CN104688747B - Pharmaceutical composition comprising tenofovir disoproxil fumarate - Google Patents
Pharmaceutical composition comprising tenofovir disoproxil fumarate Download PDFInfo
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- CN104688747B CN104688747B CN201310638483.3A CN201310638483A CN104688747B CN 104688747 B CN104688747 B CN 104688747B CN 201310638483 A CN201310638483 A CN 201310638483A CN 104688747 B CN104688747 B CN 104688747B
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- Prior art keywords
- tenofovir disoproxil
- disoproxil fumarate
- tenofovir
- succinic acid
- stabilizer
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Abstract
The present invention relates to a kind of Pharmaceutical compositions, include tenofovir disoproxil fumarate dipivoxil, succinic acid, filler and lubricant.Wherein succinic acid improves the stability of tenofovir disoproxil fumarate composition as stabilizer, reduces the degradation of tenofovir disoproxil fumarate, reduces impurity content, improves product quality.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, it is related to a kind of pharmaceutical composition and preparation method thereof, in particular to one kind contains
There is the tenofovir disoproxil fumarate Pharmaceutical composition and preparation method thereof of succinic acid.
Background technique
Tenofovir disoproxil fumarate is a kind of open nucleoside phosphine diester analogue of adenosine monophosphate.It is rich
The hydrolysis that horse acid tenofovir disoproxil passes through diester in vivo is tenofovir, then forms two by the phosphorylation of cellular enzymes
Phosphoric acid tenofovir.Diphosphonic acid tenofovir with natural substrate 5 '-deoxyadenosine triphosphate by competing, and whole with DNA
DNA chain is terminated after conjunction, to inhibit the activity of HIV-1 reverse transcriptase.Tenofovir disoproxil fumarate with other degeneration-resistant turns
Record virus drugs are combined for treating adult and children HIV-1 infection in 12 years old or more, it may also be used for the treatment B-mode disease of Adult chronic
Virus hepatitis.
Tenofovir disoproxil fumarate is prodrug, and active constituent is tenofovir.Tenofovir is due to its structure
In phosphonyl group it is usually negatively charged and polarity not easily passs through by force very much biomembrane under physiological ph conditions, cause it effective
Infiltration gastrointestinal tract lipophilicity film and Various Tissues cell, therefore oral absorption effect is poor.It can be by being sheltered at ester
Phosphate group increases the absorption of gastrointestinal tract, efficiently solves the problems, such as that tenofovir oral absorption is poor.Clinical test results table
The oral administration biaavailability of bright tenofovir disoproxil (the class prodrug forms of tenofovir) is significantly greater than tenofovir.But replace promise
The bioavilability of good fortune Wei monoesters significantly reduces, even less than tenofovir.
But prodrug have one it is considerable the disadvantage is that the significant unstability of prodrug, in synthesis, preparation or storage
Its ester bond is susceptible to hydrolysis when (being stored individually or with formulation of pharmaceutical products), to lose its protectiveness masking group, such as replaces promise good fortune
Wei ester facile hydrolysis in preparation and storage is degraded into Tenofovir, to reduce its oral administration biaavailability.
In order to solve the disadvantage, the Chinese patent CN1264387A of Yuan Yanji Reed company application discloses fumaric acid for promise
Good fortune Wei ester all improves stabilization compared with its prodrug tenofovir ester and another crystal salt (i.e. citric acid tenofovir disoproxil)
Property.But tenofovir disoproxil fumarate is stored under 40 DEG C and 75 DEG C of RH and has still increased separately 0.9% and 1.9% 30 days and 60 days
Tenofovir.And disclose the method that tenofovir disoproxil fumarate piece is prepared using wet granulation technology.Because
Raw material proportion is larger in preparation, and the mobility of raw material is poor without being able to satisfy direct tablet compressing or dry granulation process to object
The requirement for expecting mobility can be good at improving the mobility of material by wet granulation.But wet-granulation process may increase
The probability for adding raw material to hydrolyze.
Chinese patent CN103338754A discloses Orally active nucleotide analog or Orally active nucleotide analog
The highly stable composition of prodrug improves Orally active nucleotide analog or Orally active nucleotide by the way that polymer is added
Analog prodrug (bis- (POM) PMEA diester of bis- (POM) PMEA diester of such as adefovirdipivoxil, tenofovir) storage-stable
And/or show superior water degradation-resistant, reduce 9- [(R) -2- [[[(propoxycarbonyl) oxygroup] methoxyl group phosphino-] first
Oxygroup]-propyl] adenine (i.e. monoesters impurity) content, which can reduce the bioavilability of tenofovir disoproxil.
Chinese patent CN102228464A discloses a kind of tenofovir composition and preparation method, pastes by using β-ring
The mode that spermatophore closes achievees the purpose that improve stability.Prepare the mode of inclusion compound compared with ordinary preparation method, technique is cumbersome,
Industrial production cost is high.
This patent technical problem to be solved is to provide a kind of Pharmaceutical composition of tenofovir disoproxil fumarate, with
Its production, storage and the stability in liquid solution are improved, the probability that its degradation generates monoesters impurity is reduced, makes the steady of product
It is qualitative more preferable.
Summary of the invention
In order to solve the problems, such as that tenofovir dipivoxil is easy hydrolysis during storage, the present invention provides a kind of rich horse
Sour tenofovir dipivoxil oral solid formulation, the product stability are more preferable.
The present inventor is found surprisingly that by a large number of experiments, in tenofovir disoproxil fumarate oral administration solid
Succinic acid is added in the prescription of preparation, the stabilization of tenofovir disoproxil fumarate oral solid formulation can be greatly improved
Property.
The purpose of the present invention is to provide a kind of tenofovir disoproxil fumarate Pharmaceutical composition comprising succinic acid.
The present invention is mixed together by the auxiliary materials such as tenofovir disoproxil fumarate bulk pharmaceutical chemicals and succinic acid, filler
It is even.Then suitable lubricant is added, oral solid dose forms are made.Succinic acid is used as stabilizer in this product, overcomes
The shortcomings that tenofovir disoproxil fumarate hydrolabil, significantly improve product quality.
Tenofovir disoproxil fumarate Pharmaceutical composition of the present invention, the fumaric acid comprising 25%-60% replace promise
Good fortune Wei dipivoxil, the stabilizer of 5%-30%, the filler of 30%-50%, the adhesive of 0%-5%, the disintegrating agent of 1%-5%,
The lubricant of 0.5%-5%, wherein the stabilizer is succinic acid, the above content is by weight percentage.
Further, the preferred 10%-20% of amount of the stabilizer succinic acid, by weight percentage.
The filler is selected from microcrystalline cellulose, lactose, mannitol, pregelatinized starch, starch.
The disintegrating agent is selected from crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxy-propyl
Cellulose.
The lubricant is selected from magnesium stearate, stearic acid, sodium stearyl fumarate, rilanit special.
Further, it can add or be not added adhesive in prescription.Described adhesive be selected from copolyvidone, hydroxypropyl cellulose and
Hydroxypropyl methylcellulose.
Tenofovir disoproxil fumarate Pharmaceutical composition of the present invention can be made into the mouth appropriate such as tablet, capsule
Take drug-delivery preparation.
Pharmaceutical composition of the invention can be prepared using standard technique commonly known in the art and preparation method, such as
By prepared by the dry-mixed method of each component.
Specifically, can be tenofovir disoproxil fumarate, succinic acid, one or more fillers, Yi Zhonghuo
A variety of adhesives and one or more disintegrating agents and other additional excipient mix.Then mixture is pressed into piece
Agent loads capsule.
Dry granulation process can also be used, tenofovir disoproxil fumarate, succinic acid, one or more fillings
Agent, one or more adhesives and one or more disintegrating agents and other additional excipient mix, dry granulation,
Lubricant (if necessary) is added in the grain, mixture is then pressed into tablet or loads capsule.
Due to the addition of stabilizer succinic acid, the stability of tenofovir disoproxil fumarate in the solution is improved,
Therefore wet granulation technique can be applied.For example, can be tenofovir disoproxil fumarate, succinic acid, one or more
Filler, one or more adhesives and one or more disintegrating agents and other additional excipient (if necessary) are blended in
Together, adhesive or water granulation is added.Lubricant is added in the particle being dried to obtain, then mixture be pressed into tablet or
Load capsule.
The advantage of the invention is that succinic acid plays the role of stabilizer in the formulation, is conducive to the stability of product, mentions
The high stability of product in the solution, will not increase the generation of Tenofovir using wet granulation, improve its mouth
Take bioavilability.
Specific embodiment
The following example purpose is to illustrate the present invention, but there is no restriction to the scope or spirit of the invention.
Main equipment to be used is as follows in embodiment:
| Equipment | Model | Producer |
| Wet granulator | VG25 | Glatt |
| Fluidized bed | GPCG2 | Glatt |
| Mixing machine | HDB-10 | Canaan science and technology |
| Dry granulating machine | WP 120Pharma | Alexandria |
| Tablet press machine | 8Mx EU-B/D | IMA |
Embodiment 1
Preparation process:
1, it by except for magnesium stearate plus material is uniformly mixed, adds magnesium stearate and is uniformly mixed；
2, dry granulation in suitable device (such as rolling granulator) is added；
3, additional microcrystalline cellulose, crospovidone is added in particle, is uniformly mixed, and adds magnesium stearate and is uniformly mixed；
4, required product is made in tabletting.
Embodiment 2
Preparation process:
1, tenofovir disoproxil fumarate, succinic acid, sodium carboxymethyl starch (interior to add) are uniformly mixed；
2, the granulation of PVP K30 solution is added；
3, by obtained particle drying；
4, microcrystalline cellulose is added in dry particl and sodium carboxymethyl starch is (additional) uniformly mixed；
5, stearic acid is added, is uniformly mixed；
6, required product is made in tabletting.
Embodiment 3
Preparation process:
1, pregelatinized starch, croscarmellose sodium (interior to add) and lactose (interior to add) are mixed in a mixer, is added
Water granulation；
2, dry particle to moisture is not higher than 3%；
3, dry particl is uniformly mixed in a mixer with croscarmellose sodium (additional) and lactose (additional)；
4, stearic acid is added, is uniformly mixed；
5, required product is made in tabletting.
Embodiment 4
Preparation process:
1, material used is uniformly mixed；
2, required product is made in tabletting.
Comparative example 1
The prescription mentioned in the patent CN1264387A of pharmaceutical factory man (Ji Lide company) and technique preparation comparison are ground according to original
Sample 1.
Preparation process:
1, pregelatinized starch, croscarmellose sodium (interior to add) and lactose (interior to add) are mixed in a mixer, is added
Water granulation；
2, dry particle to moisture is not higher than 3%；
3, dry particl is uniformly mixed in a mixer with croscarmellose sodium (additional) and lactose (additional)；
4, stearic acid is added, is uniformly mixed；
5, required product is made in tabletting.
Comparative example 2
In addition to succinic acid is not added, remaining component and embodiment 4 are almost the same.
Preparation process:
1, material used is uniformly mixed；
2, required product is made in tabletting.
Embodiment 1-4 is the product obtained using succinic acid；Comparative example 1-2 is the product without using succinic acid.We
The stability of two kinds of products is studied, the content of Tenofovir in sample is measured, data are as follows.
Embodiment 3 and comparative example 1, embodiment 4 are similar to 2 prescription of comparative example, and succinic acid only is added in embodiment prescription.
The stability data of comparing embodiment 3 and comparative example 1 and embodiment 4 and comparative example 2, it can be seen that the product that succinic acid is added is steady
Stability qualitative and in the solution is better than the product for not adding succinic acid.
It can be seen that from aforementioned stable data using no matter the product of succinic acid uses wet granulation technology or dry method
Granulating process or direct tablet compressing technique, stability are substantially better than the product of unused succinic acid.
Claims (2)
1. a kind of Pharmaceutical composition of tenofovir disoproxil fumarate, the fumaric acid tenofovir two comprising 25%-60%
Pyrrole furan ester, the stabilizer of 5%-30%, the filler of 30%-50%, the adhesive of 0%-5%, the disintegrating agent of 1%-5%,
The lubricant of 0.5%-5%, the above content by weight percentage, and weight percentage of each component summation be 100%；Wherein
The stabilizer is succinic acid, and the filler is selected from microcrystalline cellulose, lactose, mannitol, pregelatinized starch, starch, described
Disintegrating agent is selected from crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, described
Lubricant is selected from magnesium stearate, stearic acid, sodium stearyl fumarate, rilanit special.
2. composition as described in claim 1, the weight percent content of the stabilizer is 10%~20%, and each component weight
Measuring percentage summation is 100%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310638483.3A CN104688747B (en) | 2013-12-04 | 2013-12-04 | Pharmaceutical composition comprising tenofovir disoproxil fumarate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310638483.3A CN104688747B (en) | 2013-12-04 | 2013-12-04 | Pharmaceutical composition comprising tenofovir disoproxil fumarate |
Publications (2)
| Publication Number | Publication Date |
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| CN104688747A CN104688747A (en) | 2015-06-10 |
| CN104688747B true CN104688747B (en) | 2019-04-12 |
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| CN201310638483.3A Active CN104688747B (en) | 2013-12-04 | 2013-12-04 | Pharmaceutical composition comprising tenofovir disoproxil fumarate |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110507625A (en) * | 2019-09-19 | 2019-11-29 | 苏州东瑞制药有限公司 | A kind of novel tenofovir disoproxil fumarate piece and preparation method thereof |
| CN113456651A (en) * | 2021-06-30 | 2021-10-01 | 无锡道科森医药有限公司 | Stable pharmaceutical composition of tenofovir disoproxil fumarate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE69809750T2 (en) * | 1997-07-25 | 2003-08-21 | Gilead Sciences Inc | NUCLEOTIDE ANALOG COMPOSITION AND SYNTHESIS PROCEDURE |
| EP2389929A1 (en) * | 2010-05-30 | 2011-11-30 | Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi | Pharmaceutical formulations of tenofovir |
| JP5932829B2 (en) * | 2010-12-10 | 2016-06-08 | シグマファーム ラボラトリーズ エルエルシー | Highly stable compositions of orally active nucleotide analogs or orally active nucleotide analog prodrugs |
| CN103127028A (en) * | 2013-03-14 | 2013-06-05 | 南京恒道医药科技有限公司 | Capsule containing tenofovir disoproxil fumarate |
| CN103211826A (en) * | 2013-05-14 | 2013-07-24 | 福建广生堂药业股份有限公司 | Antiviral pharmaceutical composition as well as preparation method and application thereof |
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