阅读说明：本技术 包含索磷布韦和拉维达韦的片剂及其制备方法 (Tablet containing Sofosbuvir and Lavidavir and preparation method thereof ) 是由 吴登仪 柴旭煜 吴劲梓 施方震 于 2019-09-17 设计创作，主要内容包括：本发明提供了包含索磷布韦和拉维达韦的片剂及其制备方法,所述片剂包含分开的索磷布韦部分和拉维达韦部分,其中所述索磷布韦部分包含索磷布韦或其药学上可接受的盐,和作为崩解剂的交联羧甲基纤维素钠和/或交联聚乙烯吡咯烷酮,并且不包含拉维达韦或其药学上可接受的盐；所述拉维达韦部分包含拉维达韦或其药学上可接受的盐,和作为崩解剂的交联聚乙烯吡咯烷酮,并且不包含索磷布韦或其药学上可接受的盐。本发明制备的片剂可以降低双组分索磷布韦和拉维达韦在溶出过程中的相互干扰作用,实现快速完全的溶出。同时,其制备方法简单易行,适合工业化生产。(The invention provides a tablet comprising sofosbuvir and ravidavir and a preparation method thereof, wherein the tablet comprises a separate sofosbuvir part and a ravidavir part, wherein the sofosbuvir part comprises sofosbuvir or a pharmaceutically acceptable salt thereof, and croscarmellose sodium and/or crospovidone as a disintegrant, and does not comprise ravidavir or a pharmaceutically acceptable salt thereof; the ravidavir fraction comprises ravidavir or a pharmaceutically acceptable salt thereof, and cross-linked polyvinylpyrrolidone as a disintegrant, and does not comprise fosbuvir or a pharmaceutically acceptable salt thereof. The tablet prepared by the invention can reduce the mutual interference effect of the bi-component Sofosbuvir and the Lavidavir in the dissolution process, and realize rapid and complete dissolution. Meanwhile, the preparation method is simple and feasible, and is suitable for industrial production.)

1. A tablet comprising sofosbuvir and ravidavir, comprising separate sofosbuvir and ravidavir moieties, wherein the sofosbuvir moieties comprise sofosbuvir or a pharmaceutically acceptable salt thereof, and croscarmellose sodium and/or crospovidone as a disintegrant and do not comprise ravidavir or a pharmaceutically acceptable salt thereof; the ravidavir fraction comprises ravidavir or a pharmaceutically acceptable salt thereof, and cross-linked polyvinylpyrrolidone as a disintegrant, and does not comprise fosbuvir or a pharmaceutically acceptable salt thereof.

2. The tablet comprising sofosbuvir and ravidavir according to claim 1, wherein the sofosbuvir portion comprises sofosbuvir or a pharmaceutically acceptable salt thereof and a disintegrant in a mass ratio of 40.0 to 62.5: 2.0 to 20.0;

preferably, the mass ratio of the sofosbuvir or the pharmaceutically acceptable salt thereof, the disintegrant and other pharmaceutically acceptable auxiliary materials contained in the sofosbuvir part is 40.0-62.5: 2.0-20.0: 17.5 to 58.0.

3. The tablet comprising sofosbuvir and ravidavir according to claim 1 or 2, wherein the ravidavir portion comprises the ravidavir or a pharmaceutically acceptable salt thereof and a disintegrant in a mass ratio of 32.0 to 62.5: 2.0 to 10.0;

preferably, the ratio of the lavendavir part containing lavendavir or the pharmaceutically acceptable salt thereof, the disintegrant and other pharmaceutically acceptable auxiliary materials is 32.0-62.5: 2.0-10.0: 21.5 to 62.9.

4. The tablet comprising sofosbuvir and lavida according to any of claims 1 to 3, which is a bi-layer tablet wherein one layer comprises the sofosbuvir moiety and the other layer comprises the lavida moiety.

5. The tablet comprising sofosbuvir and lavida according to any of claims 1 to 3, further comprising an intermediate portion between the sofosbuvir and lavida portions; preferably, the intermediate part is free of fosbuvir or a pharmaceutically acceptable salt thereof and/or of ravidavir or a pharmaceutically acceptable salt thereof.

6. The tablet comprising sofosbuvir and ravidavir of claim 5 which is a trilayer tablet wherein a first layer comprises the sofosbuvir portion, a second layer comprises the ravidavir portion and an intermediate layer comprises the intermediate portion.

7. The tablet comprising sofosbuvir and lavivavir according to any of claims 1 to 6, which is a unit formulation wherein the sofosbuvir fraction comprises 400mg sofosbuvir and the lavivavir fraction comprises 200mg lavivavir or 219.1mg lavivavir dihydrochloride.

8. The tablet comprising sofosbuvir and ravidavir according to any of claims 1 to 7, which is a coated tablet.

9. Process for the preparation of tablets comprising fosbuvir and ravidavir according to any of claims 1 to 8, comprising the following steps:

(1) mixing the sofosbuvir or the pharmaceutically acceptable salt thereof with part or all of the disintegrant and part or all of other pharmaceutically acceptable auxiliary materials, after dry granulation, optionally adding the rest of the disintegrant and other pharmaceutically acceptable auxiliary materials, and uniformly mixing to obtain a sofosbuvir part material;

(2) mixing the Lavidavir or the pharmaceutically acceptable salt thereof with part or all of the disintegrant and part or all of other pharmaceutically acceptable auxiliary materials, after dry granulation, optionally adding the rest of the disintegrant and other pharmaceutically acceptable auxiliary materials, and uniformly mixing to prepare a Lavidavir partial material, or mixing the Lavidavir or the pharmaceutically acceptable salt thereof with all of the disintegrant and all of the other pharmaceutically acceptable auxiliary materials to prepare a Lavidavir partial material;

(3) optionally, the intermediate part material is prepared by directly mixing pharmaceutically acceptable auxiliary materials through powder, or after wet granulation and dry granulation and/or adding additional auxiliary materials;

(4) pressing the Sofosbuvir part material and the Lavidavir part material into a double-layer tablet; optionally, the Sofosbuvir part material, the middle part material and the Lavidavir part material are pressed into a three-layer tablet.

10. The process for preparing tablets containing fosbuvir and ravidavir according to claim 9, wherein in step (4), the fosbuvir partial material and the ravidavir partial material, or the ravidavir partial material and the fosbuvir partial material, are separately filled in order in a rotary tablet press and compressed into a double-layer tablet;

optionally, respectively filling materials according to the sequence of the Sofosbuvir part material, the middle part material and the Lavidavir part material, or the sequence of the Lavidavir part material, the middle part material and the Lavidavir material, and pressing into a three-layer tablet.

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a tablet containing Sofosbuvir and Lavidavir and a preparation method thereof.

Background

Sofosbuvir (Sofosbuvir) is an inhibitor acting on the polymerase target of the NS5B polymerase of Hepatitis C Virus (HCV) and acts by interfering with the synthesis of antiviral genetic material RNA and stopping the replication of HCV. The chemical name of the sofosbuvir is as follows: (S) -isopropyl-2- ((S) - ((((2R, 3R,4R,5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) - (phenoxy) phosphinylamino) propionate, having the structure shown in formula (I):

ravidavir (Ravidasvir) is a potent inhibitor acting on the NS5A replication complex and has the chemical name: methyl-N- [ (2S) -1- [ (2S) -2- [5- (6- {2- [ (2S) -1- [ (2S) -2- (methoxycarbonyl) amino ] -3-methylbutyryl ] pyrrolidin-2 yl ] -1H-1, 3-benzoxadiazol-6-yl } naphthalen-2-yl) -1H-imidazol-2-yl ] pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl ] carbamate dihydrochloride, which has the following structure represented by formula (II):

the combination of the two drugs with different action targets of the Sofosbuvir and the Lavidavir is expected to form a new oral universal-genotype once-a-day HCV treatment drug.

When two active ingredients with different chemical properties are designed and compressed into a single tablet, the chemical compatibility of the two ingredients needs to be considered firstly. The chemical incompatibility among the effective components can cause the degradation reaction in the preparation process and the long-term storage process, so that the content is reduced, the degradation impurities are increased, and the development failure of the compound preparation is caused. It is a conventional formulation technique to granulate (CN105534980A) or compress the chemically incompatible components separately into bilayer tablets (CN1615123A) to ensure chemical stability by physical separation. In addition, the development of the compound preparation sometimes needs to adopt a solubilization technology, for example, the component ledipasvir is prepared into a solid dispersion for solubilization through spray drying, and then the solid dispersion is compressed into a tablet (CN104144682A) together with the fosbuvir, so that reasonable in vivo and in vitro dissolution and in vivo bioavailability are ensured.

The sofosbuvir is slightly soluble in water, and the solubility of the sofosbuvir is more than or equal to 2mg/mL in the condition ranges of 37 ℃ and pH value of 2.0-7.7. The commercial 400mg Sofosbuvir tablets can achieve the rapid dissolution target (CN105287424A) of more than 85% in water, hydrochloric acid solution with pH1.0, acetic acid buffer solution with pH4.5 and phosphate buffer solution with pH6.8 after 15 minutes dissolution under the condition of paddle method of 75 r/min. Lavidavir is a dihydrochloride salt, whose solubility is pH dependent, 122mg/mL in hydrochloric acid solution at pH1.0 at 25 ℃, 73.5mg/mL in phosphate buffer at pH3.5, and a further increase in pH to 7.5, the solubility drops abruptly to 0.007 mg/mL.

The Sofosbuvir structurally has phosphoryl groups, the dissolution rate of the Sofosbuvir is related to the ionization process of the Sofosbuvir, and the local ionic strength in a preparation can obviously influence the dissolution rate of a medicament. Lavidavir is dihydrochloride, and the free base of the Lavidavir has stronger positive charge. The Sofosbuvir and the Lavidavir have good chemical compatibility in a solid state, and can meet the aim that two components are quickly dissolved out without mutual influence in a dissolving medium with the pH value of less than 3.0. However, researches find that in a dissolution medium with a high pH value (pH is more than or equal to 3.0), the solubility of the Lavidavir is limited, so that the local ionic strength of the tablet is too high, and the dissolution of the Sofosbuvir is influenced; on the other hand, the dissolution rate of the Sofosbuvir is reduced, and the undissolved part of the medicine is subjected to gelation phenomenon, which can also interfere with the dissolution rate of the Lavidavir.

Disclosure of Invention

Therefore, the technical problem to be solved by the invention is to provide a tablet containing the fosbuvir and the ravidavir and a preparation method thereof. The tablet prepared by the invention can reduce the mutual interference effect of the bi-component Sofosbuvir and the Lavidavir in the dissolution process, and realize rapid and complete dissolution. Meanwhile, the preparation method is simple and feasible, and is suitable for industrial production.

In one aspect, the present invention provides a tablet comprising sofosbuvir and ravidavir comprising separate sofosbuvir and ravidavir moieties, wherein the sofosbuvir moieties comprise sofosbuvir or a pharmaceutically acceptable salt thereof, and croscarmellose sodium and/or crospovidone as a disintegrant and do not comprise ravidavir or a pharmaceutically acceptable salt thereof; the ravidavir fraction comprises ravidavir or a pharmaceutically acceptable salt thereof, and cross-linked polyvinylpyrrolidone as a disintegrant, and does not comprise fosbuvir or a pharmaceutically acceptable salt thereof.

Preferably, in the tablet containing the sofosbuvir and the ravidavir, the sofosbuvir part contains the sofosbuvir or the pharmaceutically acceptable salt thereof and the disintegrant in a mass ratio of 40.0-62.5: 2.0 to 20.0. More preferably, the mass ratio of the sofosbuvir or the pharmaceutically acceptable salt thereof, the disintegrant and other pharmaceutically acceptable auxiliary materials contained in the sofosbuvir part is 40.0-62.5: 2.0-20.0: 17.5 to 58.0.

Preferably, in the tablet containing the Sofosbuvir and the Lavidavir, the Lavidavir part contains the Lavidavir or the pharmaceutically acceptable salt thereof and the disintegrant in a mass ratio of 32.0-62.5: 2.0 to 10.0. More preferably, the ratio of the lavendavir or the pharmaceutically acceptable salt thereof, the disintegrant and other pharmaceutically acceptable auxiliary materials contained in the lavendavir part is 32.0-62.5: 2.0-10.0: 21.5 to 62.9.

According to one embodiment of the invention, the tablet comprising sofosbuvir and ravidavir of the invention is a bi-layer tablet, wherein one layer comprises the sofosbuvir moiety and the other layer comprises the ravidavir moiety.

Preferably, the tablet comprising sofosbuvir and ravidavir of the present invention further comprises an intermediate portion located between the sofosbuvir portion and the ravidavir portion; more preferably, the intermediate part is free of fosbuvir or a pharmaceutically acceptable salt thereof and/or of ravidavir or a pharmaceutically acceptable salt thereof.

According to one embodiment of the invention, the tablet comprising fosbuvir and ravidavir of the invention is a trilayer tablet, wherein the first layer comprises the fosbuvir fraction, the second layer comprises the ravidavir fraction and the intermediate layer comprises the intermediate fraction.

According to one embodiment of the invention, the tablet comprising sofosbuvir and ravidavir provided by the invention is a unit formulation, wherein the sofosbuvir fraction comprises 400mg sofosbuvir and the ravidavir fraction comprises 200mg ravidavir or 219.1mg ravidavir dihydrochloride.

Preferably, the tablets of the invention comprising fosbuvir and ravidavir are coated tablets.

In another aspect, the present invention provides a preparation method of the tablet containing the fosbuvir and the ravidavir, which comprises the following steps:

(1) mixing the sofosbuvir or the pharmaceutically acceptable salt thereof with part or all of the disintegrant and part or all of other pharmaceutically acceptable auxiliary materials, after dry granulation, optionally adding the rest of the disintegrant and other pharmaceutically acceptable auxiliary materials, and uniformly mixing to obtain a sofosbuvir part material;

(2) mixing the Lavidavir or the pharmaceutically acceptable salt thereof with part or all of the disintegrant and part or all of other pharmaceutically acceptable auxiliary materials, after dry granulation, optionally adding the rest of the disintegrant and other pharmaceutically acceptable auxiliary materials, and uniformly mixing to prepare a Lavidavir partial material, or mixing the Lavidavir or the pharmaceutically acceptable salt thereof with all of the disintegrant and all of the other pharmaceutically acceptable auxiliary materials to prepare a Lavidavir partial material;

(3) optionally, the intermediate part material is prepared by directly mixing pharmaceutically acceptable auxiliary materials through powder, or after wet granulation and dry granulation and/or adding additional auxiliary materials;

(4) pressing the Sofosbuvir part material and the Lavidavir part material into a double-layer tablet; optionally, pressing the Sofosbuvir part material, the middle part material and the Lavidavir part material into a three-layer tablet;

preferably, in a rotary tablet press, respectively filling materials according to the sequence of the Sofosbuvir part material and the Lavidavir part material, or the sequence of the Lavidavir part material and the phosphorus buvir part material, and pressing into a double-layer tablet; optionally, respectively filling materials according to the sequence of the Sofosbuvir part material, the middle part material and the Lavidavir part material, or the sequence of the Lavidavir part material, the middle part material and the Lavidavir material, and pressing into a three-layer tablet.

The inventor of the invention unexpectedly finds that the mutual interference effect of the fosbuvir and the ravidavir in the dissolution process can be reduced by adjusting the specific types and the specific proportion of the pharmaceutical excipients and combining the technology of pressing the double-layer tablet or the three-layer tablet.

The invention has the advantages that:

(1) by adding the disintegrating agent with specific types and characteristic proportions, the tablet can be quickly disintegrated, and the contact time in water is reduced. The physical contact between the two components is reduced by the design of the two-layer sheet or the three-layer sheet. The two effects act synergistically to minimize the interference between the dissolution of the two active ingredients;

(2) the invention has another advantage that the surface of the coated tablet is flat and smooth, and is suitable for industrialized production.

Drawings

Fig. 1 to 7 are graphs comparing dissolution curves of fosbuvir and ravidavir when compressed into multi-layer tablets and compressed into single-layer tablets using the same formulation, respectively, according to example 1 and comparative example 1 of the present invention, in which:

FIG. 1 is a comparison of the dissolution profiles of composition A1 of example 1 and composition A2 of comparative example 1;

FIG. 2 is a comparison of the dissolution profiles of composition B1 of example 1 and composition B2 of comparative example 1;

FIG. 3 is a comparison of the dissolution profiles of composition C1 of example 1 and composition C2 of comparative example 1;

FIG. 4 is a comparison of the dissolution profiles of composition D1 of example 1 and composition D2 of comparative example 1;

FIG. 5 is a comparison of the dissolution profiles of composition E1 of example 1 and composition E2 of comparative example 1;

FIG. 6 is a comparison of the dissolution profiles of composition F1 of example 1 and composition F2 of comparative example 1;

FIG. 7 is a comparison of the dissolution profiles of composition G1 of example 1 and composition G2 of comparative example 1;

fig. 8 to 11 are comparative graphs showing the effect on the dissolution profile of tablets prepared using the formulation of composition a1 in example 1 and the formulation of composition A3 in comparative example 2 due to the difference in the amount of disintegrant, wherein:

FIG. 8 is a comparison of the dissolution profiles of composition A1 of example 1 and composition A3 of comparative example 2 in hydrochloric acid solution at pH 1.2;

FIG. 9 is a comparison of the dissolution profiles of composition A1 of example 1 and composition A3 of comparative example 2 in acetate buffer at pH 4.0;

FIG. 10 is a comparison of the dissolution profiles of composition A1 of example 1 and composition A3 of comparative example 2 in phosphate buffer at pH 6.8;

FIG. 11 is a comparison of the dissolution profiles in water of composition A1 of example 1 and composition A3 of comparative example 2.

FIG. 12 is a comparison of the dissolution profiles in water of compositions E3, F3, and G3 of comparative example 3.

Detailed Description

The present invention is further illustrated by the following examples, which are intended to be purely exemplary of the invention and are not intended to be limiting.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in experimental or practical applications, the materials and methods are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.