CN103705478B - Oral tablet containing tenofovir disoproxil fumarate - Google Patents
Oral tablet containing tenofovir disoproxil fumarate Download PDFInfo
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Abstract
The invention discloses an oral tablet containing tenofovir disoproxil fumarate, which is characterized by containing mannitol and low-substituted hydroxypropyl cellulose. The invention solves the problem of stability of tenofovir disoproxil fumarate by adding mannitol and low-substituted hydroxypropyl cellulose. The tenofovir disoproxil fumarate tablet provided by the invention is attractive in surface and stable in quality.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a new formula of tenofovir disoproxil fumarate tablets, which can ensure that the tenofovir disoproxil fumarate can be quickly dissolved out and the stability of the tablets can be remarkably improved.
Background
Tenofovir Disoproxil Fumarate (Tenofovir Disoproxil Fumarate), chemical name 9- [ (R) -2- [ [ bis [ [ (isopropoxycarbonyl) oxy ] methoxy ] phosphinyl ] methoxy ] -propyl ] adenine Fumarate (1: 1), structural formula as follows:
tenofovir disoproxil fumarate tablets (TDF tablets for short) are nucleotide reverse transcriptase inhibitors developed by Gillede science, USA, and are available under the trade name Viread in English and Werred in Chinese. TDF tablets were approved by the FDA and the european union in the united states for the treatment of aids in 2001 and 2002, respectively; in 2008, FDA in the eu and us approved it for the treatment of hepatitis b again based on the results of a number of clinical trials; TDF tablets are currently marketed in china for the treatment of aids, and clinical trials are underway for the treatment of hepatitis b indications. According to TDF tablet specifications developed by gillidd science, usa: it is shown that the core contains lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium and magnesium stearate.
The formulation composition and preparation of TDF tablets was first reported by gillidd scientific in the patent document CN 1264387A: the tenofovir disoproxil fumarate tablets as claimed in the patent claims contain pregelatinized starch, croscarmellose sodium, lactose monohydrate and magnesium stearate.
TDF is water soluble and is rapidly absorbed from the gastrointestinal tract after oral administration in the form of tablets, but has poor storage stability. The inventors of the present invention found that the increase of impurities in the TDF sheet was rapid after preparing the tablet by referring to the method reported in the patent document CN1264387A, and further confirmed the instability of the TDF sheet produced under the prior art conditions by studying the original TDF tablet (chinese trade name: virreed). And those skilled in the art know that: the degradation of impurities due to tablet instability is likely to affect clinical safety, and it is therefore desirable to provide a more stable TDF tablet.
The CN102198110A patent document discloses a TDF dispersible tablet and a preparation method thereof, which aims to solve the problem of taking by patients with dysphagia and achieve the purpose of faster dissolution. TDF dispersible tablets, although easier to take orally and dissolve quickly, use sodium lauryl sulfate in the formulation process, which is known to have irritating effects on the eye, skin, respiratory system, mucous membranes. There remains a need to provide a formulation that does not contain surfactant, yet allows rapid dissolution of TDF.
Disclosure of Invention
The invention aims to research a proper prescription composition according to the existing auxiliary materials and production equipment, and the TDF tablet is prepared by utilizing the existing preparation process, can effectively control the generation of degradation impurities, obviously improves the storage stability, and can ensure the rapid dissolution of the TDF.
Particle diameter D of TDF according to the invention(V，0.9)Less than or equal to 100 mu m. The inventors have studied and found that when the particle size of TDF is less than 100 μm, the TDF sheet can achieve a rapid dissolution effect without adding a surfactant to the formulation for solubilization.
The TDF tablet is characterized in that besides the main medicine, the tablet core also contains mannitol, low-substituted hydroxypropyl cellulose and other pharmaceutically acceptable carriers except a surfactant.
Mannitol is widely used in oral preparations, is mainly used as a filler (10-90%) in a tablet formulation, and has special value because it does not absorb moisture and can be compatible with moisture-sensitive active ingredients. The mannitol is divided into different specifications according to different particle sizes and is respectively applied to wet granulation tabletting and direct tabletting processes.
In the present specification, "%" means weight percent.
The low-substituted hydroxypropyl cellulose is a common disintegrant in oral preparations, and can be applied to wet granulation tabletting and direct tabletting processes.
The present inventors have conducted extensive experimental studies over a long period of time in order to improve the stability of TDF tablets, and have unexpectedly found that tablets using both mannitol and low-substituted hydroxypropylcellulose have excellent storage stability. Under the condition of being beneficial to preparing tablets, according to the weight of each unit tablet core, the mannitol accounts for 10.0-50.0% of the weight of the tablet core preferably, the low-substituted hydroxypropyl cellulose accounts for 2.0-30.0% of the weight of the tablet core more preferably, the mannitol accounts for 20.0-40.0% of the weight of the tablet core more preferably, and the low-substituted hydroxypropyl cellulose accounts for 5.0-20.0% of the weight of the tablet core. The tablet core referred to herein also contains TDF300mg per unit tablet core, the weight per unit tablet core being 600mg to 1000mg, preferably 650mg to 800 mg.
The inventors have found that the instability of TDF during its preparation and storage is mainly related to its chemical structure, which contains multiple ester bonds and is therefore susceptible to hydrolysis. Therefore, the present inventors used mannitol and low-substituted hydroxypropylcellulose together to improve the storage stability of the TDF sheet. The stability of TDF improved by mannitol and low substituted hydroxypropyl cellulose is mainly due to two reasons: the low-substituted hydroxypropyl cellulose is related to the good compatibility of mannitol and the low-substituted hydroxypropyl cellulose with TDF, and the low-substituted hydroxypropyl cellulose is weaker in moisture absorption than other disintegrating agents and then is mixed with the mannitol to obviously reduce the moisture absorption of a tablet core, so that the influence of hydrolysis is reduced.
According to TDF of the inventionParticle diameter D(V，0.9)Less than or equal to 100 mu m. The inventors have studied and found that when the particle size of TDF is less than 100 μm, the TDF sheet can achieve a rapid dissolution effect without adding a surfactant to the formulation for solubilization.
The inventor finds that the TDF has good water solubility, so that a surfactant is not required to be added at all to improve the solubility of the TDF, and the mannitol is a water-soluble auxiliary material and the low-substituted hydroxypropyl cellulose is a disintegrating agent, so that the self-ground TDF tablet can be rapidly dissolved after being disintegrated into small particles, and the TDF can be rapidly dissolved.
Further, to prepare suitable tablets, other pharmaceutically acceptable carriers are added to the core composition, including other types of fillers to improve compressibility, binders to aid in granulation for improved flow, and lubricants to aid in tablet release during compression.
As other kinds of fillers used, cellulose derivatives such as microcrystalline cellulose are preferred.
As binders used, there may optionally be used binders selected from the group consisting of starches, such as pregelatinized starch; cellulose ethers such as methyl cellulose, hydroxypropyl methyl cellulose; hydroxypropyl cellulose and hydroxypropyl methylcellulose are preferred, and hydroxypropyl cellulose is more preferred.
As lubricant used, it is selected from metal stearates, such as calcium stearate, magnesium stearate, preferably magnesium stearate.
Preferably, the first and second electrodes are formed of a metal,
wherein the microcrystalline cellulose accounts for 5.0-30.0% of the weight of the tablet core, the hydroxypropyl cellulose accounts for 1.0-10.0% of the weight of the tablet core, and the magnesium stearate accounts for 0.5-3.0% of the weight of the tablet core.
More preferably still, the first and second liquid crystal display panels are,
wherein the microcrystalline cellulose accounts for 10.0-20.0% of the weight of the tablet core, the hydroxypropyl cellulose accounts for 2.0-5.0% of the weight of the tablet core, and the magnesium stearate accounts for 1.0-2.0% of the weight of the tablet core.
The above-mentioned tablets may be plain tablets or immediate release film-coated tablets, preferably immediate release film-coated tablets.
The tenofovir disoproxil fumarate tablet prepared by the invention is attractive in surface and fast in dissolution, and particularly has excellent impurity stability.
Detailed Description
The following examples illustrate the invention in more detail without limiting the scope of the invention.
Comparative example 1
Referring to the formulation of the components and proportions of the TDF formulation disclosed in example 4 of the CN1264387A patent specification: batch 500 pieces
The preparation method comprises the following steps: 150.0G of TDF, 246.4G of lactose monohydrate, 17.6G of croscarmellose sodium and 22.0G of pregelatinized starch were weighed into a wet granulator (model: SHL-3), premixed, thoroughly mixed, made into suitable wet granules by adding purified water, and wet-granulated in a rotary granulator (FZB-150J), then dried in a fluidized bed (model: WBF-3G) until the moisture content was not higher than 2.0%, and dry-granulated in a rotary granulator (FZB-150J), and the dry granules were collected in a calculated yield of 96.0%. The collected dry granules were collectively blended with 8.4g of magnesium stearate in a hopper blender (model: HSD-50), uniformly blended, and then tabletted on a single punch tablet machine (model: DP30A) to make plain tablets of 300mg (TDF). Finally coating the plain tablets in a high-efficiency coating machine (model: BGB-5F) to obtain the quick-release film coated tablets.
Example 1
TDF sheet: 1000 pieces in batch
TDF(V，0.9)=95μm。
The preparation method comprises the following steps: 28.8g of hydroxypropyl cellulose is weighed and dissolved in a proper amount of purified water to prepare a binder solution for later use. 300.0G of TDF, 164.2G of mannitol, 144.0G of low-substituted hydroxypropylcellulose and 72.0G of microcrystalline cellulose were weighed into a wet granulator (model: SHL-3) and premixed, mixed well, added with a binder solution to prepare suitable wet granules, and wet-granulated in a rotary granulator (FZB-150J), followed by drying in a fluidized bed (model: WBF-3G) until the moisture content was not higher than 2.0%, and dry-granulated in a rotary granulator (FZB-150J), and the dry granules were collected, and the calculated yield was 97.1%. The collected dry granules were mixed with 10.5g magnesium stearate in a hopper mixer (model: HSD-50), and after mixing uniformly, tabletted on a rotary tablet press (model: ZP14) to make plain tablets of 300mg (TDF). Finally coating the plain tablets in a high-efficiency coating machine (model: BGB-5F) to obtain the quick-release film coated tablets.
Example 2
TDF sheet: 1000 pieces in batch
TDF(V，0.9)=13μm。
The preparation method comprises the following steps: 14.4g of hydroxypropyl cellulose was weighed and dissolved in an appropriate amount of purified water to prepare a binder solution for use. 300.0G of TDF, 250.6G of mannitol, 72.0G of low-substituted hydroxypropylcellulose and 72.0G of microcrystalline cellulose were weighed into a wet granulator (model: SHL-3) and premixed, mixed well, added with a binder solution to prepare suitable wet granules, and wet-granulated in a rotary granulator (FZB-150J), followed by drying in a fluidized bed (model: WBF-3G) until the moisture content was not higher than 2.0%, and dry-granulated in a rotary granulator (FZB-150J), and the dry granules were collected, and the calculated yield was 96.6%. The collected dry granules were mixed with 10.4g magnesium stearate in a hopper mixer (model: HSD-50), and after mixing uniformly, tabletted on a rotary tablet press (model: ZP14) to make plain tablets of 300mg (TDF). Finally coating the plain tablets in a high-efficiency coating machine (model: BGB-5F) to obtain the quick-release film coated tablets.
The immediate release film-coated tablets obtained in example 1-2 and TDF raw research tablets (Chinese trade name: Werred) purchased from the market were subjected to a dissolution measurement (XC second method, second appendix of 2010 version of Chinese pharmacopoeia) using 900mL of a 0.1 mol/L hydrochloric acid solution as a dissolution medium at a rotation speed of 50rpm, and the amount of dissolution of the tablets was measured at 260nm by an ultraviolet-visible spectrophotometry, and the measurement results are shown in Table 1:
TABLE 1
As seen from Table 1, the TDF sheets produced by the present invention dissolved rapidly, consistent with the original ground sheets.
The immediate release film-coated tablets obtained in comparative example 1 and examples 1 to 2 and TDF raw research tablets (Chinese trade name: Warded) purchased from the market were stored in a bare tablet form or a bottled form (containing 1g of silica gel desiccant) in an environment of 60 ℃ and a relative humidity of 80% (a closed desiccator containing a saturated potassium chloride solution was placed in an oven of 60 ℃) and stability was examined, and impurities were measured by high performance liquid chromatography under the following measurement conditions:
a chromatographic column: c18 column (250X 4.6mmI.D., S-5 μm, 12nm, model: YMC-Pack ODS-AQ)
Mobile phase: the mobile phase A is methanol/tert-butanol/0.01 mol/L disodium hydrogen phosphate (pH5.5) = 11/1/28 (v/v), and the mobile phase B is methanol/tert-butanol/0.01 mol/L disodium hydrogen phosphate (pH5.5) = 27/1/12 (v/v)
Column temperature: 35 deg.C
Detection wavelength: 260nm
The results of the impurity measurements are shown in table 2:
TABLE 2
As is clear from table 2, the tablets containing mannitol and low-substituted hydroxypropylcellulose (example 1 and example 2) are more excellent in stability than the tablets containing no mannitol and low-substituted hydroxypropylcellulose (comparative example 1 and ground tablets).
Claims (4)
1. An oral tablet containing tenofovir disoproxil fumarate, characterized in that: the tablet core contains mannitol, low-substituted hydroxypropyl cellulose and a pharmaceutically acceptable carrier except a lauryl sodium sulfate surfactant, wherein the mannitol accounts for 10.0-50.0% of the weight of the tablet core, and the low-substituted hydroxypropyl cellulose accounts for 2.0-30.0% of the weight of the tablet core; the pharmaceutically acceptable carriers except the sodium dodecyl sulfate surfactant are filler, adhesive and lubricant, wherein the filler is microcrystalline cellulose, the adhesive is hydroxypropyl cellulose, and the lubricant is magnesium stearate, wherein the microcrystalline cellulose accounts for 5.0-30.0% of the weight of the tablet core, the hydroxypropyl cellulose accounts for 1.0-10.0% of the weight of the tablet core, and the magnesium stearate accounts for 0.5-3.0% of the weight of the tablet core; the particle size D of the tenofovir disoproxil fumarate(v，0.9)≤100μm。
2. The oral tablet of claim 1, wherein the mannitol is present in an amount of 20.0 to 40.0% by weight of the core and the low-substituted hydroxypropylcellulose is present in an amount of 5.0 to 20.0% by weight of the core.
3. A tablet according to claim 1 wherein the microcrystalline cellulose is present in an amount of 10.0 to 20.0% by weight of the core, the hydroxypropyl cellulose is present in an amount of 2.0 to 5.0% by weight of the core and the magnesium stearate is present in an amount of 1.0 to 2.0% by weight of the core.
4. A tablet according to any one of claims 1 to 3 which is an immediate release film coated tablet.
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105125511A (en) * | 2014-05-30 | 2015-12-09 | 北京星昊医药股份有限公司 | Tenofovir disoproxil fumarate tablet and preparation method thereof |
| CN104288118A (en) * | 2014-07-08 | 2015-01-21 | 南京卡文迪许生物工程技术有限公司 | Tenofovir disoproxil fumarate tablet and preparation method thereof |
| CN104644598A (en) * | 2014-12-05 | 2015-05-27 | 乐普药业股份有限公司 | Tenofovir disoproxil fumarate tablets |
| CN109010317A (en) * | 2018-07-20 | 2018-12-18 | 南京海纳医药科技股份有限公司 | A kind of tenofovir disoproxil fumarate particle and preparation method thereof |
| CN111407736A (en) * | 2020-03-30 | 2020-07-14 | 苏州弘森药业股份有限公司 | Preparation process of tenofovir disoproxil fumarate tablets |
| WO2023056933A1 (en) * | 2021-10-08 | 2023-04-13 | 正大天晴药业集团股份有限公司 | Pharmaceutical combination containing capsid protein inhibitor and reverse transcriptase inhibitor |
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| CN1264387A (en) * | 1997-07-25 | 2000-08-23 | 吉里德科学公司 | Nucleotide analog composition and synthesis method thereof |
| CN101948485A (en) * | 2010-08-30 | 2011-01-19 | 杭州和素化学技术有限公司 | Alpha crystal form of tenofovir disoproxil fumarate, and preparation method and application thereof |
| CN102198110A (en) * | 2011-05-27 | 2011-09-28 | 杭州科本药业有限公司 | Tenofovir disoproxil fumarate dispersible tablets and preparation method thereof |
| EP2389929A1 (en) * | 2010-05-30 | 2011-11-30 | Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi | Pharmaceutical formulations of tenofovir |
| CN103230404A (en) * | 2013-05-14 | 2013-08-07 | 福建广生堂药业股份有限公司 | Novel use of adefovir dipivoxil or medicinal salt thereof |
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2013
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264387A (en) * | 1997-07-25 | 2000-08-23 | 吉里德科学公司 | Nucleotide analog composition and synthesis method thereof |
| EP2389929A1 (en) * | 2010-05-30 | 2011-11-30 | Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi | Pharmaceutical formulations of tenofovir |
| CN101948485A (en) * | 2010-08-30 | 2011-01-19 | 杭州和素化学技术有限公司 | Alpha crystal form of tenofovir disoproxil fumarate, and preparation method and application thereof |
| CN102198110A (en) * | 2011-05-27 | 2011-09-28 | 杭州科本药业有限公司 | Tenofovir disoproxil fumarate dispersible tablets and preparation method thereof |
| CN103230404A (en) * | 2013-05-14 | 2013-08-07 | 福建广生堂药业股份有限公司 | Novel use of adefovir dipivoxil or medicinal salt thereof |
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