CN113288905A - Pharmaceutical composition containing dortavir sodium, lamivudine and norfovir disoproxil fumarate - Google Patents
Pharmaceutical composition containing dortavir sodium, lamivudine and norfovir disoproxil fumarate Download PDFInfo
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Abstract
The invention relates to the technical field of pharmaceutical preparations, and provides a pharmaceutical composition containing dorzolavir and salts thereof, lamivudine, tenofovir and prodrugs thereof. Through the technical scheme, the problem that the tenofovir is degraded due to incompatibility with the doramevir is solved, the stability of the medicine is ensured, and the problems that a double-layer tablet in the prior art is complex in process, high in equipment requirement and low in yield are solved.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a single-layer erosion tablet containing dorzolavir sodium, tenofovir disoproxil fumarate and lamivudine and a preparation method thereof.
Background
Infiltration with Human Immunodeficiency Virus (HIV) may lead to acquired immunodeficiency syndrome (AIDS). At present, hiv infection is said to be incurable, and it is therefore a major target for preventing or at least significantly slowing down the spread of the corresponding virus. Since the treatment of HIV infection is quite complex, combination therapies have been proposed. Combination therapy is therapy with two or more pharmaceutically active agents.
Clinical workers and related data prove that the dorzolavir sodium, the tenofovir disoproxil fumarate and the lamivudine preparation are combined clinically, the curative effect of the combination on HIV is better than that of the single preparation, but the problems of reduced stability of the product and serious degradation of tenofovir are easy to occur in the production process.
The first wet granulation procedure, in which three drugs (active drug intermediates or APIs) were simply mixed directly, produced products that were not chemically stable. In the compound tablet, tenofovir is very unstable and rapidly degraded in stability research, and the biological equivalence of the doramevir in the compound preparation and a single doramevir sodium tablet in human clinical tests is difficult to realize.
Then, the compound tablet is prepared by adopting dry granulation, and the three medicines (active medicine intermediates or APIs) are combined to prepare the product by adopting a dry granulation mode, so that the stability of the product cannot reach a satisfactory degree.
By carrying out compatibility test investigation on the dorzolavir sodium, the tenofovir disoproxil fumarate and the lamivudine, the compatibility problem of the dorzolavir sodium and the tenofovir disoproxil fumarate is found, the dorzolavir sodium can promote the degradation of the tenofovir disoproxil fumarate, and the problem that the compatibility of the dorzolavir sodium and the tenofovir disoproxil fumarate is a key technical problem is solved.
In patent CN 101252920B, in order to avoid the problem of compatibility between tenofovir and sodium dodecyl sulfate in efavirenz granules, a compound tablet composed of tenofovir, emtricitabine and efavirenz is designed into a double-layer tablet, in which tenofovir and emtricitabine are the first layer, efavirenz and sodium dodecyl sulfate are the second layer, and the contact between incompatible two components is reduced by spatial isolation, so as to achieve the purpose of improving stability.
In patent CN 106822155B, in order to avoid the problem of compatibility between tenofovir and sodium dodecyl sulfate in efavirenz granules, a triple compound tablet composed of efavirenz, lamivudine and tenofovir fumarate is prepared by making tenofovir into a tablet core, and then including efavirenz, lamivudine and auxiliary materials in the tablet core to prepare a product, and a space isolation manner is also adopted to reduce the contact between incompatible two components, thereby achieving the purpose of improving stability.
However, the two methods for improving the stability by adopting the space isolation method have extremely high requirements on equipment, so that the product investment is increased by about 4-5 times of that of common equipment; and the process risk in production is large, such as: by adopting the multilayer tabletting, the problem of material mixing of different layers is easy to occur, so that the stability is influenced; meanwhile, due to the influence of the control precision of the equipment, the hardness and the thickness of the batch products are different, and the quality of the products is greatly influenced. From the aspect of product yield, the product yield prepared by the two methods is low, and is about 70-95%, and the method limits the industrial production of the product.
Disclosure of Invention
The invention prepares the dorzolavir sodium, the lamivudine and the tenofovir disoproxil fumarate into the single-layer erosion tablet, has good stability under the acceleration condition, is consistent with the in-vitro erosion of the single original developing agent of the dorzolavir sodium, the lamivudine and the tenofovir disoproxil fumarate, overcomes the defects of high requirement on equipment, low yield and the like in a space isolation mode in the prior art, and is suitable for industrial mass production.
The technical scheme of the invention is as follows:
a pharmaceutical composition in the form of a single-layer erosion tablet comprises the following components:
A. one or more of dolastavir and salts thereof,
B. the content of the lamivudine is determined,
C. one or more of tenofovir and prodrugs thereof,
D. one or more pharmaceutically acceptable adjuvants.
Further, the composition comprises:
a.10-75mg of dolastavir and one or more of the salts thereof,
b.100-600mg lamivudine,
c.10-400mg of one or more of tenofovir and its prodrug,
D. one or more pharmaceutically acceptable adjuvants.
Further, the dorzolavir salt is dorzolavir sodium, and the tenofovir prodrug is tenofovir disoproxil fumarate.
Further, the weight ratio of the dorzolavir sodium to the tenofovir disoproxil fumarate is 1:0.5-1: 15.
Further, the weight ratio of the dorzolavir to the tenofovir disoproxil fumarate is 1: 12.
Further, the corrosion time of the corrosion slice is 1-40 minutes.
More preferably, the erosion time of the erosion sheet is 5 to 30 minutes.
Further, the auxiliary materials are selected from one or more of diluents, binders, lubricants and disintegrants.
Still further, the binder is selected from one or more of povidone, starch, hypromellose, and ethyl cellulose.
Preferably, the binder is povidone.
Still further, the diluent is selected from one or more of lactose, mannitol, microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate.
Preferably, the diluent is a combination of lactose, microcrystalline cellulose and mannitol.
Still further, the disintegrant is selected from one or more of croscarmellose sodium, sodium starch glycolate, starch, crospovidone, low substituted hydroxypropyl cellulose, dry starch.
Preferably, the disintegrant is sodium starch glycolate and/or croscarmellose sodium.
Still further, the lubricant is selected from one or more of magnesium stearate, stearic acid, talc, sodium stearyl fumarate.
Preferably, the lubricant is selected from magnesium stearate.
Further, the single layer erosion tablet is a solid oral dosage form fast release dosage form.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: the component A, C is prepared into granule A and granule C separately, and the component B is prepared into powder or granule B and A, C by mixing, tabletting and coating.
Further, the moisture of the particles A, the particles B and the particles C is less than 3%.
Still further, the preparation method comprises the following steps:
(1) granulating the doramevir sodium, the diluent, the disintegrating agent and the adhesive to obtain doramevir sodium granules;
(2) granulating tenofovir disoproxil fumarate with a diluent and a disintegrating agent to obtain tenofovir disoproxil fumarate granules;
(3) granulating lamivudine, a diluent and a disintegrating agent to obtain lamivudine granules;
(4) mixing the dorzolavir sodium granules, the tenofovir disoproxil fumarate granules and the lamivudine granules with a disintegrant and a lubricant uniformly, tabletting and coating to obtain the finished product.
Further, the step (1) is to prepare granules by a dry granulation or wet granulation process; step (2) preparing granules by a dry granulation or wet granulation process; and (3) preparing granules in a wet granulation mode.
The invention further provides application of the pharmaceutical composition in preparation of drugs for treating and/or preventing AIDS.
The working principle and the beneficial effects of the invention are as follows:
1. the invention prepares the dorzolavir sodium, lamivudine, tenofovir disoproxil fumarate and proper auxiliary materials into the single-layer erosion tablet, and overcomes the defects of high requirement on multi-layer space isolation equipment, low yield and the like. The composition has good stability, is consistent with the in vitro dissolution of a single original preparation of the dorzolavir sodium, the lamivudine and the tenofovir disoproxil fumarate, has high product yield, is not limited by production equipment, and is suitable for industrial production.
2. When the auxiliary materials are selected, a large number of experiments are carried out aiming at the characteristics of the raw material medicines, and finally, the mannitol is determined to have excellent moisture absorption resistance and is particularly suitable for the main medicine which is unstable in moisture; the microcrystalline cellulose has good compressibility and capillary characteristics, the disintegration time and the brittle strength are improved by the co-use of the microcrystalline cellulose and the lactose, and the product stability of the main drug in the storage period due to the instable wetting can be ensured by the addition of the mannitol, so that the product can be quickly disintegrated to reach the drug concentration in use and can keep stable performance in the storage period.
Drawings
FIG. 1 is a graph showing in vitro dissolution profiles of examples 1-2 of the present invention, comparative examples 1-3, and the original formulation
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any inventive step, are intended to be within the scope of the present invention.
Example 1
The preparation method comprises the following steps:
(1) preparing doramevir sodium particles: putting dorawivir sodium, mannitol, microcrystalline cellulose, carboxymethyl starch sodium and polyvidone into a high-shear wet granulation machine, and stirring at low speed for 10 min. Granulating with purified water. And (5) carrying out wet granulation by adopting a 20-mesh sieve, and drying until the moisture content is less than 3%. Drying and granulating by adopting a 20-mesh sieve.
(2) Preparation of TDF particles: mixing TDF, microcrystalline cellulose, lactose and croscarmellose sodium uniformly, performing dry granulation in a dry granulation machine, and sieving with a 20-mesh sieve to obtain granules with water content of less than 3%.
(3) Preparation of lamivudine particles: uniformly mixing lamivudine, microcrystalline cellulose and croscarmellose sodium, stirring, and mixing at low speed for 10 min. Granulating with purified water. And (3) carrying out wet granulation by adopting a 20-mesh sieve, drying until the moisture content is less than 3%, and carrying out dry granulation by adopting the 20-mesh sieve.
(4) Total mixing: mixing the dorzolawir sodium granules, the TDF granules, the lamivudine granules, the added carboxymethyl starch sodium and the magnesium stearate uniformly.
(5) Tabletting: compressed into tablets on a high-speed tablet press.
(6) Film coating: an aqueous suspension of yellow Opadry at 18% by weight was prepared and the compressed tablets were film coated.
Example 2
The preparation method comprises the following steps:
(1) preparing doramevir sodium particles: putting dorawivir sodium, mannitol, microcrystalline cellulose, carboxymethyl starch sodium and polyvidone into a high-shear wet granulation machine, and stirring at low speed for 10 min. Granulating with purified water. And (5) carrying out wet granulation by adopting a 20-mesh sieve, and drying until the moisture content is less than 3%. Drying and granulating by adopting a 20-mesh sieve.
(2) Preparation of TDF particles: TDF, microcrystalline cellulose, lactose and croscarmellose sodium are put into a high-speed wet granulating machine, and stirring and low-speed mixing are started for 10 min. And (5) granulating by using purified water. And (3) carrying out wet granulation by adopting a 20-mesh sieve, drying until the moisture content is less than 3%, and carrying out dry granulation by adopting the 20-mesh sieve.
(3) Lamivudine granules: putting lamivudine, microcrystalline cellulose and croscarmellose sodium into a high-speed wet granulating machine, stirring and mixing at low speed for 10 min. And (5) granulating by using purified water. And (3) carrying out wet granulation by adopting a 20-mesh sieve, drying until the moisture content is less than 3%, and carrying out dry granulation by adopting the 20-mesh sieve.
(4) Total mixing: mixing the dorzolawir sodium granules, the TDF granules, the lamivudine granules and the added microcrystalline cellulose, the carboxymethyl starch sodium and the magnesium stearate uniformly.
(5) Tabletting: the mixture is compressed into tablets on a high speed tablet press.
(6) Film coating: a suspension of 18% yellow Opadry was prepared and the compressed tablets were film coated.
Example 3
The preparation method comprises the following steps:
(1) preparing doramevir sodium particles: and putting the doramevir sodium, the mannitol, the microcrystalline cellulose, the hydroxypropyl methylcellulose and the starch into a high-shear wet granulation machine, and stirring and mixing at a low speed for 10 min. And (5) granulating by using purified water. And (5) carrying out wet granulation by adopting a 20-mesh sieve, and drying until the moisture content is less than 3%. Drying and granulating by adopting a 20-mesh sieve.
(2) Preparation of TDF particles: TDF, microcrystalline cellulose, lactose and low-substituted hydroxypropyl cellulose are mixed in a high-speed wet granulating machine for 10min under stirring at a low speed. And (5) granulating by using purified water. And (3) carrying out wet granulation by adopting a 20-mesh sieve, drying until the moisture content is less than 3%, and carrying out dry granulation by adopting the 20-mesh sieve.
(3) Lamivudine granules: and starting stirring and mixing the lamivudine, the calcium carbonate and the dry starch at a low speed for 10min in a high-speed wet granulating machine. Granulating with purified water. And (3) carrying out wet granulation by adopting a 20-mesh sieve, drying until the moisture content is less than 3%, and carrying out dry granulation by adopting the 20-mesh sieve.
(4) Total mixing: mixing the dorzolawir sodium particles, the TDF particles, the lamivudine particles and the added mannitol, carboxymethyl starch sodium and talcum powder uniformly.
(5) Tabletting: the mixture is compressed into tablets on a high speed tablet press.
(6) Film coating: a suspension of 18% yellow Opadry was prepared and the compressed tablets were film coated.
Example 4
The preparation method comprises the following steps:
(1) preparing doramevir sodium particles: putting dorawivir sodium, lactose, microcrystalline cellulose, pregelatinized starch and crospovidone into a high-shear wet granulation machine, stirring and mixing at low speed for 10 min. And (5) granulating by using purified water. And (5) carrying out wet granulation by adopting a 20-mesh sieve, and drying until the moisture content is less than 3%. Drying and granulating by adopting a 20-mesh sieve.
(2) Preparation of TAF granules: feeding TAF, microcrystalline cellulose, lactose, and croscarmellose sodium into high-speed wet granulating machine, stirring, and mixing at low speed for 10 min. And (5) granulating by using purified water. And (3) carrying out wet granulation by adopting a 20-mesh sieve, drying until the moisture content is less than 3%, and carrying out dry granulation by adopting the 20-mesh sieve.
(3) Lamivudine granules: putting lamivudine, microcrystalline cellulose and crospovidone into a high-speed wet granulating machine, stirring and mixing at low speed for 10 min. And (5) granulating by using purified water. And (3) carrying out wet granulation by adopting a 20-mesh sieve, drying until the moisture content is less than 3%, and carrying out dry granulation by adopting the 20-mesh sieve.
(4) Total mixing: mixing the dorzolawir sodium particles, the TDF particles, the lamivudine particles and the added lactose, the cross-linked sodium carboxymethyl cellulose and the sodium stearyl fumarate uniformly.
(5) Tabletting: the mixture is compressed into tablets on a high speed tablet press.
(6) Film coating: a suspension of 18% yellow Opadry was prepared and the compressed tablets were film coated.
Example 5
The preparation method comprises the following steps: the same as in example 1.
Comparative example 1 was prepared using direct mixing followed by wet granulation
The preparation method comprises the following steps:
(1) and (3) wet granulation: TDF, lamivudine, doritavir sodium, mannitol, lactose, microcrystalline cellulose, croscarmellose sodium, carboxymethyl starch sodium and povidone are placed in a high-shear wet granulation machine, stirred at a low speed and mixed uniformly, wet granulation is carried out by purified water, wet granulation is carried out by adopting a 20-mesh sieve, and drying is carried out until the moisture content is less than 3%. Drying and granulating by adopting a 20-mesh sieve, and uniformly mixing with the added microcrystalline cellulose, the croscarmellose sodium and the magnesium stearate.
(2) Compression: the upper material was compressed into tablets on a tablet press.
(3) Film coating: an aqueous suspension of yellow Opadry at 18% by weight was prepared and the compressed tablets were film coated.
Comparative example 2 was prepared by direct mixing followed by dry granulation
The formulation composition is the same as that of comparative example 1
The preparation method comprises the following steps:
(1) and (3) dry granulation: TDF, lamivudine, dorzolavir sodium, mannitol, lactose, microcrystalline cellulose, croscarmellose sodium, carboxymethyl starch sodium, polyvidone and magnesium stearate are placed in a mixer and mixed uniformly. Dry granulation is carried out by adopting a dry granulator, and dried and granulated by adopting a 20-mesh sieve. Adding the added microcrystalline cellulose, the croscarmellose sodium and the magnesium stearate, and uniformly mixing.
(2) Compression: the upper material was compressed into tablets on a tablet press.
(3) Film coating: an aqueous suspension of yellow Opadry at 18% by weight was prepared and the compressed tablets were film coated.
Comparative example 3 multilayer tablet preparation
The preparation method comprises the following steps:
(1) preparing first layer particles: putting dorawivir sodium, mannitol, microcrystalline cellulose, carboxymethyl starch sodium and polyvidone into a high-shear wet granulation machine, and stirring at low speed for 10 min. Granulating with purified water. And (5) carrying out wet granulation by adopting a 20-mesh sieve, and drying until the moisture content is less than 3%. Drying and granulating by adopting a 20-mesh sieve. Adding additional sodium carboxymethyl starch and magnesium stearate, and mixing.
(2) Preparing second-layer particles:
TDF particles: TDF, microcrystalline cellulose, lactose and croscarmellose sodium are uniformly mixed, and dry granulation is carried out in a dry granulation machine, and the granules are granulated by a 20-mesh screen.
(vii) lamivudine particles: uniformly mixing lamivudine, microcrystalline cellulose and croscarmellose sodium, stirring, and mixing at low speed for 10 min. Granulating with purified water. And (3) carrying out wet granulation by adopting a 20-mesh sieve, drying until the moisture content is less than 3%, and carrying out dry granulation by adopting the 20-mesh sieve.
③ Total Mixed particles: mixing TDF granule, lamivudine granule, and additional carboxymethyl starch sodium and magnesium stearate.
(3) Tabletting: the first and second layers were compressed into a bilayer tablet on a high speed tablet press with a 300mg layer 1 fill weight and a 1200mg second layer fill weight.
(4) Film coating: an aqueous suspension of yellow Opadry at 18% by weight was prepared and the compressed tablets were film coated.
Comparative example 4 preparation of a Process granule having a Water content of greater than 3%
The composition was the same as in example 1.
The preparation process is the same as example 1 except that the content and the water content of the particles are controlled to be 3.5 percent, and the preparation process comprises the following steps:
(1) preparing doramevir sodium particles: putting dorawivir sodium, mannitol, microcrystalline cellulose, carboxymethyl starch sodium and polyvidone into a high-shear wet granulation machine, and stirring at low speed for 10 min. Granulating with purified water. And (5) carrying out wet granulation by adopting a 20-mesh sieve, and drying until the moisture content is 3.5%. Drying and granulating by adopting a 20-mesh sieve.
(2) Preparation of TDF particles: TDF, microcrystalline cellulose, lactose and croscarmellose sodium are uniformly mixed, and dry granulation is carried out in a dry granulation machine, a 20-mesh screen is used for carrying out granulation, and the water content of granules is 3.5%.
(3) Preparation of lamivudine particles: uniformly mixing lamivudine, microcrystalline cellulose and croscarmellose sodium, stirring, and mixing at low speed for 10 min. Granulating with purified water. And (3) carrying out wet granulation by adopting a 20-mesh sieve, drying until the moisture content is 3.5%, and carrying out dry granulation by adopting the 20-mesh sieve.
(4) Total mixing: mixing the dorzolawir sodium granules, the TDF granules, the lamivudine granules, the added carboxymethyl starch sodium and the magnesium stearate uniformly.
(5) Tabletting: compressed into tablets on a high-speed tablet press.
(6) Film coating: an aqueous suspension of yellow Opadry at 18% by weight was prepared and the compressed tablets were film coated.
Comparative example 5 pharmaceutical composition with modified adjuvant
The diluents in the doramevir sodium granules and the tenofovir disoproxil fumarate granules are changed into starch and dextrin.
The preparation method is the same as example 1.
Comparative example 6 pharmaceutical composition with modified adjuvant
The procedure of example 1 was otherwise the same as that of example 1 except that the binder in the doramevir sodium particles was changed to polyvinyl alcohol.
The preparation method is the same as example 1.
Experimental example 1 tabletting yields of tablets prepared by different methods
The press batch was prepared in batches of 10 ten thousand tablets per batch according to the recipe procedures of examples 1-5 and comparative examples 1-6, respectively. The tablets were individually tabletted, and the tabletting yields were calculated, and the results are shown in Table 1.
TABLE 1 tabletting yields for the respective processes
| Sample (I) | Amount of tabletting material (kg) | Amount of qualified tablet (kg) | Yield (%) |
| Example 1 | 148.5 | 145.68 | 98.1 |
| Example 2 | 148.1 | 145.75 | 98.4 |
| Example 3 | 280 | 276.4 | 98.7 |
| Example 4 | 40 | 37.6 | 94 |
| Example 5 | 210 | 207.8 | 98.9 |
| Comparative example 1 | 147.6 | 142.9 | 96.8 |
| Comparative example 2 | 149.5 | 146.7 | 98.1 |
| COMPARATIVE EXAMPLE 3 (bilayer tablet) | 148.2 | 119.2 | 80.4 |
| Comparative example 4 | 148.6 | 133.7 | 89.9 |
| Comparative example 5 | 147.9 | 140.5 | 94.9 |
| Comparative example 6 | 148.7 | 137.6 | 92.5 |
The results in the table show that the comparative example 3 is prepared by a double-layer sheet process, the process is complex, the requirement is higher, and the yield is obviously reduced compared with the single-layer corrosion sheet of the invention, which indicates that the single-layer corrosion sheet process of the invention is more suitable for industrial mass production. And the yield of the final product is also affected if the moisture content of the granules is not well controlled in the manufacturing process (comparative example 4). The technical scheme of the invention can be realized by selecting proper auxiliary materials, and the yield of the product can be reduced to a certain extent by changing the auxiliary materials.
Experimental example 2 stability of tablets prepared under different process conditions
The samples of examples 1-5 and comparative examples 1-3 were packaged in plastic bottles, and the packaged products were subjected to accelerated stability tests while being left at 40 ℃ and 75% RH (accelerated conditions) for 3 months, and the results are shown in Table 2.
TABLE 2 content of relevant substances after acceleration of samples prepared under different processes for 3 months
The data in table 2 show that, in comparative example 1 and comparative example 2, TDF and dolabrawir sodium are directly mixed and then granulated and tableted, and after 3-month accelerated tests, the content of related impurities in comparative example 1 and comparative example 2 is obviously higher than that in examples 1-5 and comparative example 3 of the application, which shows that the single-layer corrosion-resistant tablet and the existing double-layer tablet process can improve the stability of the product and well solve the problem that tenofovir is degraded due to incompatibility with dolabrawir. Comparative example 4 does not control the water content of the granules during the preparation to within 3%, resulting in a decrease in the stability of the final product, and the impurity content significantly increases with the standing time. Comparative examples 5 and 6 had the adjuvants replaced therein, so that the TDF underwent moisture absorption degradation during storage and the impurity content was significantly increased.
Experimental example 3 the brittle strength of the product prepared in each example
Hardness tests were conducted on the products of examples 1 to 5 and comparative examples 1 to 6 using a tablet hardness tester (YD-20KZ), and the results are shown in Table 3.
TABLE 3 hardness of the products prepared by different processes
The data in table 3 show that, in comparative example 3, the hardness of the tablet is significantly higher than that of the technical scheme of the present invention, which indicates that the hardness of the product is improved by the double-layer tablet process, but the hardness of the tablet should be maintained within a certain range, and the disintegration of the tablet may be affected if the hardness is too high. Comparative example 4 controls the moisture of granules during the preparation process to 3%, so that the hardness of the finally compressed tablet is reduced, while comparative examples 5 and 6 also obviously reduce the hardness of the product after changing the types of auxiliary materials, and the formability of the tablet is affected by the excessively low hardness of the tablet.
Experimental example 4 dissolution test of the product prepared in each example
The products prepared in examples 1 to 2 and comparative examples 1 to 3 were subjected to dissolution test with the original ground product (Totiravivir sodium tablets, trade name: TIVICAY): according to a dissolution rate determination method (XC second method which is an appendix of the second part of the 2020 version of Chinese pharmacopoeia), 900ml of buffer solution with the pH value of 6.8 and containing 0.25 percent SDS is used as a dissolution medium, and the rotation speed is set to be 65 revolutions per minute, and the dissolution amount of the dorzolawiram sodium in the product is respectively detected by sampling for 5min, 10min, 15min, 20min, 30min, 45min and 60 min. The test results of the dissolution curve are shown in figure 1.
According to the attached figure 1, the preparation method can be seen in that after the dolabrawir sodium, the lamivudine and the norfuvirate fumarate are independently granulated and tableted to form the erosion tablet, the in-vitro dissolution of the erosion tablet is basically consistent with that of the original preparation.
The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A pharmaceutical composition, wherein said composition is formulated as a single layer erosion tablet comprising the following components:
A. one or more of dolastavir and salts thereof,
B. the content of the lamivudine is determined,
C. one or more of tenofovir and prodrugs thereof,
D. one or more pharmaceutically acceptable adjuvants.
2. The pharmaceutical composition of claim 1, wherein the composition comprises
A.10-75mg of dolastavir and one or more of the salts thereof,
b.100-600mg lamivudine,
c.10-400mg of one or more of tenofovir and its prodrug,
D. one or more pharmaceutically acceptable adjuvants.
3. The pharmaceutical composition of claim 1, wherein the dorzolavir salt is dorzolavir sodium and the tenofovir prodrug is tenofovir disoproxil fumarate.
4. The pharmaceutical composition according to claim 3, wherein the weight ratio of the dorzolavir sodium to the tenofovir disoproxil fumarate is 1:0.5-1: 15.
5. The pharmaceutical composition of claim 1, wherein the erosion time of the erosion patch is 1-40 minutes.
6. The pharmaceutical composition of claim 1, wherein the excipient is selected from one or more of a diluent, a binder, a lubricant, and a disintegrant.
7. The pharmaceutical composition according to claim 6, wherein the binder is selected from one or more of povidone, starch, pregelatinized starch, hypromellose, ethylcellulose;
the diluent is selected from one or more of lactose, mannitol, microcrystalline cellulose, calcium hydrogen phosphate and calcium carbonate;
the disintegrant is selected from one or more of croscarmellose sodium, carboxymethyl starch sodium starch, crospovidone, low-substituted hydroxypropyl cellulose and dry starch;
the lubricant is selected from one or more of magnesium stearate, stearic acid, talcum powder and sodium stearyl fumarate.
8. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 7, comprising the steps of: the component A, C is prepared into granule A and granule C separately, and the component B is prepared into powder or granule B and A, C by mixing, tabletting and coating.
9. The method according to claim 8, wherein the moisture content of the particles A, B and C is less than 3%.
10. Use of a pharmaceutical composition according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prevention of aids.
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| CN114191404A (en) * | 2022-01-10 | 2022-03-18 | 安徽贝克生物制药有限公司 | Totiravi tablet and preparation method thereof |
| CN116270699A (en) * | 2023-03-07 | 2023-06-23 | 上海复星医药产业发展有限公司 | Three-party preparation, preparation method and application |
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| WO2009106954A1 (en) * | 2008-02-27 | 2009-09-03 | Aurobindo Pharma Limited | Stable dosage forms of lamivudine and tenofovir |
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| CN114191404A (en) * | 2022-01-10 | 2022-03-18 | 安徽贝克生物制药有限公司 | Totiravi tablet and preparation method thereof |
| CN116270699A (en) * | 2023-03-07 | 2023-06-23 | 上海复星医药产业发展有限公司 | Three-party preparation, preparation method and application |
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