CN110693887B - Tablet containing Sofosbuvir and Lavidavir and preparation method thereof - Google Patents
Tablet containing Sofosbuvir and Lavidavir and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
The invention provides a tablet containing sofosbuvir and ravidavir and a preparation method thereof, wherein the tablet contains separate sofosbuvir and ravidavir parts, wherein the sofosbuvir parts contain sofosbuvir or a pharmaceutically acceptable salt thereof, and croscarmellose sodium and/or crospovidone as a disintegrant and do not contain 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 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.
Description
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 the 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 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.
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 herein 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 and are not intended to limit the scope of the invention.
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 the practice or experimental 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.
Example 1
1. The prescription composition is as follows:
table 1 prescription of the sofosbuvir fraction
TABLE 2 Lavidavir fraction prescription
TABLE 3 prescription without drug moiety
2. The preparation process comprises the following steps:
sofosbuvir part: the compositions A1, B1, C1, E1, F1 and G1 are respectively prepared into the sofosbuvir composition by uniformly mixing a part of raw materials and auxiliary materials in granules, performing dry granulation, adding a part of auxiliary materials in the granules and the auxiliary materials according to the proportion of the composition, and uniformly mixing to prepare the sofosbuvir composition; and the composition D1 is prepared by directly and uniformly mixing the raw materials and auxiliary materials according to the proportion of the composition.
Lavida part: respectively mixing part of the raw materials and adjuvants with the granules of the compositions B1, D1 and F1, dry granulating, adding part of the adjuvants and mixing to obtain Lavidavir composition; the compositions A1, C1, E1 and G1 are prepared into the Lavidavir composition by directly and uniformly mixing the raw materials and the auxiliary materials according to the proportion of the compositions.
No drug moiety: the composition D1 and E1 are prepared by weighing pretreated adjuvant, mixing, and making into composition without medicinal part.
Preparation of tablets: in a rotary tablet press, the first layer of material is added with the prepared Sofosbuvir composition, and prepressing and forming are carried out; optionally adding non-medicated layer (D1 group and E1 group) according to composition group, and pre-pressing for molding, or optionally adding non-pre-pressing (A1, B1, C1, F1 and G1); finally, the formulated ravidavir composition is added and compressed into the final tablet.
Comparative example 1
Taking the Sofosbuvir part and the Lavidavir part in the compositions A1, B1, C1, D1, E1, F1 and G1 in example 1, mixing the two parts uniformly, and directly pressing into a single-layer tablet, wherein the corresponding single-layer tablets have the composition groups with the numbers of A2, B2, C2, D2, E2, F2 and G2 respectively.
Comparative example 2
1. The prescription composition is as follows:
table 4 prescription of the fosbuvir portion
TABLE 5 Lavidavir fraction prescription
TABLE 6 prescription without drug moiety
2. The preparation process comprises the following steps:
sofosbuvir part: respectively adding part of raw materials and auxiliary materials into the granules of the compositions A3, B3 and C3, uniformly mixing, performing dry granulation, adding the granules and part of auxiliary materials into the granules according to the proportion of the compositions, and uniformly mixing to prepare the sofosbuvir composition; and the composition D3 is prepared by directly and uniformly mixing the raw materials and auxiliary materials according to the proportion of the composition.
Lavida part: respectively mixing part of the raw materials and the auxiliary materials in the granules, performing dry granulation, adding part of the auxiliary materials in the granules according to the proportion of the composition, and mixing uniformly to prepare the Lavidavir composition in the groups B3 and D3; the compositions A3 and C3 are prepared by directly and uniformly mixing the raw materials and auxiliary materials according to the proportion of the compositions to prepare the Lavidavir composition.
No drug moiety: and the composition D3 is prepared by weighing the pretreated auxiliary materials, uniformly mixing and preparing the composition without the medicine part.
Preparation of tablets: in a rotary tablet press, the first layer of material is added with the prepared Sofosbuvir composition, and prepressing and forming are carried out; optionally adding a non-medicated layer (group D3), and pre-pressing again, or optionally adding no pre-pressing (groups A3, B3, and C3) according to composition group; finally, the formulated ravidavir composition is added and compressed into the final tablet.
Comparative example 3
1. The prescription composition is as follows:
TABLE 7 prescription of Sofosbuvir
TABLE 8 Lavidavir fraction prescription
TABLE 9 prescription without drug moiety
2. The preparation process comprises the following steps:
sofosbuvir part: the compositions E3, F3 and G3 are prepared by respectively taking the granules, adding part of the raw materials and the auxiliary materials, uniformly mixing, performing dry granulation, adding the granules and part of the auxiliary materials according to the proportion of the compositions, and uniformly mixing to prepare the sofosbuvir composition.
Lavida part: composition G3, mixing part of the raw materials and adjuvants respectively, dry granulating, adding part of the adjuvants, mixing, and making into Lavidavir composition; the compositions E3 and F3 are prepared by directly and uniformly mixing the raw materials and auxiliary materials according to the proportion of the compositions to prepare the Lavidavir composition.
No drug moiety: and the composition G3 is prepared by weighing the pretreated auxiliary materials, uniformly mixing and preparing the composition without the medicine part.
Preparation of tablets: in a rotary tablet machine, the first layer of material is added with the prepared sofosbuvir composition, and pre-pressing forming is carried out; optionally adding a non-medicated layer (G3 group), and pre-pressing again, or optionally adding no pre-pressing (E3 and F3 groups) according to composition group; finally, the formulated lavivavir composition is added and compressed into the final tablet.
Effect example 1
Taking A1-G1 under the item of example 1 and A2-G2 under the item of comparative example 1, taking 6 tablets each (each containing 400mg of sofosbuvir and 200mg of Lavidavir), measuring the dissolution curve under the condition of paddle method 75rpm in 50mM phosphate buffer solution with degassed concentration of 900mL at 37 ℃ and pH3.5, respectively sampling 5mL with 5, 10, 15, 20, 30, 45 and 60min, simultaneously supplementing 5mL, filtering by a nylon filter membrane, removing 2mL of crude filtrate, taking the subsequent filtrate, respectively measuring the concentrations of the sofosbuvir and the Lavidavir by an HPLC-UV method, and calculating the cumulative dissolution percentage.
HPLC determination conditions: a chromatographic column: inertsil ODS-3column (150 x 4.6mm, 5 μm); mobile phase system: water: acetonitrile: trifluoroacetic acid 60: 40: 0.1; the detection wavelength is 265 nm; flow rate: 1.0 mL/min; column temperature: 30 ℃; sample introduction volume: 10 mu L of the solution; the concentration of the two components was determined by peak area external standard method. Under the chromatographic condition, the retention time of the Lavidavir and the Sofosbuvir is 2.8min and 5.0min respectively, so that complete baseline separation can be realized, and the requirement of rapid determination is met.
And (4) conclusion: from the comparison results of the dissolution curves of the ravidavir and the fosbuvir in fig. 1-7, it can be seen that after the composition is made into tablets with the same composition and is pressed into multilayer tablets (double-layer or three-layer tablets), the mutual interference of the ravidavir and the fosbuvir in the single-layer tablets can be reduced, and the faster and more complete dissolution of the two components can be promoted.
Effect example 2
The dissolution curves of A1 in example 1 and A3 in comparative example 2 were compared with each other for pH1.2 hydrochloric acid solution, pH4.0 acetic acid buffer, pH6.8 phosphoric acid buffer and water. Other dissolution test conditions were: 37 ℃, 900mL volume, paddle method at 75rpm, sampling time 5, 10, 15, 20, 30, 45 and 60min respectively.
HPLC determination conditions: the same effect as in example 1 was obtained.
And (4) conclusion: as can be seen from the comparison results of the dissolution curves of the ravidavir and the fosbuvir in the figures 8-11, in a hydrochloric acid solution with the pH value of 1.2, because the ravidavir is acid and easy to dissolve, both components can be quickly dissolved, and the dosage difference of the disintegrating agent is not large; whereas, in the acetate buffer solution of ph4.0, the phosphate buffer solution of ph6.8 and water, the a3 composition of comparative example 2, in which the amount of the disintegrant was outside the range of the present invention, caused interference between the ravidavir and the fosbuvir during dissolution due to the decreased disintegration rate, resulting in a sudden drop in the dissolution curve.
Effect example 3
Tablets compressed with the formulation of the compositions B1, C1 and D1 under example 1 were compared to tablets compressed with the formulation of the compositions B3, C3 and D3 under comparative example 2 in terms of the appearance of the tablets after gastric film coating.
Coating materials:
type II film coating premix (supplied by Carlaconica, model number OPADRY II 85F640004-CN PINK).
And (3) coating process: according to the preparation method of the coating solution of the supplier, the coating solution with 20 percent of solid content is prepared by purified water, the drug-containing tablets with the same weight are added in a high-efficiency coating machine, and the round blank tablets are added to the coating solution to the proper total weight. In the coating process, the temperature of a tablet bed is controlled to be 40-45 ℃ by adjusting the liquid spraying speed, the air inlet temperature and the air inlet flow, and the weight of the coating is increased to 2.5% of the initial total weight of the tablet.
And (5) judging a result: 3 tablets of each group were randomly taken out, and the surface condition of the coated tablets was observed on a white background, and the results are shown in the following table.
TABLE 10 comparison of appearance before and after coating of the compositions of example 1 and comparative example 3
| Surface condition of the skin | B1 | C1 | D1 | B3 | C3 | D3 |
| Noodle 1 | Smooth and clean | Smooth and clean | Smooth and clean | Roughness and unevenness | With pock marks | Is relatively flat |
| Noodle 2 | Smooth and clean | Smooth and clean | Smooth and clean | Roughness and unevenness | Is relatively flat | With hard spots |
| Side surface | Is smooth and level | Smooth and clean | Smooth and clean | Roughness and unevenness | With hard spots | With pock marks |
And (4) conclusion: in the tablets of the composition B3 in comparative example 3, the amounts of the disintegrants in the Sofosbuvir portion and the Lavidavir portion in the bilayer tablet were both in excess of the ratio of the present invention, and a high proportion of the disintegrant made difficulty in the aqueous coating, and the coated tablets had rough and uneven surfaces, and the presence of fine needle-like pores was observed. The bilayer tablets compressed with the compositions of C3 and D3 in comparative example 3 each had a layer of disintegrant in an amount exceeding the ratio of the present invention, and as a result, it was found that the contrast between the two layers of the tablets obtained by coating was significant, and the overrun side of the disintegrant was significantly uneven and pitted.
Effect example 4
Taking E3, F3 and G3 of comparative example 3, taking 6 tablets each (each containing 400mg of sofosbuvir and 200mg of Lavidavir), measuring the dissolution curve under the condition of paddle method 75rpm in 50mM phosphate buffer solution with degassed concentration of 50mM and pH3.5 at 37 ℃ and 900mL, respectively sampling 5mL and simultaneously supplementing 5mL for 5, 10, 15, 20, 30, 45 and 60min, filtering by a nylon filter membrane, removing 2mL of crude filtrate, taking subsequent filtrate, measuring the concentrations of the sofosbuvir and the Lavidavir respectively by an HPLC-UV method, and calculating the cumulative dissolution percentage.
HPLC determination conditions: a chromatographic column: inertsil ODS-3column (150 x 4.6mm, 5 μm); mobile phase system: water: acetonitrile: trifluoroacetic acid 60: 40: 0.1; the detection wavelength is 265 nm; flow rate: 1.0 mL/min; column temperature: 30 ℃; sample introduction volume: 10 mu L of the solution; the concentration of the two components was determined by peak area external standard method. Under the chromatographic condition, the retention time of the Lavidavir and the Sofosbuvir is 2.8min and 5.0min respectively, so that complete baseline separation can be realized, and the requirement of rapid determination is met.
And (4) conclusion: as can be seen from the results of the dissolution curve measurements of ravidavir and ravidavir in fig. 12, changing the type of disintegrant in the ravidavir layer to low-substituted hydroxypropyl cellulose (group E3), or changing the type of disintegrant in the ravidavir layer to croscarmellose sodium (group F3 and group G3), even after compression into a multilayer tablet (bilayer or trilayer tablet), the dissolution curves of both ravidavir and ravidavir are reduced by mutual interference, wherein the dissolution curves of both ravidavir and ravidavir are less than 90% for 1h and less than 70% for 1 h.
Although the present invention has been described to a certain extent, it is apparent that appropriate changes in the respective conditions may be made without departing from the spirit and scope of the present invention. It is to be understood that the invention is not limited to the described embodiments, but is to be accorded the scope consistent with the claims, including equivalents of each element described.
Claims (11)
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 does not comprise ravidavir or a pharmaceutically acceptable salt thereof; the ravidavir moiety 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;
wherein the mass ratio of the Sofosbuvir or the pharmaceutically acceptable salt thereof contained in the Sofosbuvir part to the disintegrant is 40.0-62.5: 2.0 to 20.0; the ratio of the Lavidavir or pharmaceutically acceptable salt thereof contained in the Lavidavir part to the disintegrant is 32.0-62.5: 2.0 to 10.0.
2. The tablet containing the sofosbuvir and the ravidavir as claimed in claim 1, wherein the sofosbuvir part contains the sofosbuvir or the pharmaceutically acceptable salt thereof, the disintegrant and other pharmaceutically acceptable auxiliary materials in a mass ratio of 40.0-62.5: 2.0-20.0: 17.5 to 58.0.
3. The tablet containing the Sofosbuvir and the Lavidavir according to claim 1, wherein the Lavidavir part contains the Lavidavir or the pharmaceutically acceptable salt thereof, the disintegrant and other pharmaceutically acceptable auxiliary materials in a mass ratio of 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.
6. The tablet comprising fosbuvir and ravidavir according to claim 5, wherein the intermediate portion is free of fosbuvir or a pharmaceutically acceptable salt thereof and/or ravidavir or a pharmaceutically acceptable salt thereof.
7. 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.
8. The tablet comprising sofosbuvir and ravidavir according to any of claims 1 to 3, which is a unit formulation wherein the sofosbuvir fraction comprises 400mg sofosbuvir and the ravidavir fraction comprises 200mg ravidavir or 219.1mg ravidavir dihydrochloride.
9. The tablet comprising sofosbuvir and ravidavir according to any of claims 1 to 3, which is a coated tablet.
10. Process for the preparation of tablets comprising fosbuvir and ravidavir according to any of claims 1 to 9 comprising the steps of:
(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, directly mixing pharmaceutically acceptable auxiliary materials through powder, or granulating through a wet method or a dry method and/or adding additional auxiliary materials to prepare the intermediate part material;
(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.
11. The process for preparing tablets containing fosbuvir and ravidavir according to claim 10, 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.
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