buffered salt solution is selected from phosphate buffered solutions with a pH value of 6.8-7.4.
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