CN114404377B

CN114404377B - Abacavir, lamivudine and efavirenz compound tablet and preparation method thereof

Info

Publication number: CN114404377B
Application number: CN202210020801.9A
Authority: CN
Inventors: 陈小峰; 王哲; 王志邦; 朱礼根; 柏俊; 廖结海; 郭立新; 刘安友; 何麓璐; 刘斌
Original assignee: Anhui Biochem Bio Pharmaceutical Co ltd
Current assignee: Anhui Biochem Bio Pharmaceutical Co ltd
Priority date: 2022-01-10
Filing date: 2022-01-10
Publication date: 2023-07-25
Anticipated expiration: 2042-01-10
Also published as: CN114404377A

Abstract

The invention provides abacavir, lamivudine and efavirenz compound tablets and a preparation method thereof, wherein the compound tablets are formed by mixing and tabletting 11-15 parts of first particles, 9-12 parts of second particles and 0.8-2 parts of glidant, and the weight ratio of the first particles to the second particles is 1-1.5:1. According to the compound tablet disclosed by the invention, the first particles are prepared by coating abacavir with efavirenz, the second particles are prepared by mixing efavirenz and lamivudine, the efavirenz is contained on the surfaces of the particles, only a glidant is added for mixing, the dosage of auxiliary materials is small, and the uniformity of the tablet is good.

Description

Abacavir, lamivudine and efavirenz compound tablet and preparation method thereof

Technical Field

The invention relates to the technical field of pharmaceutical preparations, in particular to an abacavir, lamivudine and efavirenz compound tablet and a preparation method thereof.

Background

Since the first anti-HIV-1 drug zidovudine appeared in 1987, humans have been continually explored in the field of anti-HIV-1 research, ultimately converting AIDS from absolute to controllable life-long chronic disease. However, current anti-HIV-1 drugs do not completely clear HIV-1 from the patient, and side effects and resistance problems due to long-term use are increasingly prominent.

To address the rapid evolution of HIV and HIV resistance, oral combination antiretroviral therapy (smart) or high-efficiency antiretroviral therapy (HAART) has evolved. At present, more than ten related composite preparations are marketed in batches, and various HIV proteins or different binding sites on the same protein are targeted through oral administration of the combined medicament, so that the permanent inhibition of HIV can be realized for a long time, and the life expectancy of HIV patients can be prolonged.

The efficacy of treatment of HIV with abacavir, lamivudine and efavirenz has proven to be ideal, and the combination has a better therapeutic effect on HIV than one of the single formulations alone, but with the precondition that accurate dosing at exactly the prescribed time is required, patient compliance being a primary problem. In order to avoid missed or incorrect taking caused by excessive dosage of patients and improve compliance, the design of the three medicaments into a compound preparation with fixed dosage becomes one of key directions for developing new medicaments.

Because of the differences in morphology and rheology of the individual pharmaceutical ingredients in the compound formulation, the uniformity of mixing of the pharmaceutical formulation is an important parameter in the development of pharmaceutical products. In addition, considering that efavirenz has hydrophobicity, while lamivudine and abacavir are hydrophilic antiviral agents, the physical properties of active pharmaceutical ingredients vary greatly, so that the dissolution performance of the drug also needs to be considered. The triple compound preparation which can be successfully commercialized is also required to be at least equivalent to a commercial product, has good storage stability and moderate size of tablets, and is convenient for patients to take orally and swallow.

Disclosure of Invention

In view of the above, the invention aims to provide abacavir, lamivudine and efavirenz compound tablets and a preparation method thereof, so as to solve the problems of poor uniformity of tablets and poor compliance of patients in the prior art.

In order to achieve the above purpose, the technical scheme of the invention is realized as follows:

the compound tablet is formed by mixing and tabletting 11-15 parts of first particles, 9-12 parts of second particles and 0.8-2 parts of glidant, wherein the weight ratio of the first particles to the second particles is 1-1.5:1. Preferably, the dose ratio of the efavirenz in the first particles and the second particles is 3:5.

Preferably, the first particles comprise a pellet core and an outer layer coated on the pellet core, wherein the pellet core consists of abacavir and colloidal silica, and the outer layer consists of efavirenz, a binder and a lubricant.

Preferably, the second granule is composed of lamivudine, efavirenz and a third pharmaceutic adjuvant, wherein the third pharmaceutic adjuvant comprises an adhesive and a disintegrating agent.

Preferably, the third pharmaceutic adjuvant further comprises a modifier, wherein the modifier consists of mannitol, polyvinylpyrrolidone and lactose monohydrate according to a weight ratio of 2-4:6-9:1-3.

Preferably, the adhesive is one or more selected from sodium alginate, dextrin, ethyl cellulose, hydroxypropyl cellulose, furcellaran and povidone. Preferably, the disintegrating agent is one or more selected from pregelatinized starch, crosslinked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.

The invention also provides a preparation method of the abacavir, lamivudine and efavirenz compound tablets, which comprises the following steps: s1, preparing first particles; s2, preparing second particles; s3, stirring the first particles, the second particles and the glidant for 15-35min, and tabletting.

Preferably, step S3 includes: 45g of the first particles, the second particles and microcrystalline cellulose are stirred for 20min, then 15g of colloidal silicon dioxide is added into the mixture, and the mixture is mixed for 2.5min, and then 1000 tablets are pressed to obtain the composite material.

Preferably, step S1 includes:

s11, dissolving 45-72g of adhesive with 15-30% ethanol according to a ratio of 1:10-18 (W/V), adding 150-240g of efavirenz and 14-22g of lubricant, conveying to a constant temperature tank, controlling the temperature to be 50-60 ℃, and stirring at 100-120rpm for 10-15min to obtain adhesive solution for later use;

s12, feeding 351g of abacavir and 20-35g of colloidal silicon dioxide into a granulating chamber, and introducing dry hot air, and adjusting the frequency of a fan to 28-40HZ to keep the boiling height to 73-77cm; preferably, the colloidal silica in step S12 has a D90.ltoreq.25. Mu.m.

Preferably, the step S12 includes: adding 351g of abacavir into 650-700ml of 55-60% ethanol solution (V/V) and stirring vigorously to dissolve, adding 20g of colloidal silica with D90 less than or equal to 25 mu m, stirring at 30-40rpm for 15-20min, drying under reduced pressure, pulverizing, and sieving with 80 mesh sieve to obtain solid dispersion; feeding the solid dispersion into a granulating chamber, introducing dry hot air, and adjusting the frequency of a blower to 28-40HZ to keep the boiling height to 73-77cm.

S13, regulating the pressure of compressed air entering a spray gun to be 0.35-0.39MPa and the temperature to be 57-62 ℃; and (3) starting spraying liquid, conveying the adhesive in the step (S11) to a granulating chamber for boiling granulation, controlling the flow rate of the adhesive to be 3.9-4.5L/h, drying and cooling to room temperature to obtain the adhesive. Preferably, the air pressure is 0.42Mpa, the feeding flow is 4.0L/h, the particle size distribution of the first particles is more than 350+/-15, 200+/-9.1-350+/-15, 125+/-4.9-200+/-9.1, and the ratio of less than or equal to 125+/-4.9 is 18%, 42%, 33% and 7% respectively.

Preferably, step S2 includes:

s21, dispersing 20-80g of adhesive into 350-400ml of 70% ethanol solution, heating to 55-60 ℃, and stirring at 150-180rpm for 9-12min to prepare an adhesive solution;

s22, adding 150g of lamivudine and 20-60g of disintegrating agent and 160-320g of efavirenz into a high-speed shearing mixer-granulator for mixing; and then adding the adhesive solution of S21, rapidly stirring, shearing and granulating, and drying by a fluidized bed to obtain second granules.

Preferably, the efavirenz is subjected to the following treatment: adding 160-250g of efavirenz and a modifier into 480-600ml of 32% ethanol solution to dissolve the efavirenz and the modifier, stirring for 30-45min at 60-72 ℃, vacuum drying for 4.5-10h at 50-57 ℃, grinding and sieving with a 80-mesh sieve to obtain a modified intermediate; preferably, the modifier consists of mannitol: polyvinylpyrrolidone: lactose monohydrate = 10:36:7.3.

Compared with the prior art, the abacavir, lamivudine and efavirenz compound tablet disclosed by the invention has the following advantages: 1) The first particles are prepared by coating the abacavir with the efavirenz, the second particles are prepared by mixing the efavirenz and the lamivudine, the efavirenz is contained on the surfaces of the particles, only the glidant is added for mixing, the using amount of auxiliary materials is small, and the uniformity of tablets is good; 2) The modifier is used for modifying the Efevern by mixing and freeze-drying, so that most Efevern can be dissolved out conveniently; meanwhile, the aggregation trend of the micronized efavirenz can be inhibited, the particle has good fluidity, and the uniformity of the second particles is excellent; 3) The proportion of the efavirenz in the first particles and the second particles is reasonably adjusted, the variation coefficient of the mixed material is low, the production cost is low, and the mixing uniformity is excellent.

Detailed Description

Embodiments of the invention and features of the embodiments may be combined with each other without conflict. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. The abacavir refers to abacavir Wei Ban sulfate, and the preparation method is in the prior art; the other reagents are all commonly used reagents and are commercially available from conventional reagent manufacturing and selling companies.

Lamivudine and abacavir are used as nucleoside reverse transcriptase inhibitors, and have obvious HIV-1 inhibition activity clinically; and the efavirenz is used as a non-nucleoside reverse transcriptase inhibitor, has different action targets with lamivudine and abacavir, has remarkable effect of treating HIV-1 by combining the three, is not easy to cause drug resistance problem, and can provide a new choice for treating AIDS patients by preparing the abacavir, the lamivudine and the efavirenz compound tablet.

Patient compliance, uniformity of formulation, stability are always issues that need to be considered when preparing a compound formulation. For example, the applicant has studied tenofovir, lamivudine and efavirenz compound preparations in early stage and filed a Chinese patent with application number 201210598054.3, and the triple compound pellet tablet prepared by tenofovir DF coated pellets, lamivudine coated pellets and efavirenz Wei Lunwei pellets has good stability and dissolution rate; however, the prepared tablet has the specification of 1.56 g/tablet, and the compliance of patients when taking the tablet is poor. The tablet in the triple compound tablet of the efavirenz, the lamivudine and the tenofovir disoproxil fumarate prepared by the Chinese patent with application number 201611241400.7 comprises a coated tablet core of the tenofovir disoproxil fumarate, and the efavirenz, the lamivudine and auxiliary materials comprise the tablet core, so that the tablet has good stability; however, due to the different material properties of efavirenz and lamivudine, the uniformity of the final tablet is poor due to the fact that the mixture is difficult to mix uniformly, and the drug resistance risk exists after long-term administration. For this, the applicant proposes the following technical solution.

Example 1

An abacavir, lamivudine and efavirenz compound tablet comprises the following components:

the preparation process comprises the following steps: s1, preparation of first particles

1.1, dissolving 60g of povidone with 30% ethanol according to a ratio of 1:15 (W/V), adding 200g of efavirenz and 15g of magnesium stearate, conveying to a constant temperature tank, controlling the temperature to be 50 ℃, and stirring at 120rpm for 10min to serve as an adhesive for later use;

1.2, feeding 351g of abacavir and 35g of colloidal silica with D90 less than or equal to 25 mu m into a granulating chamber, introducing dry hot air at 62 ℃, and regulating the frequency of a fan to 40HZ to keep the boiling height to be about 77cm;

1.3, regulating the pressure of compressed air entering a spray gun to be 0.37MPa and the temperature to be 57 ℃; starting spraying liquid, conveying the adhesive in the step S1.1 to a granulating chamber for boiling granulation, and controlling the flow rate of the adhesive to be 4.5L/h;

1.4, adjusting the frequency of a fan to 25HZ after spraying liquid for granulation and the air inlet temperature to 60 ℃, and drying the materials in the granulating chamber for 30min; turning off the heater, and cooling to room temperature to obtain first particles with a bulk density of 1.02g/mL for later use;

s2, preparation of second particles

2.1 dispersing 64g of povidone in 70% ethanol solution heated to 50 ℃ and stirring at 150rpm for 12min to prepare a binder solution;

2.2 adding 150g of lamivudine, 65g of croscarmellose sodium and 200g of efavirenz into a high-speed shearing mixer-granulator for mixing; and then adding the adhesive solution in the step S2.1, rapidly stirring, shearing and granulating, and drying by a fluidized bed to obtain second granules.

S3, stirring 100g of the first particles, the second particles and the microcrystalline cellulose for 20min, and pressing 1000 tablets to obtain the finished product.

Example 2

the preparation process comprises the following steps:

s1, preparation of first particles

1.1, dissolving 72g of sodium alginate with 15% ethanol according to a ratio of 1:10 (W/V), adding 240g of efavirenz and 22g of calcium stearate, conveying to a constant temperature tank, controlling the temperature to 55 ℃, and stirring at 100rpm for 15min to serve as an adhesive for later use;

1.2, adding 351g of Abacavir into 1500ml of 55% ethanol solution (V/V) and stirring vigorously to dissolve, adding 25g of colloidal silica with D90 less than or equal to 25 μm, stirring at 30rpm for 20min, drying under reduced pressure, pulverizing, and sieving with 80 mesh sieve to obtain solid dispersion for later use;

1.3, uniformly putting the solid dispersion into a granulating chamber, introducing dry hot air with the temperature of 65 ℃, and adjusting the frequency of a fan to 38HZ to keep the boiling height to be 75cm; the pressure of the compressed air which is introduced into the spray gun is regulated to be 0.35MPa, and the temperature is regulated to be 59 ℃;

1.4, starting spray liquid, conveying the adhesive in the step S1.1 to a granulating chamber for boiling granulation, and controlling the flow rate of the adhesive to be 4.2L/h; after spraying liquid and granulating, adjusting the frequency of a fan to 27HZ and the air inlet temperature to 62 ℃, and drying the materials in the granulating chamber for 35min; turning off the heater, and cooling to room temperature to obtain first particles with a bulk density of 1.01g/mL for later use;

s2, preparation of second particles

2.1 dispersing 60g of sodium alginate into 650ml of 45% ethanol solution, heating to 55 ℃, and stirring at 150rpm for 12min to prepare an adhesive solution;

2.2 adding 150g of lamivudine and 60g of carboxymethyl starch sodium and 160g of efavirenz into a high-speed shearing mixer-granulator for mixing; and then adding the adhesive solution in the step S2.1, rapidly stirring, shearing and granulating, and drying by a fluidized bed to obtain second granules.

S3, stirring 55g of the first particles, the second particles and the microcrystalline cellulose for 25min, and pressing 1000 tablets to obtain the finished product.

Example 3

the preparation method comprises the following steps:

s1, preparation of first particles

1.1, dissolving 60g of ethyl cellulose with 18% ethanol according to a ratio of 1:13 (W/V), adding 210g of efavirenz and 15g of talcum powder, conveying to a constant temperature tank, controlling the temperature to 58 ℃, and stirring at 110rpm for 12min to serve as an adhesive for later use;

1.2, adding 351g of Abacavir into 1250ml of 60% ethanol solution (V/V) and stirring vigorously to dissolve the Abacavir, adding 20g of colloidal silica with D90 less than or equal to 25 mu m, stirring at 40rpm for 15min, drying under reduced pressure, pulverizing, and sieving with 80-mesh sieve to obtain solid dispersion for later use;

1.3, uniformly putting the solid dispersion into a granulating chamber, introducing dry hot air with the temperature of 64 ℃, and adjusting the frequency of a fan to 37HZ to keep the boiling height of 73cm; the pressure of compressed air fed into the spray gun is regulated to be 0.37MPa, and the temperature is regulated to be 60 ℃;

1.4, starting spray liquid, conveying the adhesive in the step S1.1 to a granulating chamber for boiling granulation, and controlling the flow rate of the adhesive to be 3.9L/h; after spraying liquid and granulating, adjusting the frequency of a fan to 31HZ and the air inlet temperature to 65 ℃, and drying the materials in the granulating chamber for 30min; turning off the heater, and cooling to room temperature to obtain first particles with a bulk density of 1.03g/mL for later use;

s2, preparation of second particles

2.1 dispersing 64g of ethyl cellulose into 350ml of 70% ethanol solution, heating to 55 ℃ and stirring at 150rpm for 12min to prepare a binder solution;

2.2 grinding 190g of Efevirenz, 15g of mannitol, 54g of polyvinylpyrrolidone and 11g of lactose monohydrate, and sieving with a 80-mesh sieve; mixing with 150g of lamivudine and 25g of hydroxypropyl cyclodextrin in a high-speed shearing mixer granulator; and then adding the adhesive solution in the step S2.1, rapidly stirring, shearing and granulating, and drying by a fluidized bed to obtain second granules.

S3, stirring 45g of the first particles, the second particles and the microcrystalline cellulose for 25min, and pressing 1000 tablets to obtain the finished product.

Example 4

the preparation process comprises the following steps:

s1, preparation of first particles

1.1, dissolving 45g of hydroxypropyl cellulose with 18% ethanol according to a ratio of 1:15 (W/V), adding 150g of efavirenz and 14g of magnesium stearate, conveying to a constant temperature tank, controlling the temperature to be 60 ℃, and stirring at 100rpm for 15min to serve as an adhesive for later use;

1.2, adding 351g of abacavir which is crushed and sieved by a 40-mesh sieve into 1400ml of 55% ethanol solution (V/V), stirring to dissolve, adding 25g of colloidal silica with D90 less than or equal to 25 mu m, stirring at 30rpm for 18min, drying under reduced pressure, crushing and sieving by a 80-mesh sieve to obtain a solid dispersion for later use;

1.3, uniformly putting the solid dispersion into a granulating chamber, introducing dry hot air with the temperature of 65 ℃, and adjusting the frequency of a fan to 38HZ to keep the boiling height of 74cm; the pressure of compressed air fed into the spray gun is regulated to be 0.39MPa, and the temperature is regulated to be 62 ℃;

1.4, starting spray liquid, conveying the adhesive in the step S1.1 to a granulating chamber for boiling granulation, and controlling the flow rate of the adhesive to be 4.0L/h; after spraying liquid and granulating, adjusting the frequency of a fan to 30HZ and the air inlet temperature to 58 ℃, and drying the materials in the granulating chamber for 60min; turning off the heater, and cooling to room temperature to obtain first particles with a bulk density of 1.02g/mL for later use;

s2, preparation of second particles

2.1, 250g of efavirenz and a modifier are added into 880ml of 32% ethanol solution to be dissolved, stirred for 45min at 72 ℃, dried for 8.5h at 57 ℃ in vacuum, ground and sieved by a 80-mesh sieve to obtain a modified intermediate; the modifier consists of 10g of mannitol, 36g of polyvinylpyrrolidone and 7.3g of lactose monohydrate.

2.2 hydroxypropyl cellulose 80g dispersed in 400ml 70% ethanol solution, heated to 60 ℃ and stirred at 180rpm for 9min to prepare a binder solution;

2.3, 150g of lamivudine and 32g of low-substituted hydroxypropyl cellulose are sieved by a 90-mesh sieve, and then are fed into a high-speed shearing mixing granulator together with the modified intermediate for mixing; and then adding the adhesive solution in the step S2.2, rapidly stirring, shearing and granulating, and drying by a fluidized bed to obtain second granules.

Example 5

the preparation process comprises the following steps:

s1, preparation of first particles

1.1, dissolving 45g of hydroxypropyl cellulose with 18% ethanol according to a ratio of 1:18 (W/V), adding 150g of efavirenz and 14g of magnesium stearate, conveying to a constant temperature tank, controlling the temperature to be 60 ℃, and stirring at 100rpm for 15min to serve as an adhesive for later use;

1.2, adding 351g of abacavir which is crushed and sieved by a 40-mesh sieve into 1650ml of 40% ethanol solution (V/V), stirring to dissolve, adding 25g of colloidal silica with D90 less than or equal to 25 mu m, stirring at 30rpm for 18min, drying under reduced pressure, crushing and sieving by a 80-mesh sieve to obtain a solid dispersion for later use;

s2, preparation of second particles

2.1, 250g of efavirenz and a modifier are added into 980ml of 32% ethanol solution to be dissolved, stirred for 45min at 72 ℃, dried for 9.5h at 57 ℃ in vacuum, ground and sieved by a 80-mesh sieve to obtain a modified intermediate; the modifier consists of 15g of mannitol, 42g of polyvinylpyrrolidone and 10g of lactose monohydrate.

2.2 hydroxypropyl cellulose 72g was dispersed in 600ml of 35% ethanol solution, heated to 60℃and stirred at 180rpm for 9min to prepare a binder solution;

2.3, sieving 150g of lamivudine and 28g of carboxymethyl starch sodium with a 80-mesh sieve, and then feeding the lamivudine and the modified intermediate together into a high-speed shearing mixing granulator for mixing for 30min; and then adding the adhesive solution in the step S2.2, rapidly stirring, shearing and granulating, and drying by a fluidized bed to obtain second granules.

S3, stirring 45g of the first particles, the second particles and the microcrystalline cellulose for 20min, adding 15g of colloidal silicon dioxide into the mixture, mixing for 2.5min, and pressing 1000 tablets.

Comparative example 1

Adopting the same formula as in example 5, weighing the raw materials and auxiliary materials with the prescription amount, putting into a wet mixing granulator, starting stirring and mixing for 40min, adding a proper amount of purified water, performing wet granulation, drying and granulating, and sieving; adding microcrystalline cellulose, mixing, and tabletting.

Comparative example 2

A compound tablet was prepared according to the method of preparation example 1 in publication No. CN106822155A, the composition of the raw materials of which is the same as that of example 1, except that abaca Wei Daiti efavirenz was used.

Comparative example 3

Prepared using the same ingredients and method as in example 5, except that microcrystalline cellulose and colloidal silicon dioxide were added directly during mixing.

Experimental example 1 investigation of different technological conditions

1.1 partition ratio of Efevirenz

The dosage proportion of the efavirenz in the first particles and the second particles is adjusted according to the proportion of the table 1, the dosage and the proportion of other components are the same as those of the example 5, and tablets are prepared according to the method of the example 5; 10 samples were taken separately and the percentage content of abacavir, efavirenz, lamivudine in the samples was determined by HPLC. The average content and standard deviation were calculated, and the coefficient of variation representing the uniformity of mixing was calculated therefrom, and the coefficient of variation of the three main drugs was averaged. The HPLC detection method is a prior art and is not described in detail herein.

Coefficient of variation C.V = (standard deviation SD/average value M) ×100%, and the calculation results are shown in table 1.

TABLE 1 influence of partition ratio of Efevirenz on mixing uniformity

Coating abacavir with part of efavirenz to prepare first particles, wherein part of efavirenz is distributed on the surfaces of the first particles; the same part of Efevirenz and lamivudine are used for preparing second particles, the difference of material properties of the surfaces of the second particles and the first particles is small, and the second particles and the first particles are easy to mix uniformly; as can be seen from table 1, when the dose ratio of efavirenz in the first and second particles is 3:5, 150g: at 250g, the coefficient of variation after mixing the materials is the lowest, and the mixing uniformity is the best.

Experimental example 2 modifier optimization

As a hydrophobic antiviral agent, efavirenz has poor in vitro dissolution and low in vivo bioavailability. For insoluble drugs, common methods for improving drug dissolution include solid dispersion, cyclodextrin inclusion, micronization, surfactant solubilization, microemulsification, liposome preparation, etc.; considering the influence of compound tablet weight on patient compliance, micronization becomes the first choice of efavirenz; however, the raw materials are easy to reagglomerate due to electrostatic adsorption after micronization treatment, so that the particle size becomes large and the dissolution effect becomes poor. The applicant found through research that the interaction of efavirenz with excipients during freeze-drying can alter its stability and water solubility. For this purpose, second particles were prepared and their dissolution properties were measured by the preparation methods of examples 3 and 5, respectively, according to the amount ratio of the modifier in table 2.

The dissolution rate was measured by referring to the XC second method of appendix 2 of 2015 of Chinese pharmacopoeia, and the cumulative dissolution rate was measured by adding 900ml of acetate buffer (2.99 g of sodium acetate, 1000ml of water, 1.66ml of glacial acetic acid and 20ml of 10% SDS solution, adjusting pH to 8.21.+ -. 0.1) to dissolution medium with sodium hydroxide, and stirring at 75rpm for 30 min.

TABLE 2 Effect of different proportions of modifiers on the dissolution properties of the second particles

After about 62% of the efavirenz and lamivudine in the tablet are prepared into second particles, the efavirenz is uniformly distributed in the particles, and the dissolution effect is not ideal; while the rest about 38% of the efavirenz is distributed on the surface of the first particles, and the dissolution performance is still available; as can be seen from table 2, the material properties of the mixture of efavirenz and the modifier were changed by freeze drying again, and the dissolution performance was significantly better; and when mannitol: polyvinylpyrrolidone: lactose monohydrate = 15:42:10, mannitol can inhibit aggregation trend of the efavirenz micropowder, and avoid overlarge particle size of the efavirenz micropowder so as to improve dissolution performance. The inventor finds that the mutual synergistic effect of lactose monohydrate, polyvinylpyrrolidone and mannitol can improve the fluidity of the modified intermediate by screening, and ensures that the second particles and the first particles have good mixing uniformity.

Experimental example 3 granulation condition optimization

The first granule and the compound tablet were prepared according to the composition and method of example 5, the compressed air pressure and the adhesive flow were adjusted, the content of abacavir in the prepared compound tablet was measured by HPLC, and the mixing uniformity and dissolution rate of the tablet were calculated therefrom, and the results are shown in table 3; specific measurement methods of the mixing uniformity and the dissolution rate are shown in experimental examples 1 and 2, and are not described herein.

TABLE 3 influence of different granulation parameters on tablet quality

The particle size distribution and density of the particles are one of the parameters affecting the mixing uniformity and dissolution performance of the preparation; the inventor optimizes the technological parameters of the preparation of the first particles and finally influences the mixing uniformity and dissolution of the tablets. As is clear from Table 3, when the air pressure is 0.42MPa and the feed flow rate is 4.0L/h, the particle size distribution of the prepared first particles is more than 350+ -15, 200+ -9.1-350+ -15, 125+ -4.9-200+ -9.1 and less than or equal to 125+ -4.9 respectively accounting for 18%, 42%, 33% and 7%, and the first particles have good mixing uniformity and dissolution performance.

To further demonstrate the superiority of the present invention, the inventors conducted experiments on the uniformity of mixing, dissolution, long-term stability of the products obtained in examples and comparative examples of the present invention.

1. Mixing uniformity experiment

The mixing uniformity problem always exists when auxiliary materials and active ingredients are mixed to prepare tablets under the influence of the density, the shape and the granularity of the granules, and the mixing uniformity problem affects the quality of a final tablet product. 10 batches of compound tablets were prepared by the methods of examples 1-5 and comparative examples 1-3, three samples were taken from each batch, the percentage content of lamivudine in each sample was detected by HPLC, the average value and standard deviation of the content were calculated as the lamivudine content of the tablets in the batch, and the mixing uniformity was expressed by the coefficient of variation, and the results are shown in Table 4.

TABLE 4 uniformity of mixing of samples of different groups

As can be seen from table 4, compared with the method of directly mixing the raw materials, wet granulating and then adding microcrystalline cellulose for mixing and tabletting, the colloidal silica is used for adsorbing the abaca Wei Zhicheng dispersion and forming the first granules through the efavirenz coating; meanwhile, the second particles are prepared by utilizing lamivudine and efavirenz to granulate, and the materials of the second particles and the efavirenz are similar in property and convenient to mix uniformly; meanwhile, the glidant is added twice to reduce the separation of active ingredients, so that the uniformity is good.

2. Stability test

Taking the compound tablets prepared in examples 1-5 and comparative example 1, storing for 6 months at 40 ℃ under the condition of 75% humidity for accelerated test, and respectively measuring related substances in samples for 0 month and 6 months, wherein the related measuring method is the prior art.

Table 5 stability data for different groups of tablets

As shown in Table 5, the compound tablet prepared by the invention has no obvious increase of the content of related substances after being stored for 6 months, and has good stability.

3. Dissolution test

The dissolution rates of the compound tablets prepared in examples 1 to 5 and comparative example 1 were measured as described above for 15 minutes, and the results are shown in Table 6.

TABLE 6 dissolution data for different groups of tablets

	Efevirenz	Lamivudine	Abacavir
				Example 1	81.9	95.8	90.9
Example 2	83.5	96.4	92.7
				Example 3	89.2	97.1	93.1
Example 4	91.3	95.7	93.5
				Example 5	91.9	96.2	93.9
Comparative example 1	82.1	97.9	92.7

As is clear from Table 6, the dissolution rate of efavirenz is significantly higher and the dissolution effect is excellent after the modifier is added to the second particles prepared in example 3, compared with examples 1-2 and comparative example 1; in example 4, after the modified intermediate is prepared from the efavirenz by using the modifier, the dissolution rate of the efavirenz is further improved; whereas the dissolution rates of lamivudine and abacavir in the examples differ less.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims

1. An abacavir, lamivudine and efavirenz compound tablet is characterized by being prepared by the following method:

s1, preparing first particles, wherein the preparation method comprises the following steps of:

s11, dissolving 45-72g of adhesive with 15-30% ethanol according to a ratio of 1:10-18W/V, adding 150-240g of efavirenz and 14-22g of lubricant, conveying to a constant temperature tank, controlling the temperature to be 50-60 ℃, and stirring at 100-120rpm for 10-15min to obtain adhesive solution for later use;

s12, feeding 351g of abacavir and 20-35g of colloidal silicon dioxide into a granulating chamber, introducing dry hot air, and adjusting the frequency of a fan to 28-40HZ so as to keep the boiling height of 73-77cm, wherein D90 of the colloidal silicon dioxide is less than or equal to 25 mu m;

s13, regulating the pressure of compressed air entering a spray gun to be 0.35-0.39MPa and the temperature to be 57-62 ℃; starting spraying liquid, conveying the adhesive in the step S11 to a granulating chamber for boiling granulating, controlling the flow rate of the adhesive to be 3.9-4.5L/h, drying and cooling to room temperature to obtain the adhesive;

s2, preparing second particles, wherein the second particles comprise:

s22, adding 150g of lamivudine and 20-60g of disintegrating agent and 160-320g of efavirenz into a high-speed shearing mixer-granulator for mixing; the efavirenz is pretreated by: adding 160-250g of efavirenz and a modifier into 480-600ml of 32% ethanol solution to dissolve the efavirenz and the modifier, stirring for 30-45min at 60-72 ℃, vacuum drying for 4.5-10h at 50-57 ℃, grinding and sieving with a 80-mesh sieve; then adding the adhesive solution of S21, rapidly stirring, shearing and granulating, and drying by a fluidized bed to obtain second granules;

s3, stirring 45g of the first particles, the second particles and the microcrystalline cellulose for 20min, then adding 15g of colloidal silicon dioxide into the mixture, mixing for 2.5min, and pressing 1000 tablets to obtain the product;

the weight ratio of the first particles to the second particles is 1-1.5:1; the modifier consists of mannitol, polyvinylpyrrolidone and lactose monohydrate according to a weight ratio of 15:42:10, and the dosage ratio of the efavirenz in the first particles and the second particles is 3:5.

2. The abacavir, lamivudine and efavirenz compound tablet according to claim 1, wherein the adhesive is selected from one or more of sodium alginate, dextrin, ethylcellulose, hydroxypropyl cellulose, furcellaran and povidone.

3. The abacavir, lamivudine and efavirenz compound tablet according to claim 1, wherein the disintegrating agent is selected from one or more of pregelatinized starch, crosslinked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.