CN110623933B - Metformin hydrochloride controlled release tablet and preparation method thereof - Google Patents
Metformin hydrochloride controlled release tablet and preparation method thereof Download PDFInfo
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- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 title claims abstract description 36
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960004329 metformin hydrochloride Drugs 0.000 title claims abstract description 34
- 238000013270 controlled release Methods 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 29
- 230000008569 process Effects 0.000 claims abstract description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 32
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 32
- 229940079593 drug Drugs 0.000 claims description 30
- 239000011248 coating agent Substances 0.000 claims description 25
- 238000000576 coating method Methods 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 16
- 239000000377 silicon dioxide Substances 0.000 claims description 16
- -1 Polyoxyethylene Polymers 0.000 claims description 13
- 239000012528 membrane Substances 0.000 claims description 13
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 230000001965 increasing effect Effects 0.000 claims description 11
- 229920002472 Starch Polymers 0.000 claims description 10
- 239000008187 granular material Substances 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 10
- 239000008107 starch Substances 0.000 claims description 10
- 235000019698 starch Nutrition 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- 239000007779 soft material Substances 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000004677 Nylon Substances 0.000 claims description 8
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims description 8
- 238000005553 drilling Methods 0.000 claims description 8
- 229920001778 nylon Polymers 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 8
- 235000012239 silicon dioxide Nutrition 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- 229940069328 povidone Drugs 0.000 claims description 7
- 238000004080 punching Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 239000007888 film coating Substances 0.000 claims description 6
- 238000009501 film coating Methods 0.000 claims description 6
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 229920002301 cellulose acetate Polymers 0.000 claims description 5
- 238000004806 packaging method and process Methods 0.000 claims description 5
- 238000009423 ventilation Methods 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- 229960001631 carbomer Drugs 0.000 claims description 4
- 239000011888 foil Substances 0.000 claims description 4
- 230000002496 gastric effect Effects 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 2
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 abstract description 15
- 230000008901 benefit Effects 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 7
- 239000003405 delayed action preparation Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000003111 delayed effect Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 48
- 239000010410 layer Substances 0.000 description 39
- 230000003204 osmotic effect Effects 0.000 description 14
- 239000000047 product Substances 0.000 description 12
- 238000005516 engineering process Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 239000002861 polymer material Substances 0.000 description 3
- 239000007939 sustained release tablet Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 229940027775 fortamet Drugs 0.000 description 2
- 230000030136 gastric emptying Effects 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 241000124033 Salix Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960000197 esomeprazole magnesium Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000005606 hygroscopic expansion Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003870 intestinal permeability Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- KWORUUGOSLYAGD-WLHYKHABSA-N magnesium;5-methoxy-2-[(r)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [Mg+2].C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-WLHYKHABSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000009475 tablet pressing Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Images
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- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Abstract
The invention relates to the field of pharmaceutical preparations, and particularly provides a metformin hydrochloride controlled release tablet and a preparation method thereof. The metformin hydrochloride in the controlled release tablet can be stably released at a constant speed, the problem of delayed release of the medicament at the early stage is solved, the problem of sudden release or non-release at the middle and later stages of medicament release is avoided, and the problem of medicament residue at the non-release stage of the medicament is solved. The controlled release curve of the metformin hydrochloride controlled release preparation is more controllable and stable through the invention, the absorption and utilization degree of the medicament is improved, and the clinical treatment effect is further ensured. The preparation method of the controlled release tablet has the advantages of large production and feasible process, stable product quality and good reproducibility of the main quality index release degree of the product.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a metformin hydrochloride osmotic pump controlled release tablet and a preparation method thereof.
Technical Field
Metformin hydrochloride is an antidiabetic agent, reduces hepatic glucose production, decreases intestinal glucose absorption, and increases insulin sensitivity by increasing peripheral glucose uptake and utilization. It is a first-line medicine for patients with type II diabetes, and has effects of improving blood sugar tolerance of patients with type II diabetes, and reducing basal and postprandial blood sugar.
The metformin hydrochloride sustained-release preparation can achieve the effect of twice or even three times daily administration of a common preparation by once daily administration, maintain stable blood concentration, improve the adaptability of patients and avoid the adverse effect of out-of-control blood sugar caused by missed administration. Metformin hydrochloride sustained release tablets (BRISTOL MYERS SQUIBB) and (SALIX PHARMS INC) adopt a skeleton type sustained release tablet technology, and a hydrophilic gel layer formed by matrix in water is used for controlling the drug release. The product patents (US6660300, US6488962) emphasize the swelling of the formulation in the gastric juice which increases the residence time of the formulation in the upper part of the digestive tract, thereby improving drug absorption. The hydrophilic gel skeleton swells in water to form a gel barrier, and the slow release effect of the medicine is formed through a diffusion or corrosion mechanism, but the slow release mechanism can be influenced by an environmental medium and an external force to cause great difference between individuals and individuals.
The release rate of the oral osmotic pump controlled release technology in vivo is not influenced by gastrointestinal tract variable factors such as peristalsis, pH value, gastric emptying time and the like, and has obvious advantages compared with the skeleton type sustained release technology. The Andrx company developed a controlled release formulation of metformin hydrochloride using osmotic pump technology under the trade name fortame (see patent document US7919116 for details). The patent is equivalent to the primary Osmotic pump (EOP) technology of ALZA company, utilizes the characteristic that metformin hydrochloride has high water solubility without adding other penetration promoters, has the advantages of high drug loading rate (75 percent higher) due to relatively less other components, and avoids the problem that the tablet is difficult to swallow due to overlarge volume. The adhesive is polyvinylpyrrolidone, the absorption enhancer is sodium dodecyl sulfate, and the preparation consists of a tablet core, a semipermeable membrane and a drug release pore.
The release rate is an important quality index of the controlled release preparation, such as Fortamet (CN 1158999C) with the release rate of 45-90% in 8 hours, not less than 60% in 12 hours and not less than 70% in 16 hours. The requirement of the release degree of the product is wide, for example, the release range of 45-90% in 8 hours cannot reflect the quality characteristics of the product, and the linear release characteristic of the osmotic pump controlled release preparation is not met, thus indicating the possibility of 'burst release'. When the commercial product is detected, the release degree of the product reaches the interval of 60% to 90%, namely the middle and later release periods, the obvious burst release phenomenon does exist, and the release uniformity has obvious problems. The Fortamet product releases the medicament only by depending on the solubility of the metformin in a tablet core, lacks the control of the medicament release process, and is easy to have burst release or non-release phenomenon because the tablet core is collapsed and quickly dissolved or locally agglomerated in the middle and later release periods.
Since metformin hydrochloride has relatively low intestinal permeability characteristics, absorption is relatively favored in the upper part of the digestive tract, while absorption is difficult in the lower part of the digestive tract, especially in the colon, and when the formulations are released in vitro differently, the drug delivery rate of the osmotic pump formulation will result in different degrees of absorption associated with the absorption site. The specification of the slow release preparation of metformin hydrochloride definitely requires that the preparation is taken after supper, and the absorption degree of the preparation can be equivalent to that of the common preparation taken twice in the morning and at night. The food can prolong the gastric emptying time, and the medicament is beneficial to stay in the upper end of the digestive tract for the reason of reducing the gastrointestinal motility at night after dinner. Various experimental data further reflect an overly broad release window design for the product, which may lead to clinically significant irrationality.
Disclosure of Invention
Because the existing metformin hydrochloride sustained release tablets and controlled release tablets have certain problems and defects in the aspect of drug release, the prior art needs to be further improved, so that the metformin hydrochloride osmotic pump preparation is superior in the aspect of release uniformity and simpler and more feasible in the aspect of process, and the application of metformin hydrochloride is safer and more effective aiming at the technical problems of the process.
According to the metformin hydrochloride controlled release tablet prepared by the invention, the appearance, related substances, release degree and content of the metformin hydrochloride controlled release tablet have no obvious change compared with 0 month when the metformin hydrochloride controlled release tablet is stored for 2 years in a constant temperature and humidity box with 40 +/-2 ℃ and 75% +/-5% of relative humidity for 6 months and under the condition of 25 +/-2 ℃ and 75% +/-5% of relative humidity, so that the metformin hydrochloride controlled release tablet can enable the effective period of the preparation to be more than one year.
The present invention relates to a metformin hydrochloride osmotic pump controlled release tablet, which mainly adopts a single composition osmotic pump technology (single composition osmotic pump technology), and the patent of the invention refers to the defects of the osmotic pump double-layer tablet core controlled release technology and the single composition osmotic pump technology, improves the prescription process of the metformin hydrochloride controlled release tablet, and overcomes the problems of delayed medicament release in the early stage, easy sudden release and non-release in the middle and later release stages and residual medicament release in the non-stage of the original product. The combination of the tablet core boosting layer, the tablet core drug layer and the semi-permeable membrane coating layer enables the drug release driving force and the drug release resistance to form a certain balance, thereby realizing the uniform release of the drug. The controlled release semi-permeable membrane group mainly takes cellulose acetate as a membrane forming material, and a plasticizer and a pore-forming agent are added through a composition test, so that the flexibility of the semi-permeable membrane is guaranteed, the permeation speed of water is also guaranteed, and the uniform release of the medicine is controlled.
In the design of the formula of the boosting layer of the medicine tablet core and the medicine layer, a high polymer material (such as polyoxyethylene and polyvinylpyrrolidone) with strong water absorption is adopted, and a high polymer material (such as sodium carboxymethyl starch) with certain expansibility and poor hygroscopicity is also adopted, so that the production process problems of granulation soft materials, such as sticky and sticky meshes, hard granules, hard tabletting spots and the like are avoided, the moisture absorption degree of the medicine is reduced, and the stability of the medicine is improved.
In the granulating process, conventional high-speed wet granulation or fluidized bed granulation is utilized, and granules which are easy to tabletting can be prepared in a large-scale production and smooth manner. The tabletting process also adopts the conventional double-layer tablet machine, can smoothly realize large-scale production, has smooth and clean tablet surface and moderate hardness, and is suitable for the next step of semi-permeable membrane coating production. The controlled-release semi-permeable membrane coating is produced by using a high-efficiency coating machine, air inlet temperature and humidity control and organic solvent recovery transformation are carried out on the high-efficiency coating machine, a spray gun device is also transformed, and the uniformity among the tablets and the uniformity among the batches of the coating membrane are ensured.
The gastric-soluble film coating layer is mainly used for enhancing the protection of the tablet core and the semi-permeable membrane, avoiding the damage of factors such as moisture permeation, package storage friction and the like to the medicinal preparation and ensuring the integrity and stability of the medicinal preparation. In addition, the outermost gastric-soluble film coating layer is added with different colors, so that the appearance can be beautified, the product identification is improved, and the market popularization and the medicine use of clinical patients are facilitated.
Compared with the prior art, the invention adopting the technical scheme has the following advantages:
(1) the tablet core of the osmotic pump adopts a single-chamber double-layer tablet, and the release of the drug is controlled in a mode that a boosting layer pushes the drug to release mainly and the drug layer releases the drug layer per se as an auxiliary, so that the delay of the early release of the drug and the phenomena of the middle and later period of empty release or no release are slowed down.
(2) The curable auxiliary materials are added in the formula of the tablet core drug layer of the double-layer tablet, so that the viscosity of a suspension formed after the drug layer absorbs water is increased, the resistance of the drug released from the small release holes is increased, the control of the drug release speed is facilitated, and the drug release is more stable.
(3) The release of the medicine is controlled by adopting a single-chamber double-layer tablet osmotic pump mode, and the residual liquid of the medicine layer can be pushed out of the tablet core by the boosting layer at the later stage of medicine release, so that the medicine residue is avoided, and the full utilization of the medicine is facilitated.
(4) The tablet core boosting layer prescription of the double-layer tablet is added with non-hygroscopic expansion high polymer materials such as sodium carboxymethyl starch and the like, so that the water absorption expansion volume of the boosting layer is ensured, the drug delivery layer is provided with sufficient driving force, the water absorption expansion speed of the boosting layer is regulated, the moisture absorption of the prescription is reduced, and the stability of the drug is improved.
(5) The stomach-soluble film coat is added on the outermost layer, so that the stomach-soluble film coat has the effects of moisture insulation, attractive appearance and the like, avoids the influence of moisture absorption on drug release, avoids the damage of friction to tablets, and is convenient for market popularization and clinical medication.
Drawings
Figure 1 is a graph of the release profile of the sample of example 1,
figure 2 is a graph of the release profile of the sample of example 2,
Detailed Description
The invention will be further described below by means of specific embodiments. It should be understood by those skilled in the art that these descriptions are not intended to limit the scope of the present invention, and equivalents or corresponding modifications made based on the descriptions in the embodiments may still fall within the scope of the present invention.
EXAMPLE 1 preparation of metformin hydrochloride controlled-release tablets
(1) Preparation of bilayer tablet core
(ii) a drug layer
Metformin hydrochloride 250g
Carbomer 50g
Povidone 30g
Silica 1g
Magnesium stearate 1g
Uniformly mixing metformin hydrochloride, carbomer and povidone according to the prescription amount, preparing a soft material by using a proper amount of 90% ethanol, granulating by using a 16-mesh nylon net, carrying out ventilation drying on the prepared granules at the temperature of 50 ℃, and then adding silicon dioxide and magnesium stearate to be uniformly mixed for later use.
② boosting layer
50g of polyoxyethylene
Sodium carboxymethyl starch 20g
Sodium chloride 30g
Red iron oxide 2g
Silica 1g
Magnesium stearate 1g
Mixing the above prescription amounts of polyoxyethylene, sodium carboxymethyl starch, sodium chloride and red ferric oxide uniformly, preparing soft material with appropriate amount of 90% ethanol, granulating with 16 mesh nylon net, air drying the obtained granule at 50 deg.C, adding silicon dioxide and magnesium stearate, and mixing uniformly for use.
③ tabletting
62 percent of drug layer particles
38 percent of boosting layer particles
The tablets were punched out in a shallow arc of 11mm diameter at a tablet weight of 536mg using a double layer tablet press and the tablet weight and hardness were measured during the compression process.
(2) Controlled release semi-permeable film coating preparation
Cellulose acetate 6g
Phthalic acid diethyl ester 1g
Polyethylene glycol 10001 g
Acetone 1000ml
The double-layer tablets prepared by the process are coated by a controlled-release semi-permeable membrane by using an efficient coating machine, the temperature of a tablet bed is 10-20 ℃, and the weight of the coating is increased by 8-15%.
Making into 1000 pieces
(3) Laser drilling
Punching holes with diameter of 0.8mm on the surface of the medicine layer by using a laser-beam drilling machine.
(4) Preparation of gastric soluble film coat
The tablets prepared by the process are coated with gastric-soluble film by an efficient coating machine, and the coating is increased by 2 percent.
(5) And packaging the prepared sheet with PVC aluminum foil.
EXAMPLE 2 preparation of metformin hydrochloride controlled-release tablets
(1) Preparation of bilayer tablet core
(ii) a drug layer
Metformin hydrochloride 500g
Polyoxyethylene 25g
Povidone 35g
Silica 1g
Magnesium stearate 1g
Uniformly mixing metformin hydrochloride, polyoxyethylene and polyvidone according to the prescription amount, preparing a soft material by using a proper amount of 90% ethanol, granulating by using a 16-mesh nylon net, carrying out ventilation drying on the prepared granules at 50 ℃, and then adding silicon dioxide and magnesium stearate to be uniformly mixed for later use.
② boosting layer
50g of polyoxyethylene
Sodium carboxymethyl starch 30g
50g of sodium chloride
Red iron oxide 2g
Silica 1g
Magnesium stearate 1g
Mixing the above formula amounts of polyoxyethylene, sodium carboxymethyl starch and red iron oxide uniformly, preparing soft material with appropriate amount of 90% ethanol, granulating with 16 mesh nylon net, air drying the obtained granule at 50 deg.C, adding silicon dioxide and magnesium stearate, and mixing uniformly for use.
③ tabletting
80 percent of medicine layer particles
20 percent of particles of the boosting layer
And punching tablets by a double-layer tablet press in a shallow arc manner with the diameter of 13mm according to the tablet weight of 696mg, and detecting the weight and the hardness of the tablets in the tablet pressing process.
(2) Controlled release semi-permeable film coating preparation
Cellulose acetate 8g
Phthalic acid diethyl ester 1g
Polyethylene glycol 4001 g
Acetone 1000ml
The double-layer tablets prepared by the process are coated by a controlled-release semi-permeable membrane by using an efficient coating machine, the temperature of a tablet bed is 10-20 ℃, and the weight of the coating is increased by 8-15%.
Making into 1000 pieces
(3) Laser drilling
Punching holes with diameter of 0.8mm on the surface of the medicine layer by using a laser-beam drilling machine.
(4) Preparation of gastric soluble film coat
The tablets prepared by the process are coated with gastric-soluble film by an efficient coating machine, and the coating is increased by 2 percent.
(5) And packaging the prepared sheet with PVC aluminum foil.
Example 1 sample detection and Mass stability analysis
Detection of Release degree according to the Release degree determination method in Chinese pharmacopoeia (2015 edition), a dissolution determination method first method device is adopted, 900ml of degassed phosphate buffer solution (pH6.8) is used as a release medium, the rotating speed of a rotating basket is 100r/min, the temperature is 37 +/-0.5 ℃, 10ml of the degassed phosphate buffer solution is sampled at 0.5, 1, 2, 4, 6, 8, 12 and 16h respectively according to the operation method, the filter is filtered, 10ml of the corresponding release medium is supplemented in time, 1ml of the subsequent filtrate is taken and placed in a 50ml volumetric flask, the subsequent filtrate is diluted to scale by the release medium, the subsequent filtrate is shaken uniformly, the absorbance is determined at the 233nm wavelength, and the drug release amount of each time point is calculated.
Example 1 results of measuring the degree of release of the sample are shown in the following table
The release curve is shown in figure 1
Example 2 sample detection and Mass stability analysis
Detection of Release degree according to the Release degree determination method in Chinese pharmacopoeia (2015 edition), a dissolution determination method first method device is adopted, 900ml of degassed phosphate buffer solution (pH6.8) is used as a release medium, the rotating speed of a rotating basket is 100r/min, the temperature is 37 +/-0.5 ℃, 10ml of samples are taken according to the method operation at 0.5, 1, 2, 4, 6, 8, 12 and 16h respectively, the samples are filtered, 10ml of corresponding release medium is supplemented in time, 1ml of subsequent filtrate is taken and placed in a 50ml bottle, the subsequent filtrate is diluted to scale by the release medium, the subsequent volumetric shaking is carried out, the absorbance is determined at 233nm wavelength, and the drug release amount at each time point is calculated.
Example 2 results of measuring the degree of release of the sample are shown in the following table
The release curve is shown in figure 2
Accelerated tests and long-term test investigation are carried out according to the commercially available package, and the results show that the indexes of the product do not change obviously under the packaging condition, and the product can meet the requirements of the medicine on storage and transportation conditions. The esomeprazole magnesium enteric capsule and the preparation method thereof have the advantages of stable product quality, low impurity content, simple and convenient formula and smooth process, ensure the product quality and clinical treatment effect, and can obtain remarkable social benefit and economic benefit.
Claims (2)
1. The controlled release metformin hydrochloride tablet is characterized by being prepared according to the following method:
(1) preparation of bilayer tablet core
First, a drug layer
Metformin hydrochloride 250g
Carbomer 50g
Povidone 30g
Silica 1g
Magnesium stearate 1g
Uniformly mixing the metformin hydrochloride, the carbomer and the povidone in the above amount, preparing a soft material by using a proper amount of 90% ethanol, granulating by using a 16-mesh nylon net, carrying out ventilation drying on the prepared granules at 50 ℃, and then adding silicon dioxide and magnesium stearate to be uniformly mixed for later use;
② boosting layer
Polyoxyethylene 50g
Sodium carboxymethyl starch 20g
Sodium chloride 30g
Red iron oxide 2g
Silica 1g
Magnesium stearate 1g
Uniformly mixing the polyoxyethylene, the sodium carboxymethyl starch, the sodium chloride and the red ferric oxide according to the prescription amount, preparing a soft material by using a proper amount of 90% ethanol, granulating by using a 16-mesh nylon net, ventilating and drying the prepared granules at 50 ℃, and then adding the silicon dioxide and the magnesium stearate to be uniformly mixed for later use;
③ tabletting
62 percent of drug layer particles
38 percent of boosting layer particles
Punching tablets by a double-layer tablet press in a shallow arc manner with the diameter of 11mm according to the tablet weight of 536mg, and detecting the weight and the hardness of the tablets in the tabletting process;
(2) controlled release semi-permeable film coating preparation
Cellulose acetate 6g
Phthalic acid diethyl ester 1g
Polyethylene glycol 10001 g
Acetone 1000ml
Coating the double-layer tablet prepared by the process with a controlled release semi-permeable membrane by using a high-efficiency coating machine, wherein the temperature of a tablet bed is 10-20 ℃, and the weight of the coating is increased by 8-15%;
making into 1000 pieces
(3) Laser drilling
Punching the surface of the medicine layer by using a laser-beam drilling machine, wherein the diameter of each hole is 0.8 mm;
(4) preparation of gastric soluble film coat
Coating the tablets prepared by the process with a gastric-soluble film by using an efficient coating machine, wherein the coating is increased by 2%;
(5) and packaging the prepared sheet with PVC aluminum foil.
2. The controlled release metformin hydrochloride tablet is characterized by being prepared according to the following method:
(1) preparation of bilayer tablet core
(ii) a drug layer
Metformin hydrochloride 500g
Polyoxyethylene 25g
Povidone 35g
Silica 1g
Magnesium stearate 1g
Uniformly mixing metformin hydrochloride, polyoxyethylene and povidone according to the prescription amount, preparing a soft material by using a proper amount of 90% ethanol, granulating by using a 16-mesh nylon net, carrying out ventilation drying on the prepared granules at 50 ℃, and then adding silicon dioxide and magnesium stearate to be uniformly mixed for later use;
② boosting layer
50g of polyoxyethylene
Sodium carboxymethyl starch 30g
50g of sodium chloride
Red iron oxide 2g
Silica 1g
Magnesium stearate 1g
Uniformly mixing the polyoxyethylene, the sodium carboxymethyl starch and the red iron oxide according to the prescription amount, preparing a soft material by using a proper amount of 90% ethanol, granulating by using a 16-mesh nylon net, carrying out ventilation drying on the prepared granules at 50 ℃, and then adding the silicon dioxide and the magnesium stearate to be uniformly mixed for later use;
③ tabletting
80 percent of medicine layer particles
20 percent of particles of the boosting layer
Punching tablets with a shallow arc with the diameter of 13mm by using a double-layer tablet press according to the weight of the tablets of 696mg, and detecting the weight and the hardness of the tablets in the tabletting process;
(2) controlled release semi-permeable film coating preparation
Cellulose acetate 8g
Phthalic acid diethyl ester 1g
Polyethylene glycol 4001 g
Acetone 1000ml
Coating the double-layer tablet prepared by the process with a controlled release semi-permeable membrane by using a high-efficiency coating machine, wherein the temperature of a tablet bed is 10-20 ℃, and the weight of the coating is increased by 8-15%;
making 1000 tablets in total;
(3) laser drilling
Punching the surface of the medicine layer by using a laser-beam drilling machine, wherein the diameter of each hole is 0.8 mm;
(4) preparation of gastric soluble film coat
Coating the tablets prepared by the process with a gastric-soluble film by using a high-efficiency coating machine, wherein the coating is increased by 2%;
(5) and packaging the prepared sheet with PVC aluminum foil.
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