CN101912375A - Metformin controlled release tablet - Google Patents
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- CN101912375A CN101912375A CN2010102636403A CN201010263640A CN101912375A CN 101912375 A CN101912375 A CN 101912375A CN 2010102636403 A CN2010102636403 A CN 2010102636403A CN 201010263640 A CN201010263640 A CN 201010263640A CN 101912375 A CN101912375 A CN 101912375A
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Abstract
The invention relates to a metformin controlled release tablet compound which contains an effective dose of metformin and polyoxyethylene and selectively contains or excludes one or more pharmaceutically acceptable auxiliary materials. The invention also relates to a metformin controlled release tablet which comprises a single-layer tablet core and a coating membrane covering the tablet core, wherein medicine release hole(s) is/are arranged on one side or two sides of each tablet, the tablet core contain an effective dose of the metformin and the polyoxyethylene and selectively contains one or more pharmaceutically acceptable auxiliary materials, and the coating membrane is a semi-permeable membrane.
Description
Technical field
The present invention relates to drug preparation technique.More specifically, the present invention relates to a kind of metformin controlled release tablet compositions, a kind of metformin controlled release tablet and their preparation method.
Background technology
Metformin (Metformin) belongs to the biguanides antidiabetic drug, has the blood glucose toleration that improves the type 2 diabetes mellitus patient, reduces the effect of basis and post-prandial glycemia.The mechanism of action of metformin hydrochloride is different from the oral anti-blood glucose medicine of other type, it can reduce the generation of glycogen, reduce the absorption of intestinal to sugar, and the sensitivity that can improve insulin by the picked-up and the utilization of increase periphery sugar, different with sulfonylureas is that metformin hydrochloride can not produce hypoglycemia to the patient of type 2 diabetes mellitus patient or euglycemia.After the metformin hydrochloride treatment, secretion of insulin remains unchanged, and reduce the fasting insulin level and every day plasma insulin level.The metformin hydrochloride chemical name is 1,1-dimethyl biguanide hydrochloride, and structural formula is as follows:
Sustained-release preparation has been compared lot of superiority with ordinary preparation, and for example, sustained-release preparation can be kept the required blood drug level of treatment the long period, and the peak valley that reduces blood drug level simultaneously changes, and reduces the incidence rate and the order of severity of toxic and side effects.Sustained-release preparation can also be taken number of times by minimizing, improves patient's compliance.Metformin is shorter owing to the half-life, and ordinary preparation needs every day to be taken 2 times or 3 times.Therefore 1 day 1 time metformin sustained-release preparation is significant to the clinical treatment of diabetic, has widespread demand in associated patient.
Chinese patent application cn99804134.3 discloses a kind of with the metformin slow releasing tablet of macromolecular material HPMC as the hydrophilic gel skeleton.Adopt biphasic controlled release delivery system to prolong the metformin pharmaceutical release time, this biphasic controlled release delivery system comprises the solid particles inside phase that (1) is formed by homogeneous granules basically, (2) outer solid continuous phase, the Dispersion of Particles of wherein above-mentioned solid particles inside phase and being embedded in the described outer solid continuous phase can be suppressed described delivery system in flakes or in incapsulating then.The shortcoming of this patent is that the metformin slow releasing tablet release that this kind technology makes generally is not constant release, and it is bigger that the interior release behavior of next body is influenced by internal milieus such as environment pH value, gastrointestinal peristalsis, thereby cause differing greatly between the therapeutic effect.
Osmotic pump tablet is made up of medicine, semipermeable membrane coating material, osmotic pressure active substance and push agent etc., with the controlled release tablet of osmotic pressure as the release energy.U.S. Patent application US6866866 discloses a kind of osmotic pump type metformin controlled release tablet, and U.S.'s approval in 2004 is produced by ANDRX LABS LLC company.What adopt the preparation of this principle and method is single chamber mono-layer osmotic pump sheet.This single chamber mono-layer osmotic pump controlled release tablets label consists of metformin, solubilizing agent and binding agent, and label adopts macromolecular material to carry out coating outward, punches on the coating membrane then.The shortcoming of this technology is because the metformin in the label is soluble in water, and contain in the label and promote the dissolved solubilizing agent of metformin, thereby permeate the voltage rise height in the coating membrane comparatively fast so in dispose procedure, be prone to too fast the making of the local metformin dissolving of sheet in-core, the burst size of metformin can increase suddenly in the case, easily increases incidence rate of adverse reaction.
The invention provides and be different from a kind of metformin controlled release tablet compositions of prior art, a kind of metformin controlled release tablet, and their preparation method.
Summary of the invention
1, one of purpose of the present invention provides a kind of metformin controlled release tablet compositions, and it contains the metformin and the polyoxyethylene of effective dose, and optionally contains one or more acceptable accessories.
2, another object of the present invention has provided a kind of metformin controlled release tablet, comprise the single-layer sheet heart and be wrapped in sheet coating membrane in the heart, and drug release hole is arranged in the tablet one or both sides, wherein the sheet heart contains the metformin and the polyoxyethylene of effective dose, and optionally containing one or more acceptable accessories, coating membrane is a semipermeable membrane.
3, a further object of the present invention has provided the preparation method of metformin controlled release tablet.
The specific embodiment
Metformin controlled release tablet of the present invention is the osmotic pump type controlled release tablet of single chamber monolayer.
Controlled releasing penetrant pump is as the typical case of controlled release preparation representative, and it is obvious to have the zero-order release feature, and drug release behavior is not subjected to the influence of factors such as media environment pH value, gastrointestinal peristalsis and food, and characteristics such as release dependency in inside and outside is good.
Existing metformin controlled release tablet is the osmotic pump type controlled release tablet that adopts the two-sided punching of single chamber monolayer equally.By the listing product
Description as can be seen, label is made up of metformin, solubilizing agent and binding agent, punch in outside coating both sides.Because the metformin in the label is soluble in water, and contain in the label and promote the dissolved solubilizing agent of metformin, thereby permeate the voltage rise height in the coating membrane comparatively fast so in dispose procedure, be prone to too fast the making of the local metformin dissolving of sheet in-core, the burst size of metformin can increase suddenly in the case, easily increases incidence rate of adverse reaction.Drug release determination result to the listing product is as follows:
Prepared the metformin hydrochloride controlled release tablet respectively and measured release according to following prescription in addition.
Sheet heart prescription: unit (mg/ sheet)
| Component | 1 | 2 | 3 | 4 |
| Metformin | 1000 | 1000 | 500 | 1000 |
| Polyvidone k90 | 58.8 | 62.1 | 32 | 62.5 |
| Sodium lauryl sulphate | 5.9 | 99.4 | / | 75 |
| Lactose | / | / | 64 | / |
| Magnesium stearate | 64.7 | 68.3 | 20 | 12.5 |
Granulation, tabletting, coating, punch out step are all identical with method among the embodiment 1.With reference to drug release determination method among the embodiment 1 tablet that makes is measured.
Measurement result
1 drug release determination result writes out a prescription
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 18.50％ | 29.23％ | 26.90％ | 27.42％ | 29.98％ | 30.21％ | 27.04％ | 16.25 |
| 4h | 39.28％ | 52.37％ | 54.87％ | 53.81％ | 55.53％ | 63.29％ | 53.19％ | 14.68 |
| 6h | 59.23％ | 67.98％ | 69.01％ | 70.21％ | 70.29％ | 83.61％ | 70.06％ | 11.17 |
| 8h | 80.21％ | 81.28％ | 80.87％ | 82.37％ | 84.28％ | 92.11％ | 83.52％ | 5.32 |
| 10h | 88.98％ | 87.29％ | 88.28％ | 87.76％ | 89.92％ | 93.21％ | 89.24％ | 2.41 |
| 12h | 93.21％ | 93.87％ | 96.28％ | 95.41％ | 92.22％ | 96.91％ | 94.65％ | 1.94 |
| 14h | 94.29％ | 96.21％ | 97.22％ | 97.19％ | 97.21％ | 96.02％ | 96.36％ | 1.19 |
| 16h | 97.98％ | 97.19％ | 97.31％ | 97.11％ | 98.91％ | 97.23％ | 97.62％ | 0.72 |
2 drug release determination results write out a prescription
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 15.47％ | 14.15％ | 15.82％ | 15.65％ | 13.36％ | 12.81％ | 14.54％ | 8.85 |
| 4h | 34.19％ | 32.53％ | 54.55％ | 35.43％ | 31.83％ | 29.90％ | 36.40％ | 24.98 |
| 6h | 48.84％ | 47.80％ | 68.70％ | 49.28％ | 45.41％ | 43.50％ | 50.59％ | 18.07 |
| 8h | 63.36％ | 59.79％ | 73.33％ | 62.11％ | 57.78％ | 56.32％ | 62.12％ | 9.80 |
| 10h | 73.28％ | 72.11％ | 82.11％ | 74.95％ | 73.99％ | 72.01％ | 74.74％ | 5.06 |
| 12h | 81.28％ | 80.28％ | 84.11％ | 84.01％ | 84.09％ | 83.71％ | 82.91％ | 2.04 |
| 14h | 87.89％ | 85.87％ | 87.90％ | 88.28％ | 87.12％ | 86.87％ | 87.32％ | 1.02 |
| 16h | 90.19％ | 92.18％ | 91.21％ | 90.01％ | 91.02％ | 90.29％ | 90.82％ | 0.90 |
3 drug release determination results write out a prescription
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 26.12％ | 28.38％ | 38.21％ | 25.31％ | 26.91％ | 29.99％ | 29.15％ | 16.26 |
| 4h | 51.21％ | 56.21％ | 67.98％ | 57.28％ | 58.12％ | 53.12％ | 57.32％ | 10.19 |
| 6h | 69.21％ | 68.28％ | 89.31％ | 68.21％ | 67.23％ | 67.23％ | 71.58％ | 12.18 |
| 8h | 79.23％ | 80.21％ | 90.23％ | 78.21％ | 81.21％ | 78.32％ | 81.24％ | 5.60 |
| 10h | 87.32％ | 86.23％ | 91.60％ | 87.22％ | 87.23％ | 88.21％ | 87.97％ | 2.14 |
| 12h | 90.42％ | 91.21％ | 93.21％ | 90.23％ | 94.21％ | 93.22％ | 92.08％ | 1.82 |
| 14h | 94.55％ | 94.51％ | 93.21％ | 95.23％ | 96.31％ | 95.31％ | 94.85％ | 1.09 |
| 16h | 94.66％ | 94.58％ | 93.51％ | 95.10％ | 96.21％ | 95.99％ | 95.01％ | 1.05 |
4 drug release determination results write out a prescription
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 16.45％ | 16.18％ | 16.02％ | 13.69％ | 14.87％ | 21.79％ | 16.50％ | 16.90 |
| 4h | 33.94％ | 38.34％ | 35.95％ | 31.55％ | 33.98％ | 48.17％ | 36.99％ | 16.03 |
| 6h | 45.86％ | 53.39％ | 61.67％ | 45.14％ | 46.80％ | 65.09％ | 52.99％ | 16.29 |
| 8h | 61.46％ | 64.95％ | 63.99％ | 58.29％ | 64.79％ | 74.86％ | 64.72％ | 8.61 |
| 10h | 77.41％ | 75.29％ | 74.11％ | 74.43％ | 76.12％ | 82.06％ | 76.57％ | 3.84 |
| 12h | 82.78％ | 80.65％ | 81.30％ | 82.12％ | 84.57％ | 86.78％ | 83.03％ | 2.74 |
| 14h | 87.23％ | 86.74％ | 87.56％ | 88.86％ | 88.34％ | 89.71％ | 88.07％ | 1.26 |
| 16h | 92.32％ | 91.17％ | 92.85％ | 91.13％ | 91.22％ | 91.46％ | 91.69％ | 0.78 |
By above-mentioned result of the test as seen, the metformin controlled release tablet for preparing by prior art is easy to prominent releasing, and each sheet discharges inconsistent.
Research worker of the present invention is on the basis of a large amount of tests, after being surprised to find the polyoxyethylene that adding suits in the label, can effectively solve metformin controlled release tablet and be easy to prominent release or discharge an inconsistent difficult problem, realize the stable and consistent of product quality by relative simple technology.
The invention provides a kind of metformin controlled release tablet compositions, it contains the metformin and the suitable polyoxyethylene of effective dose, and optionally contains one or more acceptable accessories.
Polyoxyethylene (Polyethylene oxide) is-(0CH
2CH
2)-
nNonionic homopolymer, wherein n represents the average number of oxygen ethyl, usually between 2,000 to about 100,000.It is a water-soluble resin, and molecular weight generally about 100,000 to about 7,000, between 000, has different viscositys in the aqueous solution that do not coexist according to molecular weight.Business-like polyoxyethylene often is divided into different model according to the difference of mean molecule quantity.For example, the POLYOX of Dow chemical company
TMIn the series of products, the molecular weight of WSR N-10NF is about 100,000, the molecular weight of WSR N-80NF is about 200,000, and the molecular weight of WSR N-750NF is about 300,000, the molecular weight of WSR-205NF is about 600,000, the molecular weight of WSR-1105NF is about 900,000, and the molecular weight of WSR N-12K NF is about 1,000,000, the molecular weight of WSR N-60KNF is about 2,000,000, the molecular weight of WSR-301NF is about 4,000,000, the molecular weight of WSRCoagulant NF is about 5,000,000, the molecular weight of WSR-303NF is about 7,000,000.
Polyoxyethylene is selected from molecular weight 100,000～7 among the present invention, one or more in 000,000, and preferred molecular weight 100,000～300, one or more in 000, more preferably molecular weight is a kind of polyoxyethylene of 20,000.
Polyoxyethylated consumption decides according to polyoxyethylated molecular weight of adopt and the controlled-release effect that expection reaches among the present invention, and amount ranges generally accounts for 0.1%～20% of tablet weight, preferably accounts for 0.5%～10% of tablet weight.
Polyoxyethylene among the present invention can also be the form of share with the active macromolecular material of other osmotic pressuries.The active macromolecular material of other osmotic pressuries comprises hypromellose, arabic gum, polyvidone, sodium alginate etc.
One or more pharmacy acceptable auxiliary are selected from any pharmaceutic adjuvant that can be used for controlled release tablet, include but not limited to filler, penetrating agent, solubilizing agent, binding agent, lubricant etc.
Wherein filler and penetrating agent are selected from lactose, mannitol, sodium chloride etc., preferred lactose.
Wherein solubilizing agent is selected from sodium lauryl sulphate, dodecyl sodium sulfate, tween 80 etc., preferably sodium dodecyl sulfate.
Wherein binding agent is selected from polyvidone, pregelatinized Starch, starch slurry, low-molecular-weight hypromellose etc., preferred polyvidone.
Wherein lubricant is selected from magnesium stearate, stearic acid, stearyl alcohol, hydrogenated castor wet goods, preferred magnesium stearate.
Metformin controlled release tablet compositions of the present invention can be used for treatment of diabetes, be prepared into metformin controlled release tablet after, it is stable to have a drug release rate, drug release rate is not influenced by gastrointestinal tract environment, the characteristics that patient's compliance is high.
The invention provides a kind of metformin controlled release tablet, comprise the single-layer sheet heart and be wrapped in sheet coating membrane in the heart, and one drug release hole is respectively arranged in the tablet one or both sides.The sheet heart contains the metformin and the polyoxyethylene of effective dose, and optionally contains one or more acceptable accessories.Coating membrane is a semipermeable membrane.
Preferred sheet contains metformin, polyoxyethylene, binding agent and solubilizing agent in the heart.
Coating membrane is a semipermeable membrane in the metformin controlled release tablet of the present invention, mainly contains the coating filmogen.The coating filmogen mostly is to have semipermeability and medicine not to be had chemosmotic macromolecular material liquid such as water.Be to increase the pliability of coating membrane, prevent that medicine from leaking and make the corrosion of tablet own, and guarantee inside and outside the tablet big permeable pressure head is arranged, can add plasticizer.If coating membrane adopts non-laser beam drilling, also need add porogen.
The coating filmogen is selected from cellulose acetate, acrylic resin, ethyl cellulose etc. among the present invention, preferred cellulose acetate.
Plasticizer is selected from triethyl citrate, Oleum Ricini, Tween 80, phthalic acid ester etc., optimization citric acid triethyl.
Porogen is selected from PEG400, Macrogol 600, cetomacrogol 1000 and polyethylene glycol 1500 etc., preferred polyethylene glycol 1500.
Metformin controlled release tablet of the present invention has one or two drug release hole on the surface of coating membrane.
The invention provides the preparation method of metformin controlled release tablet of the present invention.
Granulation, drying behind the mixings such as metformin and polyoxyethylene, binding agent, solubilizing agent, coating behind the tablet forming heart in the one side or the two-sided punching of tablet, makes metformin controlled release tablet at last.
Punching can adopt laser or mechanical mode to carry out.Early stage document reported with machine drilling once and prepared osmotic pump tablet that the big production of the inapplicable mechanization of this method only limited to laboratory and manufactures experimently in a small amount; Often adopt the mode of laser boring at present in the commercial production, this method is used the energy source of laser as pore, and is little to the damage of coating membrane, high efficiency; The drift that has also had bibliographical information to adopt to improve, the sheet before coating forms indenture in the heart, directly formation drug release hole behind the coating.
" effective dose " among the present invention in " metformin of effective dose " is meant the amount that can form effective treatment blood drug level behind the tablet in vivo of taking.
Metformin controlled release tablet of the present invention belongs to the slow-release tablet agent.Because controlled release tablet and slow releasing tablet are difficult to distinguish sometimes, though metformin controlled release tablet release of the present invention more approaches zero order kinetics, also may be called as the metformin slow releasing tablet, metformin slow releasing tablet in such cases still belongs within the scope of the invention.
Embodiment
Following embodiment further introduces and sets forth the present invention, but does not limit the present invention in any way.
Polyoxyethylene N80 refers to the POLYOX WSR N-80NF of Dow chemical company among the embodiment, and molecular weight is about 200,000; Polyoxyethylene N10 refers to the WSR N-10NF of Dow chemical company, and molecular weight is about 100,000.Polyoxyethylene 205 refers to the WSR-205NF of Dow chemical company, and molecular weight is about 600,000.
Embodiment 1
Sheet heart prescription:
| Component | Content mg/ sheet | Percentage ratio |
| Metformin | 1000 | 88％ |
| Polyvidone k90 | 56.8 | 5％ |
| Sodium lauryl sulphate | 11.4 | 1％ |
| Polyoxyethylene N80 | 5.7 | 0.5％ |
| Magnesium stearate | 62.5 | 5.5％ |
Sheet heart preparation method:
1, gets metformin and cross 80 mesh sieves;
2, take by weighing metformin, polyoxyethylene, polyvidone k90, sodium lauryl sulphate by recipe quantity, mix homogeneously adds an amount of water system soft material, crosses 20 mesh sieves and granulates, and 40 ℃ of forced air dryings are complete;
3, treat that particle drying fully after, 20 mesh sieve granulate are with the magnesium stearate mix homogeneously of recipe quantity, tabletting.
Coating fluid prescription (1000ml coating solution consumption)
Cellulose acetate 30g
Polyethylene glycol 1500 4g
Triethyl citrate 3g
Acetone 900ml
Water 100ml
Compound method:
1, take by weighing the 4g polyethylene glycol 1500, add water 100ml, immersion makes it dissolving fully, gets solution A;
2, take by weighing the 30g cellulose acetate and add 900ml acetone, be stirred to dissolving fully, get solution B;
3, solution A is added in the solution B, treat solution clarification after, add the triethyl citrate of 3g, stir, promptly.
The coating operation:
Adopt film-coated routine operation mode to carry out the coating operation, reach 3.0%～5.0%, after coating finishes, solidified 24 hours down in 40 ℃, promptly with the tablet coating weightening finish.
Punching:
Get the tablet behind the coating, each makes a call to the aperture of a diameter 0.4～0.8mm in the both sides of tablet to adopt laser or mechanical system, promptly gets the metformin controlled release tablet finished product.
The mensuration of release
Sample thief, according to drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2010) (adopting the device of dissolution method first method), phosphate buffered solution 900ml with pH7.4 is a solvent, rotating speed is that per minute 100 changes, operation in accordance with the law, got solution 10ml respectively at the 2nd hour, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, filter, and the instant phosphate buffered solution 10ml that in process container, replenishes pH7.4, get subsequent filtrate as test liquid.It is an amount of that precision takes by weighing the metformin reference substance in addition, and the phosphate buffered solution that adds pH7.4 is mixed with 30 μ g/ml solution, product solution in contrast.Get test sample and reference substance solution, measure trap at the wavelength place of 250nm, calculate the burst size of every different time by external standard method according to ultraviolet spectrophotometry.
Measurement result
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 23.95％ | 26.57％ | 25.72％ | 22.81％ | 23.19％ | 23.91％ | 24.36％ | 6.05 |
| 4h | 44.04％ | 48.55％ | 47.51％ | 48.71％ | 46.12％ | 43.90％ | 46.47％ | 4.62 |
| 6h | 61.64％ | 65.30％ | 64.26％ | 67.67％ | 66.18％ | 60.12％ | 64.20％ | 4.43 |
| 8h | 77.38％ | 76.40％ | 75.90％ | 77.91％ | 79.91％ | 75.63％ | 77.19％ | 2.06 |
| 10h | 82.28％ | 83.27％ | 83.10％ | 87.28％ | 88.21％ | 87.31％ | 85.24％ | 3.08 |
| 12h | 87.03％ | 87.52％ | 86.37％ | 89.10％ | 89.31％ | 89.01％ | 88.06％ | 1.41 |
| 14h | 93.12％ | 92.77％ | 92.97％ | 92.13％ | 93.12％ | 93.56％ | 92.95％ | 0.51 |
| 16h | 95.43％ | 93.48％ | 93.66％ | 94.50％ | 95.21％ | 95.67％ | 94.66％ | 0.98 |
Embodiment 2
Sheet heart prescription:
| Component | Content mg/ sheet | Percentage ratio |
| Metformin | 1000 | 85.5％ |
| Polyvidone k90 | 58.5 | 5％ |
| Sodium lauryl sulphate | 11.71 | 1％ |
| Polyoxyethylene N80 | 35.1 | 3％ |
| Magnesium stearate | 64.3 | 5.5％ |
Prepare the sheet heart according to sheet heart recipe quantity according to the sheet heart preparation method of embodiment 1, adopt the coating solution identical, and use and embodiment 1 identical coating and drilling method prepares present embodiment metformin controlled release tablet finished product with embodiment 1.
The drug release determination result
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 26.50％ | 23.03％ | 25.26％ | 24.55％ | 26.78％ | 24.21％ | 25.06％ | 5.69 |
| 4h | 48.23％ | 44.69％ | 46.92％ | 45.67％ | 47.67％ | 46.66％ | 46.64％ | 2.78 |
| 6h | 65.30％ | 61.64％ | 63.60％ | 63.54％ | 65.64％ | 65.61％ | 64.22％ | 2.47 |
| 8h | 75.41％ | 73.29％ | 74.10％ | 77.87％ | 78.42％ | 78.88％ | 76.33％ | 3.12 |
| 10h | 82.78％ | 80.65％ | 81.30％ | 82.84％ | 84.38％ | 84.53％ | 82.75％ | 1.90 |
| 12h | 85.23％ | 84.74％ | 85.56％ | 88.78％ | 89.82％ | 87.31％ | 86.91％ | 2.39 |
| 14h | 92.32％ | 93.17％ | 93.85％ | 94.32％ | 95.39％ | 91.02％ | 93.34％ | 1.65 |
| 16h | 95.15％ | 96.17％ | 97.19％ | 97.81％ | 97.88％ | 95.67％ | 96.65％ | 1.19 |
Embodiment 3
Sheet heart prescription:
| Component | Content mg/ sheet | Percentage ratio |
| Metformin | 1000 | 83.5％ |
| 30 POVIDONE K 30 BP/USP 90 | 62.5 | 5％ |
| Sodium lauryl sulphate | 12.5 | 1％ |
| Polyoxyethylene N80 | 62.5 | 5％ |
| Magnesium stearate | 68.75 | 5.5％ |
Prepare the sheet heart according to sheet heart recipe quantity according to the sheet heart preparation method of embodiment 1, adopt the coating solution identical, and use and embodiment 1 identical coating and drilling method prepares present embodiment metformin controlled release tablet finished product with embodiment 1.
The drug release determination result
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 24.34％ | 23.36％ | 24.73％ | 23.81％ | 22.87％ | 21.98％ | 23.52％ | 4.28 |
| 4h | 46.98％ | 45.74％ | 46.85％ | 44.78％ | 45.76％ | 44.38％ | 45.75％ | 2.30 |
| 6h | 62.95％ | 62.69％ | 64.65％ | 61.98％ | 60.98％ | 63.71％ | 62.83％ | 2.05 |
| 8h | 74.60％ | 72.31％ | 75.25％ | 73.68％ | 73.65％ | 72.17％ | 73.61％ | 1.66 |
| 10h | 81.47％ | 79.67％ | 82.94％ | 81.78％ | 82.71％ | 82.90％ | 81.91％ | 1.54 |
| 12h | 85.72％ | 84.90％ | 87.85％ | 88.71％ | 86.72％ | 87.11％ | 86.83％ | 1.60 |
| 14h | 90.63％ | 89.01％ | 91.28％ | 92.10％ | 92.11％ | 91.21％ | 91.06％ | 1.27 |
| 16h | 94.65％ | 93.32％ | 94.14％ | 95.71％ | 95.41％ | 94.31％ | 94.59％ | 0.93 |
Embodiment 4
Sheet heart prescription:
| Component | Content mg/ sheet | Percentage ratio |
| Metformin | 1000 | 85％ |
| Pvpk90 | 58.8 | 5％ |
| Sodium lauryl sulphate | 5.9 | 0.5％ |
| Polyoxyethylene N80 | 47.1 | 4％ |
| Magnesium stearate | 64.7 | 5.5％ |
Prepare the sheet heart according to sheet heart recipe quantity according to the sheet heart preparation method of embodiment 1, adopt the coating solution identical to carry out coating with embodiment 1.
Punching: get the tablet behind the coating, adopt laser or mechanical system to make a call to the aperture of a diameter 0.4～0.8mm, promptly get the metformin controlled release tablet finished product in a side of tablet.
The drug release determination result
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 12.81％ | 11.82％ | 10.87％ | 10.65％ | 11.46％ | 11.11％ | 11.45％ | 6.85 |
| 4h | 25.76％ | 26.71％ | 23.57％ | 25.31％ | 24.11％ | 23.12％ | 24.76％ | 5.61 |
| 6h | 37.81％ | 40.21％ | 40.87％ | 39.11％ | 42.87％ | 40.21％ | 40.18％ | 4.23 |
| 8h | 50.21％ | 47.98％ | 47.58％ | 47.26％ | 47.10％ | 45.28％ | 47.57％ | 3.35 |
| 10h | 65.87％ | 67.21％ | 64.81％ | 69.21％ | 66.43％ | 65.21％ | 66.46％ | 2.40 |
| 12h | 70.12％ | 72.67％ | 70.18％ | 71.20％ | 70.18％ | 71.11％ | 70.91％ | 1.40 |
| 14h | 76.87％ | 77.98％ | 79.01％ | 80.01％ | 78.65％ | 79.87％ | 78.73％ | 1.51 |
| 16h | 82.31％ | 86.12％ | 82.89％ | 87.21％ | 86.21％ | 87.12％ | 85.31％ | 2.53 |
| 20h | 90.11％ | 92.11％ | 89.76％ | 91.28％ | 88.27％ | 85.82％ | 89.56％ | 2.52 |
Embodiment 5
Sheet heart prescription:
| Component | Content mg/ sheet | Percentage ratio |
| Metformin | 1000 | 80.5％ |
| Pvpk90 | 62.1 | 5％ |
| Sodium lauryl sulphate | 99.4 | 8％ |
| Polyoxyethylene W205 | 12.4 | 1％ |
| Magnesium stearate | 68.3 | 5.5％ |
Prepare the sheet heart according to sheet heart recipe quantity according to the sheet heart preparation method of embodiment 1, adopt the coating solution identical, and use and embodiment 1 identical coating and drilling method prepares present embodiment metformin controlled release tablet finished product with embodiment 1.
The drug release determination result
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 15.47％ | 14.15％ | 15.82％ | 15.65％ | 13.36％ | 12.81％ | 14.54％ | 8.85 |
| 4h | 34.19％ | 32.53％ | 34.55％ | 35.43％ | 31.83％ | 29.90％ | 33.07％ | 6.18 |
| 6h | 48.84％ | 47.80％ | 48.70％ | 49.28％ | 45.41％ | 43.50％ | 47.26％ | 4.87 |
| 8h | 63.36％ | 59.79％ | 60.33％ | 62.11％ | 57.78％ | 56.32％ | 59.95％ | 4.37 |
| 10h | 73.28％ | 72.11％ | 74.00％ | 74.95％ | 73.99％ | 72.01％ | 73.39％ | 1.58 |
| 12h | 81.28％ | 80.28％ | 83.11％ | 84.01％ | 84.09％ | 83.71％ | 82.75％ | 1.93 |
| 14h | 87.89％ | 85.87％ | 86.90％ | 88.28％ | 87.12％ | 86.87％ | 87.16％ | 0.97 |
| 16h | 90.19％ | 92.18％ | 91.21％ | 90.01％ | 91.02％ | 90.29％ | 90.82％ | 0.90 |
Embodiment 6
Sheet heart prescription:
| Component | Content mg/ sheet | Percentage ratio |
| Metformin | 1000 | 80％ |
| Pvpk90 | 62.5 | 5％ |
| Sodium lauryl sulphate | 50 | 4％ |
| Polyoxyethylene N10 | 100 | 8％ |
| Magnesium stearate | 37.5 | 3％ |
Prepare the sheet heart according to sheet heart recipe quantity according to the sheet heart preparation method of embodiment 1, adopt the coating solution identical, and use and embodiment 1 identical coating and drilling method prepares present embodiment metformin controlled release tablet finished product with embodiment 1.
The drug release determination result
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 28.45％ | 28.79％ | 30.21％ | 29.12％ | 29.31％ | 26.99％ | 28.81％ | 3.72 |
| 4h | 51.34％ | 52.83％ | 51.29％ | 52.87％ | 53.12％ | 50.54％ | 52.00％ | 2.07 |
| 6h | 68.62％ | 68.95％ | 67.42％ | 70.07％ | 69.39％ | 67.91％ | 68.73％ | 1.41 |
| 8h | 81.24％ | 79.94％ | 78.36％ | 82.93％ | 82.79％ | 80.11％ | 80.89％ | 2.20 |
| 10h | 88.87％ | 88.40％ | 87.55％ | 89.63％ | 88.10％ | 89.14％ | 88.61％ | 0.85 |
| 12h | 93.82％ | 91.63％ | 91.03％ | 91.38％ | 91.53％ | 92.24％ | 91.94％ | 1.09 |
Embodiment 7
Sheet heart prescription:
| Component | Content mg/ sheet | Percentage ratio |
| Metformin | 500 | 78％ |
| Lactose | 64 | 10％ |
| Pvpk90 | 32 | 5％ |
| Polyoxyethylene N80 | 25 | 4％ |
| Magnesium stearate | 20 | 3％ |
Prepare the sheet heart according to sheet heart recipe quantity according to the sheet heart preparation method of embodiment 1, adopt the coating solution identical, and use and embodiment 1 identical coating and drilling method prepares present embodiment metformin controlled release tablet finished product with embodiment 1.
The drug release determination result
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 22.15％ | 22.58％ | 22.84％ | 24.78％ | 22.12％ | 23.85％ | 23.05％ | 4.60 |
| 4h | 45.92％ | 46.21％ | 46.48％ | 48.60％ | 46.93％ | 44.89％ | 46.51％ | 2.65 |
| 6h | 63.79％ | 62.98％ | 65.15％ | 66.11％ | 63.04％ | 62.08％ | 63.86％ | 2.36 |
| 8h | 73.92％ | 74.28％ | 73.98％ | 75.25％ | 73.32％ | 72.41％ | 73.86％ | 1.29 |
| 10h | 80.90％ | 80.11％ | 83.36％ | 85.61％ | 80.63％ | 82.12％ | 82.12％ | 2.52 |
| 12h | 87.11％ | 85.94％ | 87.36％ | 88.66％ | 89.41％ | 88.21％ | 87.78％ | 1.41 |
| 14h | 90.25％ | 88.81％ | 91.23％ | 90.68％ | 90.82％ | 89.75％ | 90.26％ | 0.97 |
| 16h | 90.81％ | 90.46％ | 91.66％ | 90.47％ | 91.19％ | 90.76％ | 90.89％ | 0.51 |
Embodiment 8
Sheet heart prescription:
| Component | Content mg/ sheet | Percentage ratio |
| Metformin | 1000 | 80％ |
| Pvpk90 | 62.5 | 5％ |
| Sodium lauryl sulphate | 75 | 6％ |
| Polyoxyethylene N80 | 125 | 10％ |
| Magnesium stearate | 12.5 | 1％ |
Prepare the sheet heart according to sheet heart recipe quantity according to the sheet heart preparation method of embodiment 1, adopt the coating solution identical, and use and embodiment 1 identical coating and drilling method prepares present embodiment metformin controlled release tablet finished product with embodiment 1.
The drug release determination result
| Time | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD(％) |
| 2h | 14.70％ | 15.38％ | 13.81％ | 13.85％ | 15.07％ | 13.85％ | 14.44％ | 4.83 |
| 4h | 31.51％ | 32.75％ | 30.25％ | 30.23％ | 31.41％ | 30.54％ | 31.12％ | 3.14 |
| 6h | 47.33％ | 47.31％ | 47.07％ | 43.94％ | 47.09％ | 45.47％ | 46.37％ | 2.97 |
| 8h | 57.91％ | 62.87％ | 65.86％ | 66.22％ | 60.44％ | 56.24％ | 61.59％ | 6.68 |
| 10h | 69.20％ | 76.21％ | 67.10％ | 70.46％ | 72.81％ | 67.38％ | 70.53％ | 4.95 |
| 12h | 80.21％ | 85.63％ | 81.87％ | 79.80％ | 86.05％ | 81.56％ | 82.52％ | 3.26 |
| 14h | 87.97％ | 91.12％ | 86.95％ | 87.00％ | 90.99％ | 89.54％ | 88.93％ | 2.14 |
| 16h | 90.20％ | 93.60％ | 92.35％ | 91.82％ | 92.43％ | 91.86％ | 92.04％ | 1.21 |
Claims (9)
1. metformin controlled release tablet, comprise the single-layer sheet heart and be wrapped in sheet coating membrane in the heart, and drug release hole is arranged in the tablet one or both sides, wherein to contain the metformin and the weight ratio of effective dose be the polyoxyethylene of 0.1%-10% to the sheet heart, and optionally contain or do not contain one or more acceptable accessories.
2. controlled release tablet as claimed in claim 1, wherein coating membrane is a semipermeable membrane, and in the tablet one or both sides drug release hole is arranged.
3. controlled release tablet as claimed in claim 1, the sheet heart is made up of the metformin of effective dose and the polyoxyethylene of weight ratio 0.1%-20%, and optionally contains or do not contain one or more acceptable accessories.
4. controlled release tablet as claimed in claim 2, semipermeable membrane is made up of cellulose acetate, plasticizer and porogen.
5. controlled release tablet as claimed in claim 2, plasticizer is a triethyl citrate in the coating membrane, porogen is a polyethylene glycol 1500.
6. the weight of metformin hydrochloride is between 500mg-1000mg in the heart for controlled release tablet as claimed in claim 3, sheet, and mean molecule quantity is 100,000-600, and 000 polyoxyethylene amount is 0.1%～20% of a tablet weight.
7. the weight of metformin hydrochloride is between 500mg-1000mg in the heart for controlled release tablet as claimed in claim 3, sheet, and mean molecule quantity is 100,000-600, and 000 polyoxyethylene amount is preferably 0.5%～10% of tablet weight.
8. controlled release tablet as claimed in claim 3, the sheet heart also contain solubilizing agent and lubricant except that metformin that contains effective dose and polyoxyethylene.
9. controlled release tablet as claimed in claim 3, the solubilizing agent that sheet contains in the heart are sodium lauryl sulphate, and lubricant is a magnesium stearate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102636403A CN101912375A (en) | 2010-08-26 | 2010-08-26 | Metformin controlled release tablet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102636403A CN101912375A (en) | 2010-08-26 | 2010-08-26 | Metformin controlled release tablet |
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|---|---|---|---|
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Cited By (9)
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| CN102058555A (en) * | 2011-01-13 | 2011-05-18 | 北京汇诚瑞祥医药技术有限公司 | Doxazosin controlled release tablet |
| CN102133204A (en) * | 2011-03-17 | 2011-07-27 | 山东新华制药股份有限公司 | Preparation method of melbinum osmotic pump controlled release tablets |
| CN105878256A (en) * | 2015-01-05 | 2016-08-24 | 合肥立方制药股份有限公司 | Controlled-release preparation containing metformin hydrochloride and glimepiride and preparation method of controlled-release preparation |
| CN105878204A (en) * | 2014-12-16 | 2016-08-24 | 合肥立方制药股份有限公司 | Metformin hydrochloride osmotic pump controlled release tablet and preparation method thereof |
| CN110075077A (en) * | 2019-05-17 | 2019-08-02 | 贵州天安药业股份有限公司 | A kind of Dimethyldiguanide hydrochloride enteric solubility tablet of effective hypoglycemic |
| CN111388438A (en) * | 2020-05-08 | 2020-07-10 | 福建东瑞制药有限公司 | Metformin hydrochloride sustained release tablet and preparation method thereof |
| CN112022823A (en) * | 2020-08-20 | 2020-12-04 | 重庆康刻尔制药股份有限公司 | Metformin hydrochloride and glimepiride sustained-release tablet and preparation method thereof |
| CN112999182A (en) * | 2020-08-19 | 2021-06-22 | 重庆康刻尔制药股份有限公司 | Metformin hydrochloride dual sustained and controlled release composition and preparation method and application thereof |
| CN113197876A (en) * | 2021-04-22 | 2021-08-03 | 广州白云山医药集团股份有限公司白云山制药总厂 | Cefaclor sustained-release tablet and preparation method thereof |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058555A (en) * | 2011-01-13 | 2011-05-18 | 北京汇诚瑞祥医药技术有限公司 | Doxazosin controlled release tablet |
| CN102133204A (en) * | 2011-03-17 | 2011-07-27 | 山东新华制药股份有限公司 | Preparation method of melbinum osmotic pump controlled release tablets |
| CN102133204B (en) * | 2011-03-17 | 2012-12-12 | 山东新华制药股份有限公司 | Preparation method of melbinum osmotic pump controlled release tablets |
| CN105878204A (en) * | 2014-12-16 | 2016-08-24 | 合肥立方制药股份有限公司 | Metformin hydrochloride osmotic pump controlled release tablet and preparation method thereof |
| CN105878204B (en) * | 2014-12-16 | 2019-04-09 | 合肥立方制药股份有限公司 | A kind of Metformin hydrochloride osmotic pump controlled release tablet and preparation method thereof |
| CN105878256A (en) * | 2015-01-05 | 2016-08-24 | 合肥立方制药股份有限公司 | Controlled-release preparation containing metformin hydrochloride and glimepiride and preparation method of controlled-release preparation |
| CN105878256B (en) * | 2015-01-05 | 2019-10-22 | 合肥立方制药股份有限公司 | Controlled release preparation and preparation method thereof containing Metformin hydrochloride and Glimepiride |
| CN110075077A (en) * | 2019-05-17 | 2019-08-02 | 贵州天安药业股份有限公司 | A kind of Dimethyldiguanide hydrochloride enteric solubility tablet of effective hypoglycemic |
| CN111388438A (en) * | 2020-05-08 | 2020-07-10 | 福建东瑞制药有限公司 | Metformin hydrochloride sustained release tablet and preparation method thereof |
| CN112999182A (en) * | 2020-08-19 | 2021-06-22 | 重庆康刻尔制药股份有限公司 | Metformin hydrochloride dual sustained and controlled release composition and preparation method and application thereof |
| CN112022823A (en) * | 2020-08-20 | 2020-12-04 | 重庆康刻尔制药股份有限公司 | Metformin hydrochloride and glimepiride sustained-release tablet and preparation method thereof |
| CN113197876A (en) * | 2021-04-22 | 2021-08-03 | 广州白云山医药集团股份有限公司白云山制药总厂 | Cefaclor sustained-release tablet and preparation method thereof |
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