CN110251476B - Emtricitabine tenofovir pharmaceutical composition - Google Patents
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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Abstract
The invention provides a stable emtricitabine tenofovir pharmaceutical composition. The pharmaceutical composition prepared by the invention can effectively control the degradation of the effective components in the preparation and storage processes, and improve the physical and chemical stability of the medicine. The invention also relates to a preparation method and application of the pharmaceutical composition.
Description
Technical Field
The invention relates to the field of medicines, in particular to an emtricitabine tenofovir pharmaceutical composition and a preparation method thereof.
Background
The emtricitabine tenofovir tablets are compound preparations of emtricitabine and tenofovir disoproxil fumarate, the specification is that each tablet contains 200mg of emtricitabine and 300mg of tenofovir disoproxil fumarate, and the trade name is
Developed by gillidd science Inc (Gilead Sciences Inc.) in the united states, first marketed in the united states in 2004, for use in combination with other antiretroviral drugs to treat HIV-1 infections in adults and children over 12 years (inclusive), and to obtain FDA approval for pre-exposure prophylaxis in adults on day 5 and 11 in 2012, to reduce the risk of high risk individuals acquiring HIV-1 infections through sexual transmission (to prevent HIV-1 infections).
CN1738628A discloses a pharmaceutical composition of emtricitabine and tenofovir disoproxil fumarate, which is prepared by wet granulation with an aqueous solution, followed by addition of an ultra-granular (extragrannlar) component, followed by addition of magnesium stearate and compression to give tablets. The tablets may be further coated with a film.
In addition, researches find that the solubility of the emtricitabine is good, but the viscosity after dissolution is large, the emtricitabine prepared by the conventional tablet preparation process is slow to dissolve out, and the dissolution is reduced after the emtricitabine is placed for a long time. The emtricitabine has large viscosity after meeting water, a layer of film is easily formed on the surface of the medicine, water molecules are prevented from entering, and the disintegrant is difficult to rapidly exert the function, so that the tablet is slowly disintegrated, and the medicine dissolution is influenced. Tenofovir disoproxil fumarate is unstable to water and heat and easy to degrade, and the stability of the tablet and the release of active ingredients are affected by improper selection of auxiliary materials used for preparing the tablet and unreasonable preparation process.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition of emtricitabine and tenofovir disoproxil fumarate and a preparation method thereof, wherein the pharmaceutical composition can effectively control the degradation of active ingredients and the change of crystal forms of the active ingredients in the preparation and storage processes, and improve the physical and chemical stability of the medicine. The invention adopts isopropanol for wet granulation, and can obviously improve the stability of the emtricitabine and tenofovir disoproxil pharmaceutical composition.
The invention provides a tablet of emtricitabine and tenofovir disoproxil fumarate, which has the in vitro dissolution behavior similar to that of Truvada, and can effectively control the degradation of effective components in the preparation and storage processes and improve the physical and chemical stability of the medicine.
The compositions of the present invention may be used in combination with other antiretroviral drugs for the treatment of viral infections, particularly for the treatment of HIV infections.
The invention provides a pharmaceutical composition, which comprises the following components: emtricitabine, tenofovir and pharmaceutically acceptable auxiliary materials.
The tenofovir in the pharmaceutical composition is selected from tenofovir disoproxil fumarate.
The pharmaceutically acceptable auxiliary materials in the pharmaceutical composition comprise a filler, a binder, a wetting agent, a disintegrating agent, a lubricant and/or an optional coating material.
The bulking agent in the above pharmaceutical composition is selected from pregelatinized starch and mannitol.
The disintegrant in the pharmaceutical composition is selected from croscarmellose sodium.
The humectant in the above pharmaceutical composition is selected from isopropanol.
The lubricant in the pharmaceutical composition is selected from magnesium stearate.
The optional coating material in the above pharmaceutical composition is selected from Opadry. The opadry is a mixture of materials including optional film formers, lubricants, plasticizers, anti-tack agents, thickeners, colorants, anti-foaming agents, opacifiers, and the like.
In a preferred embodiment, the pharmaceutical composition comprises, in weight percent, emtricitabine 20%, tenofovir disoproxil fumarate 30%, disintegrant 5%, filler and/or binder 43%, and lubricant 2%.
In a preferred embodiment, the pharmaceutical composition comprises, in weight percent, emtricitabine 20%, tenofovir disoproxil fumarate 30%, mannitol 30.5%, pregelatinized starch 12.5%, croscarmellose sodium 5% and magnesium stearate 2%.
In a preferred embodiment, the disintegrant is selected from the group consisting of croscarmellose sodium; the bulking agent is selected from pregelatinized starch and mannitol; the lubricant is selected from magnesium stearate.
In a preferred embodiment, the pharmaceutical composition is prepared into tablets by wet granulation and tabletting, wherein the wetting agent used in the wet granulation process is isopropanol.
A process for preparing a coated tablet containing the above optional pharmaceutical composition by the steps of:
1) crushing emtricitabine and sieving the emtricitabine with a 80-mesh sieve for later use; sieving tenofovir disoproxil fumarate with a 40-mesh sieve for dispersion for later use;
2) putting a disintegrating agent, a filling agent and/or an adhesive in the composition, the emtricitabine prepared in the step 1) and tenofovir disoproxil fumarate into a multi-directional motion mixer, and mixing to obtain premixed medicinal powder;
3) putting the premixed medicinal powder into a high-efficiency wet mixing granulator, adding isopropanol, stirring to prepare a soft material, sieving the soft material with a 16-mesh sieve, drying, and grading the dried granules with a 20-mesh sieve;
4) tabletting and coating: putting the product obtained in the step 3) and a lubricant into a multi-directional motion mixer, mixing, tabletting and coating film coat.
In a preferred embodiment, the disintegrant in the above preparation method is preferably croscarmellose sodium; the filler and/or binder is preferably pregelatinized starch and mannitol; the lubricant is preferably magnesium stearate.
In a preferred embodiment, the coating used in the coating film coating in the above preparation method is preferably opadry. The opadry is a mixture of materials comprising optional film forming agents, lubricants, plasticizers, anti-tack agents, thickeners, colorants, anti-foaming agents, opacifiers, and the like
A coated tablet obtained by the above preparation method.
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
Example 1
The preparation method comprises the following steps: isopropanol serves as a granulating wetting agent, is removed during drying, and floats in the range of 80% to 120% of theoretical values during the softening process, as the case may be. Special requirements of production environment: the following production environments require a relative humidity below 50%. Sieving tenofovir disoproxil fumarate with a 40-mesh sieve for dispersion for later use; crushing emtricitabine and sieving the emtricitabine with a 80-mesh sieve for later use; drying mannitol at 85 + -5 deg.C until water content is less than 0.5%, and drying pregelatinized starch and croscarmellose sodium at 90 + -5 deg.C until water content is less than 1.5%; drying magnesium stearate at 70 + -5 deg.C until water content is less than 2.5%; putting pregelatinized starch, croscarmellose sodium, emtricitabine, tenofovir disoproxil fumarate and mannitol into a multi-directional motion mixer, and mixing to obtain premixed medicinal powder. Putting the premixed medicinal powder into a high-efficiency wet mixing granulator, slowly adding isopropanol, controlling stirring, and granulating the prepared soft material by using a 16-mesh sieve; drying the obtained soft material at 50 + -5 deg.C until the water content is less than 1.5%, and grading with 20 mesh sieve. Adding magnesium stearate, mixing, tabletting, and coating with film.
Example 2 (prepared by reference to CN 1738628A)
The preparation method comprises the following steps: purified water is used as a granulation wetting agent, removed during drying, and floated in the range of 80% to 120% of theoretical values during the process of making soft mass, as the case may be. Special requirements of production environment: the following production environments require a relative humidity below 50%. Sieving tenofovir disoproxil fumarate with a 40-mesh sieve for dispersion for later use; crushing emtricitabine and sieving the emtricitabine with a 80-mesh sieve for later use; drying lactose monohydrate, pregelatinized starch, microcrystalline cellulose and croscarmellose sodium at 90 + -5 deg.C to water content of less than 1.5%; drying magnesium stearate at 70 + -5 deg.C until water content is less than 1.5%; adding croscarmellose sodium, emtricitabine, tenofovir disoproxil fumarate, lactose monohydrate, and microcrystalline cellulose into a multi-directional motion mixer, and mixing to obtain premixed medicinal powder. Putting the premixed medicinal powder into a high-efficiency wet mixing granulator, slowly adding purified water, controlling stirring, and granulating the prepared soft material by using a 16-mesh sieve; drying the obtained soft material at 50 + -5 deg.C until the water content is less than 1.5%, and grading with 20 mesh sieve. Adding magnesium stearate, mixing, tabletting, and coating with film.
Example 3
The results of comparing the dissolution rates of the samples prepared in examples 1 to 2 with those of the original sample in 900ml of 0.01mol/L hydrochloric acid solution by the dissolution rate measurement method (second method 0931, the fourth general rule of pharmacopoeia 2015, China) are shown in tables 1 to 2.
TABLE 1 dissolution curve results of emtricitabine in the present invention and the commercial product Truvada
TABLE 2 dissolution Curve results of the tenofovir disoproxil in the present invention and the commercial product Truvada
The results show that the invention releases more quickly than the original ground product and has the advantage of quicker dissolution when being used as a quick release preparation.
Example 4
The samples prepared according to examples 1-2 and the original ground product Truvada were placed at 25 + -2 deg.C and 60% + -5% humidity for 9 months and at 40 + -2 deg.C and 75% + -5% humidity for 6 months, and the impurity comparison results are shown in Table 3.
TABLE 3 comparative study results of the substances related to Truvada, a product sold in the original research
The test results show that the maximum impurities and the total amount of the impurities of the invention are better than those of the original ground product when the invention and the original ground product are placed for 9 months under the conditions of the temperature of 25 +/-2 ℃ and the humidity of 60% +/-5% and are placed for 6 months under the conditions of the temperature of 40 +/-2 ℃ and the humidity of 75% +/-5%.
Claims (2)
1. A method for preparing a pharmaceutical composition, comprising: the pharmaceutical composition consists of 20 percent of emtricitabine, 30 percent of tenofovir disoproxil fumarate, 30.5 percent of mannitol, 12.5 percent of pregelatinized starch, 5 percent of croscarmellose sodium and 2 percent of magnesium stearate in percentage by weight; the pharmaceutical composition is prepared into tablets through wet granulation and tabletting, wherein the wetting agent used in the wet granulation process is isopropanol, and the tablets are prepared through the following steps:
1) crushing emtricitabine and sieving the emtricitabine with a 80-mesh sieve for later use; sieving tenofovir disoproxil fumarate with a 40-mesh sieve for dispersion for later use; drying mannitol at 85 + -5 deg.C until water content is less than 0.5%; drying pregelatinized starch and croscarmellose sodium at 90 + -5 deg.C until water content is less than 1.5%; drying magnesium stearate at 70 + -5 deg.C until the water content is less than 2.5%;
2) putting the croscarmellose sodium prepared in the step 1), mannitol, pregelatinized starch, emtricitabine and tenofovir disoproxil fumarate into a multi-directional motion mixer, and mixing to obtain premixed medicinal powder;
3) putting the premixed medicinal powder into a high-efficiency wet mixing granulator, adding a wetting agent isopropanol, stirring to prepare a soft material, sieving the soft material with a 16-mesh sieve, drying, and grading the dried granules with a 20-mesh sieve;
4) tabletting and coating: putting the product obtained in the step 3) and magnesium stearate into a multidirectional motion mixer, mixing, tabletting and coating film coat by Opadry;
the preparation is carried out in a production environment with a relative humidity below 50%.
2. A coated tablet obtained by the production method according to claim 1.
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| CN201910705151.XA CN110251476B (en) | 2019-08-01 | 2019-08-01 | Emtricitabine tenofovir pharmaceutical composition |
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| CN201910705151.XA CN110251476B (en) | 2019-08-01 | 2019-08-01 | Emtricitabine tenofovir pharmaceutical composition |
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| CN112274488B (en) * | 2020-10-22 | 2022-08-26 | 安徽贝克生物制药有限公司 | Emtricitabine and tenofovir compound tablet and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1738628A (en) * | 2003-01-14 | 2006-02-22 | 吉里德科学公司 | Compositions and methods for combination antiviral therapy |
| CN102123700A (en) * | 2008-05-02 | 2011-07-13 | 吉里德科学公司 | The use of solid carrier particles to improve the processability of a pharmaceutical agent |
| CN102670629A (en) * | 2003-01-14 | 2012-09-19 | 吉里德科学公司 | Compositions and methods for combination antiviral therapy |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| CN107334772A (en) * | 2016-07-15 | 2017-11-10 | 安徽贝克生物制药有限公司 | A kind of antiretroviral drugs composition |
| CN107847450A (en) * | 2015-06-30 | 2018-03-27 | 吉利德科学公司 | Pharmaceutical preparation comprising tenofovir and emtricitabine |
-
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- 2019-08-01 CN CN201910705151.XA patent/CN110251476B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1738628A (en) * | 2003-01-14 | 2006-02-22 | 吉里德科学公司 | Compositions and methods for combination antiviral therapy |
| CN102670629A (en) * | 2003-01-14 | 2012-09-19 | 吉里德科学公司 | Compositions and methods for combination antiviral therapy |
| CN102123700A (en) * | 2008-05-02 | 2011-07-13 | 吉里德科学公司 | The use of solid carrier particles to improve the processability of a pharmaceutical agent |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| CN107847450A (en) * | 2015-06-30 | 2018-03-27 | 吉利德科学公司 | Pharmaceutical preparation comprising tenofovir and emtricitabine |
| CN107334772A (en) * | 2016-07-15 | 2017-11-10 | 安徽贝克生物制药有限公司 | A kind of antiretroviral drugs composition |
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