CN106619662B - Oral dry suspension containing tenofovir disoproxil fumarate and preparation method thereof - Google Patents
Oral dry suspension containing tenofovir disoproxil fumarate and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an oral dry suspension containing tenofovir disoproxil fumarate and a preparation method thereof, wherein the oral dry suspension is prepared from the following components in parts by mass: 40 parts of raw materials, 200-800 parts of carriers and 40-300 parts of pharmaceutically acceptable auxiliary materials; wherein the raw material is tenofovir disoproxil fumarate or a composition of tenofovir disoproxil fumarate and emtricitabine; the carrier is one or more of polyethylene glycol, glyceryl monostearate, polyacrylic resin and ethyl cellulose; the pharmaceutically acceptable adjuvants include suspending agent, lubricant and correctant. The oral dry suspension containing tenofovir disoproxil fumarate is stable in property, suitable for patients to take, good in dissolution rate, simple in production process and suitable for industrial scale operation.
Description
Technical Field
The invention relates to an oral dry suspension containing tenofovir disoproxil fumarate, and belongs to the technical field of pharmaceutical preparations.
Background
Tenofovir disoproxil fumarate (Tenofovir fumarate, Tenofovir disoproxil fumarate) is a prodrug of Tenofovir, a drug with no/low drug resistance and low toxicity against hepatitis B virus and HIV, which is a novel nucleotide reverse transcriptase inhibitor, which is hydrolyzed into Tenofovir after oral administration, and then phosphorylated by cellular kinases to produce a pharmacologically active metabolite Tenofovir diphosphate that competes with 5 '-deoxyadenosine triphosphate to participate in the synthesis of viral DNA, which after entering viral DNA, due to the lack of 3' -OH groups, is hindered in DNA elongation and thus blocks viral replication, Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β and mitochondrial DNA polymerase γ.
Patent CN 103330683B discloses a fine granule of tenofovir disoproxil fumarate, which is obtained by hot-melting and extruding a mixture of tenofovir disoproxil fumarate and a sweetening agent and a copolymer for hot extrusion at 120-150 ℃ and then crushing the mixture into fine granules with the grain diameter less than or equal to 30 meshes. There are reports in the literature that: the tenofovir disoproxil fumarate has poor chemical stability under the conditions of high temperature and high humidity, and is easy to degrade. The method of patent CN 103330683B cannot ensure the stability of tenofovir disoproxil fumarate, and studies show that the tenofovir disoproxil fumarate is unstable in the solution state, and the content is reduced and impurities are increased due to hydrolysis. Accordingly, a stable dosage form comprising tenofovir disoproxil fumarate suitable for patient administration is sought.
At present, tenofovir disoproxil fumarate tablets are marketed in the United states, European Union, Australia, China and the like, but the tenofovir disoproxil fumarate easily absorbs moisture to hydrolyze and needs to be stored hermetically in storage, and the traditional method is to coat the tablets by a gastric-soluble film coat for moisture protection. However, for special patients with dysphagia, children, the elderly and the like, peripheral factors restrict their ability to take drugs normally. The currently approved preparations for emtricitabine are emtricitabine capsules (specification: 200mg), compound preparations Truvada (containing 300mg of tenofovir disoproxil fumarate and 200mg of emtricitabine), compound preparations Atripla (containing 300mg of tenofovir disoproxil fumarate, 200mg of emtricitabine and 200mg of efavirenz), and the compound preparations containing tenofovir DF and emtricitabine are not only chemically stable, but also have synergistic effect and/or can reduce the side effect of the individual tenofovir DF and emtricitabine or both. Such compositions may increase patient compliance in view of the reduction in pill burden and the simplification of the dosing regimen. Accordingly, a stable dosage form suitable for patient administration is sought which further comprises a combination of tenofovir disoproxil fumarate and emtricitabine, wherein the ratio of tenofovir disoproxil fumarate to emtricitabine is 3: 2.
Disclosure of Invention
In order to solve the technical problems, the invention provides an oral dry suspension containing tenofovir disoproxil fumarate and a preparation method thereof.
The invention adopts the following technical scheme:
an oral dry suspension containing tenofovir disoproxil fumarate is prepared from the following components in parts by mass: 40 parts of raw materials, 200-800 parts of carriers and 40-300 parts of pharmaceutically acceptable auxiliary materials;
the raw material is tenofovir disoproxil fumarate or a composition of tenofovir disoproxil fumarate and emtricitabine;
the carrier is one or more of polyethylene glycol, glyceryl monostearate, polyacrylic resin and ethyl cellulose;
the pharmaceutically acceptable auxiliary materials comprise a suspending agent, a lubricating agent and a flavoring agent;
the suspending agent is one or more of colloidal microcrystalline cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose; the lubricant is one or more of magnesium stearate, stearic acid, talcum powder and superfine silica gel powder; the correctant is one or more of mannitol, sorbitol, aspartame, stevioside, and essence.
Further, the pharmaceutically acceptable auxiliary materials also comprise a binder, wherein the binder is one or more of water, ethanol, cellulose derivatives and povidone, and the mass usage of the binder is 15-40% of the mass of all materials.
Furthermore, the pharmaceutically acceptable auxiliary materials comprise a suspending agent, a lubricating agent, a binding agent and a flavoring agent.
Further, the pharmaceutically acceptable auxiliary materials comprise a suspending agent, a lubricating agent and a flavoring agent.
Further, the raw materials are a composition of tenofovir disoproxil fumarate and emtricitabine, wherein the mass ratio of the tenofovir disoproxil fumarate to the emtricitabine composition is 3: 2. The particle size D50 of the raw materials of tenofovir disoproxil fumarate and emtricitabine adopted by the invention is less than 20 μm.
Further, the carrier is polyethylene glycol 6000 or glyceryl monostearate.
Further, the mass ratio of the raw material to the carrier is preferably 40:300 to 800, more preferably 40:400 to 800.
Further, the raw materials comprise, by weight, 20-200 parts of a suspending agent, 2-10 parts of a lubricant and 1-35 parts of a flavoring agent.
Furthermore, the raw materials comprise, by weight, 40 parts of a suspending agent, 20-200 parts of a lubricating agent and 2-35 parts of a flavoring agent.
The oral dry suspension containing tenofovir disoproxil fumarate is preferably prepared from the following components in parts by mass: 40 parts of raw materials, 400-800 parts of carriers and 40-300 parts of auxiliary materials; the raw material is tenofovir disoproxil fumarate or a composition of tenofovir disoproxil fumarate and emtricitabine in a mass ratio of 3: 2;
the carrier is polyethylene glycol 6000 or glyceryl monostearate;
the pharmaceutically acceptable auxiliary materials are a combination of a suspending agent, a lubricant and a flavoring agent or a combination of a suspending agent, a lubricant, an adhesive and a flavoring agent;
the suspending agent is one or more of colloidal microcrystalline cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose; the lubricant is one or more of magnesium stearate, stearic acid, talcum powder and superfine silica gel powder; the adhesive is one or more of water, ethanol, cellulose derivatives and polyvidone; the correctant is one or more of mannitol, sorbitol, aspartame, stevioside, and essence.
The invention further discloses a preparation method of the oral dry suspension containing tenofovir disoproxil fumarate, which comprises the following steps:
(1) preparing a solid dispersion by a solvent method or a solvent-melting method by using tenofovir disoproxil fumarate or a mixture of tenofovir disoproxil fumarate and emtricitabine and a carrier; wherein the solvent adopted by the solvent method is methanol or ethanol, the recovered solvent adopts a reduced pressure distillation method, and the temperature of the recovered solvent is controlled to be 45-60 ℃; the solvent adopted by the solvent-melting method is methanol or ethanol, the temperature of the melting method is 60-80 ℃, the solvent is recovered by a reduced pressure distillation method, and the temperature of the recovered solvent is controlled to be 45-60 ℃;
(2) and mixing the solid dispersion with pharmaceutically acceptable auxiliary materials to prepare the oral dry suspension containing tenofovir disoproxil fumarate.
In the step (1) of the preparation method, a common melting method is abandoned in the preparation method of the solid dispersion, and experiments prove that the tenofovir disoproxil fumarate and the carrier melt at about 120 ℃ to greatly degrade the tenofovir disoproxil fumarate, and similarly, the composition of the tenofovir disoproxil fumarate and emtricitabine and the carrier melt at about 140 ℃ to greatly degrade the tenofovir disoproxil fumarate serving as a raw material, and the content of emtricitabine is slightly reduced.
In step (2) of the above preparation method, the mixing and granulating steps may be optionally performed using a mechanical device with stirring function and a dry granulator known in the art, for example: a mixer of HLSG-200 type from pharmaceutical machinery, Inc. in south of the Yangtze province and an LGS200 dry granulator from Longli technology, Inc. in Beijing, China can be used. Optionally, it can also be carried out using one-step pelletizers known in the art, such as: the FL series one-step granulation dryer of the whole product pharmaceutical equipment limited of yozhou city may be used. It is also optionally possible to use mechanical devices with stirring functions known in the art, such as: a mixer of model HLSG-200 of pharmaceutical machinery limited, south of the river may be used.
The oral dry suspension containing tenofovir disoproxil fumarate prepared by the invention can be packaged by a powder packaging machine or a granule packaging machine known in the art, for example: a JEV-280P powder packaging machine and a JEV-400G granule packaging machine of Jiuy machinery Co., Ltd, Wenzhou may be used.
The method can be used for preparing dry suspensions, and the prepared samples meet the quality requirements related to the dry suspensions in the Chinese pharmacopoeia of 2015 edition, so that the dry suspensions are convenient for patients to take.
The invention has the beneficial effects that: the oral dry suspension containing tenofovir disoproxil fumarate provided by the invention is stable in property, suitable for patients to take, good in dissolution rate, and especially suitable for children and old people patients, and the absorption of the medicine is not affected basically. In addition, the oral dry suspension is simple in production process, convenient and fast to operate and suitable for industrial scale operation.
Detailed Description
For a further understanding of the present invention, reference will now be made in detail to the following examples, which are intended to be illustrative, but not limiting, of the invention.
Example 1
Determination of tenofovir disoproxil fumarate in solid dispersion prepared by melting at ① 120 DEG C
Taking 3g of tenofovir disoproxil fumarate (D50 ═ 9.56 μm) and 600060g of polyethylene glycol, heating in an oil bath at 120 ℃ while stirring to melt the two components into liquid, stirring for 5min, cooling, taking out, measuring the content and total impurities of the tenofovir disoproxil fumarate in the solid dispersion by a high performance liquid chromatography, and comparing with the raw material medicaments, wherein the results are as follows:
from the above table, it can be seen that after tenofovir disoproxil fumarate is melted with polyethylene glycol 6000 at 120 ℃, the content is greatly reduced and related substances are obviously increased compared with the bulk drug.
Determination of tenofovir disoproxil fumarate and emtricitabine in solid dispersion prepared by melting at ② 140 DEG C
Taking 3g of tenofovir disoproxil fumarate (D50 ═ 9.56 μm), 2g of emtricitabine (D50 ═ 11.06 μm) and 600060g of polyethylene glycol, heating in an oil bath at 140 ℃ while stirring to melt the two components into liquid state, stirring for 5min, cooling, taking out, measuring the contents of the tenofovir disoproxil fumarate and the emtricitabine in the solid dispersion by a high performance liquid phase method, and comparing with the raw material medicaments, wherein the results are as follows:
from the above table, it can be seen that after tenofovir disoproxil fumarate and emtricitabine are melted with polyethylene glycol 6000 at 140 ℃ to prepare a solid dispersion, compared with the corresponding bulk drug, the content of tenofovir disoproxil fumarate is greatly reduced, and related substances are obviously increased; the content of emtricitabine is reduced slightly, and related substances are increased.
Trial ① and trial ② show that the melt process is not suitable for the preparation of solid dispersions containing tenofovir disoproxil fumarate.
Determination of tenofovir disoproxil fumarate in solid dispersion prepared by solvent-melting method at ③ 60 DEG C
Taking 3g of tenofovir disoproxil fumarate (D50 is 9.56 mu m) and 600050g of polyethylene glycol, heating the polyethylene glycol 6000 in an oil bath under stirring at 60 ℃ to melt, dissolving the tenofovir disoproxil fumarate in an appropriate amount of ethanol, adding the dissolved tenofovir disoproxil fumarate into a polyethylene glycol melt, stirring for 5min, cooling, taking out, recovering ethanol by a reduced pressure distillation method at 50 ℃, determining the content of the tenofovir disoproxil fumarate in the solid dispersion and related substances by a high performance liquid chromatography method, and comparing the content with the raw material medicaments, wherein the results are as follows:
from the above table, it can be seen that when the tenofovir disoproxil fumarate and polyethylene glycol 6000 are prepared into the solid dispersion at 60 ℃ by the solvent-melting method, the content is slightly reduced and related substances are increased a little compared with the bulk drug, and the content is still within an acceptable range.
④ determination of tenofovir disoproxil fumarate in solid dispersion prepared by solvent method
Taking 3g of tenofovir disoproxil fumarate (D50 is 9.56 mu m) and 600050g of polyethylene glycol, dissolving the tenofovir disoproxil fumarate and the polyethylene glycol 6000 by using a proper amount of ethanol, stirring for 5min, taking out, recovering the ethanol by a reduced pressure distillation method at 50 ℃, determining the content of the tenofovir disoproxil fumarate in the solid dispersion by using a high performance liquid chromatography, and comparing with the raw material medicaments, wherein the results are as follows:
from the above table, it can be seen that when the tenofovir disoproxil fumarate and the polyethylene glycol 6000 are prepared into the solid dispersion by the solvent method, the content is slightly reduced, and the related substances are increased a little and are still within the acceptable range compared with the bulk drug.
⑤ determination of tenofovir disoproxil fumarate and emtricitabine in solid dispersion prepared by solvent method takes 3g of tenofovir disoproxil fumarate (D50 ═ 9.56 μm), 2g of emtricitabine (D50 ═ 11.06 μm) and 600060g of polyethylene glycol, dissolves the tenofovir disoproxil fumarate, emtricitabine and polyethylene glycol 6000 with right amount of methanol and then stirs for 5min, takes out and uses high performance liquid phase method to determine the contents of tenofovir disoproxil fumarate and emtricitabine in solid dispersion and related substances after ethanol recovery at 50 ℃ by vacuum distillation method, and the results are as follows:
from the above table, it can be seen that the content of the solid dispersion prepared by tenofovir disoproxil fumarate, emtricitabine and polyethylene glycol 6000 through a solvent method is slightly reduced and the related substances are increased a little in an acceptable range compared with the raw material medicines.
Example 2
The oral suspension of tenofovir disoproxil fumarate comprises the following components:
the preparation process of the oral dry suspension comprises the following steps:
(1) preparation of solid dispersion: taking 40g of tenofovir disoproxil fumarate (D50 ═ 9.56 mu m) and 800g of polyethylene glycol, and dissolving the tenofovir disoproxil fumarate in ethanol for later use; melting polyethylene glycol in oil bath at 60 deg.C, adding tenofovir disoproxil fumarate ethanol solution, stirring, and distilling at 60 deg.C under reduced pressure to remove ethanol to obtain solid dispersion.
(2) And (3) granulating: taking colloidal microcrystalline cellulose
200g of aspartame, 2g of aspartame and the prepared solid dispersion are evenly mixed by sieving through a 60-mesh sieve, and dry granulation is carried out (the roller pressure is 70bar, the roller rotating speed is 12r/min, the material conveying speed is 60r/min), and the particle size of less than 60 meshes is controlled not to exceed 15%.
(3) Total mixing: 8g of magnesium stearate is taken and evenly mixed with the prepared granules, and the mixing time is 2 minutes.
(4) Packaging: packaging the granules with a granule packaging machine.
Example 3
The oral suspension of tenofovir disoproxil fumarate comprises the following components:
the preparation process of the oral dry suspension comprises the following steps:
(1) preparation of solid dispersion: taking 40g of tenofovir disoproxil fumarate (D50 ═ 9.56 mu m) and 280g of glycerin monostearate, and dissolving the tenofovir disoproxil fumarate with ethanol for later use; dissolving glyceryl monostearate in ethanol, adding tenofovir disoproxil fumarate ethanol solution, stirring, and distilling at 60 deg.C under reduced pressure to remove ethanol to obtain solid dispersion.
(2) And (3) granulating: preparing a proper amount of povidone K30 into 8% aqueous solution for later use; taking colloidal microcrystalline cellulose
50g of aspartame, 1g of aspartame and 30g of mannitol are evenly mixed with the prepared solid dispersion by a 60-mesh sieve, and 93g of a proper amount of 8% povidone K30 aqueous solution is added for granulation by a one-step granulation method (the air inlet frequency is 25-30 Hz, the air inlet temperature is 60 ℃, the spraying pressure is 1.5MPa, and the spraying speed is 10ml/min), the water content is controlled to be less than 2%, and the particle proportion between 24 meshes and 100 meshes is controlled to be more than 85%.
(3) Total mixing: 8g of magnesium stearate is taken and evenly mixed with the prepared granules, and the mixing time is 2 minutes.
(4) Packaging: packaging the granules with a granule packaging machine.
Example 4
The oral suspension of tenofovir disoproxil fumarate comprises the following components:
the preparation process of the oral dry suspension comprises the following steps:
(1) preparation of solid dispersion: taking 40g of tenofovir disoproxil fumarate (D50 ═ 9.56 μm), 26.67g of emtricitabine (D50 ═ 11.06 μm) and 500g of glyceryl monostearate, and dissolving the tenofovir disoproxil fumarate and the emtricitabine in methanol for later use; dissolving glyceryl monostearate in methanol, adding tenofovir disoproxil fumarate methanol solution and emtricitabine methanol solution, stirring uniformly, and distilling under reduced pressure at 60 ℃ to remove the solvent methanol to obtain a solid dispersion for later use.
(2) And (3) granulating: taking a proper amount of hydroxypropyl methylcellulose to prepare 8% aqueous solution for later use; taking colloidal microcrystalline cellulose
150g of aspartame, 1g of aspartame, 30g of sorbitol and 3g of essence are evenly mixed with the prepared solid dispersion by sieving through a 60-mesh sieve, 215g of appropriate 8 percent hydroxypropyl methylcellulose water solution is added for granulation by a one-step granulation method (the air inlet frequency is 25-30 Hz, the air inlet temperature is 60 ℃, the spraying pressure is 1.5MPa, and the spraying speed is 10ml/min), the water content is controlled to be less than 2 percent, and the proportion of particles between 24 meshes and 100 meshes is more than 85 percent.
(3) Total mixing: 8g of magnesium stearate is taken and evenly mixed with the prepared granules, and the mixing time is 2 minutes.
(4) Packaging: packaging the granules with a granule packaging machine.
Example 5
The oral suspension of tenofovir disoproxil fumarate comprises the following components:
the preparation process of the oral dry suspension comprises the following steps:
(1) preparation of solid dispersion: taking 40g of tenofovir disoproxil fumarate (D50 ═ 9.56 μm), 26.67g of emtricitabine (D50 ═ 11.06 μm) and 600g of glyceryl monostearate, and dissolving the tenofovir disoproxil fumarate and the emtricitabine in methanol for later use; dissolving glyceryl monostearate in methanol, adding tenofovir disoproxil fumarate methanol solution and emtricitabine methanol solution, stirring uniformly, and distilling under reduced pressure at 60 ℃ to remove the solvent methanol to obtain a solid dispersion for later use.
(2) And (3) granulating: preparing a proper amount of ethanol into 30% ethanol water solution for later use; 50g of sodium carboxymethylcellulose, 1g of aspartame, 50g of mannitol and 3g of essence are taken to be evenly mixed with the prepared solid dispersion by a 60-mesh sieve, 265g of 30% ethanol water solution is added to be granulated by a one-step granulation method (the air inlet frequency is 25-30 Hz, the air inlet temperature is 60 ℃, the spraying pressure is 1.5MPa, the spraying speed is 10ml/min), the water content is controlled to be less than 2%, and the particle proportion between 24 meshes and 100 meshes is controlled to be more than 85%.
(3) Total mixing: and 8g of magnesium stearate and 3g of essence are uniformly mixed with the prepared granules for 2 minutes.
(4) Packaging: packaging the granules with a granule packaging machine.
Example 6
The oral suspension of tenofovir disoproxil fumarate comprises the following components:
the preparation process of the oral dry suspension comprises the following steps:
(1) preparation of solid dispersion: taking 40g of tenofovir disoproxil fumarate (D50 ═ 9.56 μm), 26.67g of emtricitabine (D50 ═ 11.06 μm) and 1100g of glycerin monostearate, and dissolving the tenofovir disoproxil fumarate and the emtricitabine in methanol for later use; dissolving glyceryl monostearate in methanol, adding tenofovir disoproxil fumarate methanol solution and emtricitabine methanol solution, stirring uniformly, and distilling under reduced pressure at 60 ℃ to remove the solvent methanol to obtain a solid dispersion for later use.
(2) And (3) granulating: 80g of sodium carboxymethylcellulose, 2g of stevioside and 50g of mannitol are taken to be evenly mixed with the prepared solid dispersion by a 60-mesh sieve, and dry granulation (the roller pressure is 70bar, the roller rotating speed is 12r/min, the material conveying speed is 60r/min) is carried out, wherein the granules with less than 60 meshes are controlled not to exceed 15%.
(3) Total mixing: 8g of talcum powder is taken and evenly mixed with the prepared granules, and the mixing time is 2 minutes.
(4) Packaging: packaging the granules with a granule packaging machine.
Example 7
The oral suspension of tenofovir disoproxil fumarate comprises the following components:
the preparation process of the oral dry suspension comprises the following steps:
(1) preparation of solid dispersion: taking 40g of tenofovir disoproxil fumarate (D50 ═ 9.56 μm), 26.67g of emtricitabine (D50 ═ 11.06 μm) and 900g of glyceryl monostearate, and dissolving the tenofovir disoproxil fumarate and the emtricitabine in methanol for later use; dissolving glyceryl monostearate in methanol, adding tenofovir disoproxil fumarate methanol solution and emtricitabine methanol solution, stirring uniformly, and distilling under reduced pressure at 60 ℃ to remove the solvent methanol to obtain a solid dispersion for later use.
(2) Mixing: 50g of sodium carboxymethylcellulose, 2g of stevioside and 50g of mannitol are taken to be mixed with the prepared solid dispersion evenly by sieving with a 60-mesh sieve.
(3) Total mixing: 8g of talcum powder is taken and evenly mixed with the prepared powder for 2 minutes.
(4) Packaging: packaging the powder with powder packaging machine.
Example 8
The oral suspension of tenofovir disoproxil fumarate comprises the following components:
the preparation process of the oral dry suspension comprises the following steps:
(1) preparation of solid dispersion: taking 40g of tenofovir disoproxil fumarate (D50 ═ 9.56 μm), 26.67g of emtricitabine (D50 ═ 11.06 μm) and 900g of polyacrylic resin, and dissolving the tenofovir disoproxil fumarate and the emtricitabine in methanol for later use; dissolving polyacrylic resin with methanol, adding tenofovir disoproxil fumarate methanol solution and emtricitabine methanol solution, stirring uniformly, and removing solvent methanol by reduced pressure distillation at 60 ℃ to obtain solid dispersion for later use.
(2) And (3) granulating: taking colloidal microcrystalline cellulose
300g, stevioside 2g and mannitol 50g are evenly mixed with the prepared solid dispersion by a 60-mesh sieve, and dry granulation (the roller pressure is 70bar, the roller rotating speed is 12r/min, the material conveying speed is 60r/min) is carried out, and the granules with less than 60 meshes are controlled not to exceed 15%.
(3) Total mixing: 8g of talcum powder is taken and evenly mixed with the prepared granules, and the mixing time is 2 minutes.
(4) Packaging: packaging the granules with a granule packaging machine.
Example 9
The oral suspension of tenofovir disoproxil fumarate comprises the following components:
the preparation process of the oral dry suspension comprises the following steps:
(1) preparation of solid dispersion: taking 40g of tenofovir disoproxil fumarate (D50 ═ 9.56 mu m), emtricitabine
26.67g (D50 ═ 11.06 μm) and 900g of ethyl cellulose, tenofovir disoproxil fumarate and emtricitabine were dissolved in methanol for use; dissolving ethyl cellulose in methanol, adding tenofovir disoproxil fumarate methanol solution and emtricitabine methanol solution, stirring uniformly, and removing the solvent methanol by reduced pressure distillation at 60 ℃ to obtain a solid dispersion for later use.
(2) And (3) granulating: taking colloidal microcrystalline cellulose
300g, stevioside 2g and mannitol 50g are evenly mixed with the prepared solid dispersion by a 60-mesh sieve, and dry granulation (the roller pressure is 70bar, the roller rotating speed is 12r/min, the material conveying speed is 60r/min) is carried out, and the granules with less than 60 meshes are controlled not to exceed 15%.
(3) Total mixing: 8g of talcum powder is taken and evenly mixed with the prepared granules, and the mixing time is 2 minutes.
(4) Packaging: packaging the granules with a granule packaging machine.
Example 10
The samples (sample equivalent to 40mg of tenofovir disoproxil fumarate) and the raw materials of examples 2-9 were taken, 12 healthy volunteers were selected respectively, half of each male and female were contained in the middle of the tongue, about 5ml of water was added dropwise, the mixture was left for 10s and spitted out, and the mouth was rinsed with warm water several times, the closest mouth feel was selected according to the following evaluation criteria and scored, and the scoring result for each group was the average of 12 volunteers, and the results are shown in the following table.
The taste evaluation standard is as follows: the taste is 16-20 min; slightly bitter for 11-15 minutes; can endure 6-10 minutes; the taste is better when the score is higher.
The data show that the oral dry suspension has very obvious bitterness when the ratio of the carrier to the raw materials is below 10: 1, and has slight bitterness when the ratio of the carrier to the raw materials reaches 10: 1; when the ratio of the carrier to the raw materials reaches 15: 1, the oral dry suspension has almost no bitter taste and acceptable mouthfeel. Tests show that the prepared solid dispersion can obviously mask bitter taste.
Example 11
The dissolution curve of the oral dry suspension of the present invention (taking a sample corresponding to 300mg of tenofovir disoproxil fumarate) was determined by the second method of dissolution and release determination of 0931 dissolution rate and release rate in the four general guidelines of the chinese pharmacopoeia 2015 edition, and the results are shown in the following table. Wherein the dissolution medium is 900ml of 0.01NHCL solution, the rotating speed is 50r/min, the determination is carried out by adopting an ultraviolet spectrophotometry, the determination wavelength of tenofovir disoproxil fumarate is 260nm, and the determination wavelength of emtricitabine is 280 nm.
Preparation of tenofovir disoproxil fumarate standard solution: taking about 22mg of tenofovir dipivoxil fumarate reference substance (batch number: 150103, self-made, purity of 99.0%), placing in a 100ml volumetric flask, adding a proper amount of dissolution medium, performing ultrasonic dissolution, adding the dissolution medium to the scale, shaking up, taking a 5ml to 25ml volumetric flask, diluting to the scale, and shaking up to obtain the finished product.
Preparation of tenofovir disoproxil fumarate sample solution: sampling at a specified time point, and filtering with 0.45 μm microporous membrane.
Preparation of emtricitabine standard solution: taking about 20.85mg of tenofovir dipivoxil fumarate reference substance (batch number: 150303, self-made, purity of 99.4%), placing in a 100ml volumetric flask, adding a proper amount of dissolution medium, performing ultrasonic dissolution, adding the dissolution medium to the scale, shaking up, taking 5ml to 50ml volumetric flask, diluting to the scale, and shaking up to obtain the tenofovir dipivoxil fumarate.
Preparation of emtricitabine sample solution: sampling at a specified time point, and filtering with 0.45 μm microporous membrane.
Different types of high molecular polymers and different drug-loading rates have certain influence on the dissolution rate, which is mainly reflected in 10 minutes and 20 minutes, but in general, the dissolution rate of 20min of the oral dry suspension raw materials of several examples is more than 85%, the dissolution rate of 30min is more than 90%, and the retention (emptying) time of T50% in the stomach of a human body is 15-20 minutes in a fasting state, so that the oral dry suspension does not influence the absorption of the drug basically.
Example 12
Taking a sample corresponding to 300mg of tenofovir disoproxil fumarate in examples 3-9, putting the sample into a measuring cylinder with a plug, adding water to 50min, sealing, shaking vigorously for 1 min, recording the starting height H0 of the suspension, standing for 3H, recording the final height H of the suspension, and calculating according to the following formula:
sedimentation volume ratio of H/H0
The results are shown in the following table:
| sample numbering | Volume ratio of sedimentation |
| Example 2 | 0.96 |
| Example 3 | 0.97 |
| Example 4 | 0.96 |
| Example 5 | 0.96 |
| Example 6 | 0.98 |
| Example 7 | 0.95 |
| Example 8 | 0.97 |
| Example 9 | 0.95 |
The above results show that the measured sedimentation volume ratios of the samples of examples 2 to 9 meet the requirements of the Chinese pharmacopoeia of 2015.
Example 13
The samples of examples 2-9 (corresponding to 300mg of tenofovir disoproxil fumarate) were taken, placed at 40 ℃ and 75% humidity for 6 months, and the content, total impurities and sedimentation volume ratio were measured and compared with the initial samples, and the results are shown in the following table:
after the samples of the examples 2-9 are placed under the conditions of 40 ℃ and 75% humidity for 6 months, the total impurities are slightly increased, the content and the sedimentation volume ratio are basically unchanged, and the relevant requirements are met. The sample of the invention has stable quality and is suitable for large-scale production.
Claims (10)
1. An oral dry suspension containing tenofovir disoproxil fumarate is prepared from the following components in parts by mass: 40 parts of raw materials, 200-800 parts of carriers and 40-300 parts of pharmaceutically acceptable auxiliary materials;
the raw material is tenofovir disoproxil fumarate or a composition of tenofovir disoproxil fumarate and emtricitabine, wherein the mass ratio of the tenofovir disoproxil fumarate to the emtricitabine composition is 3: 2;
the carrier is one or more of polyethylene glycol, glyceryl monostearate, polyacrylic resin and ethyl cellulose;
the pharmaceutically acceptable auxiliary materials comprise 20-200 parts of a suspending agent, 2-10 parts of a lubricating agent and 1-35 parts of a flavoring agent;
the suspending agent is one or more of colloidal microcrystalline cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose; the lubricant is one or more of magnesium stearate, stearic acid, talcum powder and superfine silica gel powder; the correctant is one or more of mannitol, sorbitol, aspartame, stevioside, and essence;
the preparation method of the oral dry suspension containing tenofovir disoproxil fumarate comprises the following steps:
(1) preparing a solid dispersion by a solvent method or a solvent-melting method by using tenofovir disoproxil fumarate or a mixture of tenofovir disoproxil fumarate and emtricitabine and a carrier; wherein the solvent adopted by the solvent method is methanol or ethanol, the recovered solvent adopts a reduced pressure distillation method, and the temperature of the recovered solvent is controlled to be 45-60 ℃; the solvent adopted by the solvent-melting method is methanol or ethanol, the temperature of the melting method is 60-80 ℃, the solvent is recovered by a reduced pressure distillation method, and the temperature of the recovered solvent is controlled to be 45-60 ℃;
(2) and mixing the solid dispersion with pharmaceutically acceptable auxiliary materials to prepare the oral dry suspension containing tenofovir disoproxil fumarate.
2. Oral dry suspension containing tenofovir disoproxil fumarate according to claim 1, characterized in that: the pharmaceutically acceptable auxiliary materials also comprise a binder, wherein the binder is one or more of water, ethanol, cellulose derivatives and povidone, so that the mass usage of the binder accounts for 15-40% of the mass of all the materials.
3. Oral dry suspension containing tenofovir disoproxil fumarate according to claim 2, characterized in that: the pharmaceutically acceptable auxiliary materials comprise a suspending agent, a lubricant, an adhesive and a flavoring agent.
4. Oral dry suspension containing tenofovir disoproxil fumarate according to claim 1, characterized in that: the pharmaceutically acceptable auxiliary materials comprise a suspending agent, a lubricating agent and a flavoring agent.
5. Oral dry suspension containing tenofovir disoproxil fumarate according to any one of claims 1 to 4, characterized in that: the raw material particle size D50 of the tenofovir disoproxil fumarate and the emtricitabine is less than 20 mu m.
6. Oral dry suspension containing tenofovir disoproxil fumarate according to any one of claims 1 to 4, characterized in that: the carrier is polyethylene glycol 6000 or glyceryl monostearate.
7. Oral dry suspension containing tenofovir disoproxil fumarate according to any one of claims 1 to 4, characterized in that: the mass ratio of the raw materials to the carrier is 40: 300-800.
8. Oral dry suspension containing tenofovir disoproxil fumarate according to any one of claims 1 to 4, characterized in that: the mass ratio of the raw materials to the carrier is 40: 400-800.
9. Oral dry suspension containing tenofovir disoproxil fumarate according to claim 1, characterized in that: the oral dry suspension containing tenofovir disoproxil fumarate is prepared from the following components in parts by mass: 40 parts of raw materials, 400-800 parts of carriers and 40-300 parts of auxiliary materials; the raw materials are tenofovir disoproxil fumarate or a composition of the tenofovir disoproxil fumarate and emtricitabine according to the mass ratio of 3:2, and the particle sizes D50 of the raw materials of the tenofovir disoproxil fumarate and the emtricitabine are both smaller than 20 mu m;
the carrier is polyethylene glycol 6000 or glyceryl monostearate;
the pharmaceutically acceptable auxiliary materials are a combination of a suspending agent, a lubricant and a flavoring agent or a combination of a suspending agent, a lubricant, an adhesive and a flavoring agent;
the suspending agent is one or more of colloidal microcrystalline cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose; the lubricant is one or more of magnesium stearate, stearic acid, talcum powder and superfine silica gel powder; the adhesive is one or more of water, ethanol, cellulose derivatives and polyvidone; the correctant is one or more of mannitol, sorbitol, aspartame, stevioside, and essence.
10. Oral dry suspension containing tenofovir disoproxil fumarate according to any one of claims 1 to 4, characterized in that: the lubricant is 4-10 parts by weight of the raw materials, and the flavoring agent is 2-35 parts by weight of the raw materials.
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| CN110917197A (en) * | 2019-12-31 | 2020-03-27 | 常州恒邦药业有限公司 | Pharmaceutical composition of tenofovir disoproxil fumarate and emtricitabine and preparation method thereof |
| CN111773230A (en) * | 2020-08-17 | 2020-10-16 | 深圳市道科思医药有限公司 | Hot-melt extruded tenofovir disoproxil pharmaceutical composition |
| CN113599366B (en) * | 2021-08-12 | 2022-11-11 | 南京海纳医药科技股份有限公司 | Tenofovir disoproxil fumarate granules and preparation method thereof |
| CN114948970A (en) * | 2022-06-07 | 2022-08-30 | 安徽贝克生物制药有限公司 | Efavirenz-containing pharmaceutical composition and preparation method thereof |
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| KR20150117497A (en) * | 2014-04-10 | 2015-10-20 | 성광제약주식회사 | Tenofovir Disoproxil Fumarate film preparation and preparing method thereof |
| WO2016044182A1 (en) * | 2014-09-16 | 2016-03-24 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
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| CN102920673A (en) * | 2012-11-23 | 2013-02-13 | 南京森博医药研发有限公司 | Amorphous adefovir dipivoxil solid dispersion oral preparation and preparation method thereof |
| CN103330683B (en) * | 2013-06-26 | 2014-12-03 | 神威药业集团有限公司 | Tenofovir disoproxil fumarate fine granules |
| CN105147628A (en) * | 2015-08-24 | 2015-12-16 | 苏州弘森药业有限公司 | TDF (tenofovir disoproxil fumarate) pellets and preparation method thereof |
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| KR20150117497A (en) * | 2014-04-10 | 2015-10-20 | 성광제약주식회사 | Tenofovir Disoproxil Fumarate film preparation and preparing method thereof |
| WO2016044182A1 (en) * | 2014-09-16 | 2016-03-24 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
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