Patent Application
20190358203
The present invention belongs to the technical field of medicine, particularly, relates to an oral pharmaceutical composition comprising Tecovirimat and a preparation method thereof.
Smallpox is a highly lethal and infectious disease, which is mainly spread by droplet or clothing transmission, and the clinical manifestations of which are facial and systemic rashes until death. Although WHO declared in 1980 that smallpox had been eliminated in the nature, smallpox will still have disastrous consequences for humans or even cause wars around the world once it is unintentionally or deliberately released. Since smallpox vaccines have serious adverse reactions, medical therapy is still necessary. However, up to now, no pharmaceutical therapeutic regimen against smallpox has been approved worldwide.
Tecovirimat (designated as ST-246, with a chemical name of 4-trifluoromethyl-N-(3, 3a, 4, 4a, 5, 5a, 6, 6a-octahydro-1, 3-dioxo-4, 6-ethenocycloprop [f] isoindol-2 (1H)-yl)-benzamide, Formula 1) is a highly active small-molecule virus inhibitor, which works by binding to viral genes so as to prevent viral release in a cell. In addition, the use of Tecovirimat and a smallpox vaccine in combination can also effectively prevent and treat the adverse reactions caused by the smallpox vaccine, reduce the damage level and promote wound healing. However, Tecovirimat has a very poor water solubility, which is less than 0.003 mg/ml, and its low solubility restricts its clinical application.
CN201180048043.1 discloses a novel liquid preparation in which Tecovirimat is solubilized in cyclodextrin and a novel method for preparing the preparation. In the method, the solubility of Tecovirimat (ST-246) is increased to 1.5-11 mg/ml by using 20%-40% (w/v) hydroxypropyl-β-cyclodextrin (HP-β-CD) at 37° C. In particular, Tecovirimat (ST-246) can have a maximal solubility of 21.23 mg/ml by using 40% (w/v) HP-β-CD at 70° C. The presence of a cosolvent (PEG400) or a nonionic surfactant (Tween 80) cannot further improve the solubility of ST-246 in HP-β-CD.
Contents of Invention
After research, the inventors have creatively invented a ternary solubilizing composition containing Tecovirimat, cyclodextrin, and an additive (e.g. Meglumine (MEG)), which greatly improves the solubility (with a maximal solubility of up to 152 mg/ml) and oral dissolution rate (complete dissolution within 30 minutes) of Tecovirimat with poor solubility in water as compared with the prior art, and additionally, the composition has the advantages such as simple formulation process, short preparation time, stable quality, strong controllability, good reproducibility and low cost.
The present invention includes the following items:
1. A pharmaceutical composition, comprising Tecovirimat, cyclodextrin and an additive, and optionally a pharmaceutically acceptable excipient,
wherein said additive is selected from the group consisting of meglumine, glycine, arginine, hydroxypropyl methyl cellulose, polyethylene glycol, chitosan, and polyvinyl pyrrolidone, and is preferably meglumine.
2. The pharmaceutical composition according to Item 1 of the present invention, wherein said cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and a pharmaceutically acceptable cyclodextrin derivative (e.g. dimethyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin, trimethyl-β-cyclodextrin);
preferably, said cyclodextrin is selected from the group consisting of β-cyclodextrin, dimethyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin, trimethyl-β-cyclodextrin;
further preferably, said cyclodextrin is selected from the group consisting of 2-hydroxypropyl-β-cyclodextrin, and 3-hydroxypropyl-β-cyclodextrin;
further more preferably, said cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.
3. The pharmaceutical composition according to Item 1 or Item 2 of the present invention, wherein said cyclodextrin and Tecovirimat have a weight ratio of 4˜10:1, preferably 5˜8:1, further preferably 5:1, 6:1, 7:1 or 8:1, more preferably 6:1.
4. The pharmaceutical composition according to any one of Items 1 to 3 of the present invention, wherein said additive and Tecovirimat have a weight ratio of 0.5˜5:1, preferably 1˜4:1, further preferably 1:1, 2:1, 3:1 or 4:1, more preferably 2:1.
5. The pharmaceutical composition according to any one of Items 1 to 4 of the present invention, wherein said additive and cyclodextrin have a weight ratio of 1:1˜5, preferably 1:2˜4, further preferably 1:3.
6. The pharmaceutical composition according to any one of Items 1 to 5 of the present invention, wherein said pharmaceutical composition is an oral preparation, an injection, an infusion solution, drops, a patch, a liniment, an enema or an implant, preferably an oral preparation, an injection or an infusion solution, more preferably an oral preparation.
7. The pharmaceutical composition according to any one of Items 1 to 6 of the present invention, wherein said pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a disintegrating agent, a lubricant, a correctant, a coloring agent, a taste masking agent, a pH adjuster, a buffering agent, a preservative, a stabilizer, an antioxidant, a wetting agent, a humidity adjusting agent, a surfactant, a suspending agent and an absorption enhancer;
preferably, said pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a disintegrating agent, and a lubricant;
a preferred filler is selected from the group consisting of lactose, complex lactose, microcrystalline cellulose, anhydrous calcium dihydrogen phosphate, mannitol, starch, and pregelatinized starch;
a preferred binder is selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, and hydroxymethyl cellulose;
a preferred disintegrating agent is selected from the group consisting of cross-linked polyvinyl pyrrolidone, carboxymethyl starch sodium, croscarmellose sodium, and low-substituted hydroxypropyl cellulose;
a preferred lubricant is selected from the group consisting of talc powder, magnesium stearate, hydrogenated castor oil, and Aerosil.
8. The pharmaceutical composition according to any one of Items 1 to 7 of the present invention, comprising Tecovirimat, cyclodextrin (e.g. 2-hydroxypropyl-β-cyclodextrin), an additive (e.g. meglumine), lactose, hydroxypropyl methylcellulose, carboxymethyl starch sodium, and Aerosil, at a weight ratio of 40˜100:80˜120:200˜400:20˜50:1˜4:8˜12:1˜4, preferably 50:100:300:35.5:2:10.0:2.5 or 70:100:300:15.5:2:10.0:2.5.
9. A method for preparing the pharmaceutical composition according to any one of Items 1 to 8 of the present invention, comprising:
a) dissolving an additive and cyclodextrin in a desired volume of water, and mixing well;
b) adding Tecovirimat, and mixing well;
c) removing water by drying, wherein a preferred drying is freeze-drying or spray-drying;
d) adding a filler, a binder, and a disintegrating agent, sieving with an 80-mesh sieve, and mixing well;
e) compressing directly, or
adding a non-aqueous solvent (e.g. ethanol) as a wetting agent to prepare a soft material, preparing wet granules, drying the wet granules to obtain dry granules, adding a lubricant to the dry granules, mixing, breaking, and preparing tablets, or
adding a lubricant, and preparing capsules or granules.
10. A method for treating smallpox, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the pharmaceutical composition according to any one of Items 1 to 8 of the present invention.
11. The pharmaceutical composition according to any one of Items 1 to 8 of the present invention, for use in the treatment of smallpox.
12. Use of the pharmaceutical composition according to any one of Items 1 to 8 of the present invention for the manufacture of a medicament for treating smallpox.
In a particular embodiment, the pharmaceutical composition according to the present invention is an oral preparation, such as a granule (e.g. an instant granule), a capsule, or a tablet.
When the pharmaceutical composition according to the present invention is an oral preparation, it can be prepared by the following method comprising:
a. dissolving an additive and cyclodextrin in a desired volume of water, and mixing well;
b. adding the active ingredient-Tecovirimat, and stirring in a water bath;
c. removing water from the prepared solution by spray-drying;
d. adding a filler, a binder, and a disintegrating agent, mixing, sieving with an 80-mesh sieve, and mixing well;
e. adding a wetting agent (e.g. 50% (w/w) ethanol);
f. preparing a soft material with the as-prepared mixture, sieving with a 20-mesh sieve to prepare wet granules, and drying the wet granules at 60° C. to obtain dry granules;
g. adding a given amount of a lubricant to the dry granules, sieving with a 16-mesh sieve, mixing, breaking, and preparing tablets.
When the pharmaceutical composition according to the present invention is an oral preparation, it can also be prepared by another method comprising:
a. dissolving an additive and cyclodextrin in a desired volume of water, and mixing well;
b. adding the active ingredient-Tecovirimat, an stirring in a water bath;
c. removing water from the prepared solution by freeze-drying;
d. adding a filler, a binder, and a disintegrating agent, mixing, sieving with an 80-mesh sieve, and mixing well;
e. adding a wetting agent (e.g. 50% (w/w) ethanol);
f. using said mixing material to prepare a soft material, sieving with a 20-mesh sieve to prepare wet granules, and drying the wet granules at 60° C. to obtain dry granules;
g. adding a given amount of a lubricant to the dry granules, sieving with a 16-mesh sieve, mixing, breaking, and preparing tablets.
When the pharmaceutical composition according to the present invention is an oral preparation, it can also be prepared by another method comprising:
a. dissolving an additive and cyclodextrin in a desired volume of water, and mixing well;
b. adding the active ingredient-Tecovirimat, and stirring in a water bath;
c. removing water from the prepared solution by freeze-drying;
d. adding a filler, a binder, a disintegrating agent, and a lubricant, mixing, sieving with an 80-mesh sieve, and mixing well;
e. compressing directly to prepare tablets.
When the pharmaceutical composition according to the present invention is an oral preparation, it can also be prepared by another method comprising:
a. dissolving an additive and cyclodextrin in a desired volume of water, and mixing well;
b. adding the active ingredient-Tecovirimat, under stirring in a water bath;
c. removing water from the prepared solution by freeze-drying;
d. adding a filler, a binder, a disintegrating agent, and a lubricant, mixing, sieving with an 80-mesh sieve, and mixing well;
e. filling directly to prepare capsules.
When the pharmaceutical composition according to the present invention is an oral preparation, it can also be prepared by another method comprising:
a. dissolving an additive and cyclodextrin in a desired volume of water, and mixing well;
b. adding the active ingredient-Tecovirimat, and stirring in a water bath;
c. removing water from the prepared solution by freeze-drying;
d. adding a filler, a binder, a disintegrating agent, and a lubricant, mixing, sieving with an 80-mesh sieve, and mixing well;
e. filling directly to prepare instant granules.
In the present invention, the term “an additive” refers to a substance that can interact with an active ingredient, so as to enhance the inclusion efficiency of cyclodextrin, and further to improve drug solubility.
In the present invention, the term “soft material” refers to a wet mixture formed in a wet granulation process in which a suitable amount of a wetting agent or a binder are added to raw material and subsidiary material to form a mixture and the mixture is wetted to form a wet mixture.
In the present invention, “% (w/v)” refers to a mass/volume concentration, which represents the mass (expressed as gram) of a solute contained in a solution (100 ml). For example, 20% (w/v) represents 20 g of a solute contained in a solution (100 ml).
The embodiments of the present invention are described in detail by combining the following examples. However, a person skilled in the art will understand that the following examples and experimental examples are only used to describe the present invention, and should not be regarded as defining the scope of the present invention. In the case where the concrete conditions are not indicated in the examples and experimental examples, the examples are carried out according to conventional conditions or the conditions recommended by manufacturers. The reagents or apparatuses, the manufacturers of which are not indicated, are the conventional products that are commercially available.
In order to compare the dissolution characteristics of the drug, binary compositions (Tecovirimat/meglumine, Tecovirimat/cyclodextrin), and a ternary composition (Tecovirimat/meglumine/cyclodextrin), based on the Formulation in Table 1, tablets of a ternary composition (Tecovirimat/meglumine/cyclodextrin), a binary composition (Tecovirimat/meglumine), and a binary composition (Tecovirimat/cyclodextrin) were prepared, in which lactose was used to adjust the weight.
Preparation method: based on the prescribed amounts in the Formulation as described in Table 1, meglumine and hydroxypropyl-β-cyclodextrin were weighed, dissolved in a desired volume of water, and mixed well; a prescribed amount of the active ingredient-Tecovirimat was further added, under stirring in a water bath; water was removed from the prepared solution by freeze-drying; lactose (a filler), hydroxypropyl methylcellulose (a binder), and carboxymethyl starch sodium (a disintegrating agent) were added and mixed, then the resultant was sieved with an 80-mesh sieve, and mixed well; 50% (w/w) ethanol as a wetting agent was further added; the mixed material was prepared into a soft material, the soft material was sieved with a 20-mesh sieve to prepare wet granules, and the wet granules were dried at 60′C to obtain dry granules; to the dry granules, a prescribed amount of Aerosil (a lubricant) was added, and the resultant was sieved with 16-mesh sieve, broke, and compressed into tablets, or the resultant was subjected to filling directly to prepare instant granules.
Excess amounts of Tecovirimat (bulk drug powder) was added to an aqueous solution comprising meglumine and cyclodextrin at different ratios relative to each other to form a suspension. The suspension was placed in a constant-temperature incubation shaker, and was shaken at a temperature of 25±1° C., 37±1° C. and 60±1° C. for 72 h. After reaching equilibrium, the suspension was filtered through a 0.45 μm hydrophilic filter membrane to obtain a filtrate. After the filtrate was properly diluted with an acetonitrile-water (50:50, v/v) solution, the absorbance was measured at 224 nm, and the solubility of Tecovirimat was calculated. The corresponding solubility curve was plotted by using the solubility of the drug as the ordinate, and using the concentration of the cyclodextrin and/or meglumine as the abscissa. The solubility curves of Tecovirimat at 25° C., 37° C. and 60° C. were shown in
As seen from
As seen from
As seen from
According to the results of the phase solubility test, when the amount of cyclodextrin was in a range from 5% to 40%, the thermodynamic parameters were calculated for the formation of a drug-cyclodextrin inclusion complex. The result was shown in Table 5. A negative ΔG indicated that the inclusion process could occur spontaneously; a positive ΔH indicated that the main driving force of inclusion process was hydrophobic interaction, and meanwhile the inclusion process was an endothermic reaction, so the inclusion reaction could be promoted by increasing the temperature properly. However, the ternary composition has a lower value of ΔH, because the entrance of meglumine into the cavity resulted in release of more enthalpy-rich water; a positive ΔS indicated that the inclusion process was an enthalpy increasing process, and the ternary composition has a lower value of ΔS, because the degree of freedom for Tecovirimat and meglumine in the cavity was reduced, thereby a more stable inclusion system was formed.
Experimental method: 1000 ml water was used as dissolution medium, and according to the Dissolution Test (Pharmacopoeia of the People's Republic of China (2015 Edition), General Notices, 0931 Method II), the operation was carried out at a rotation rate of 100 rpm, and a solution (5 ml) was taken at 5, 10, 15, 30, 45, and 60 min, respectively, and was filtrated through a 0.45 μm microporous membrane, to obtain a test solution; and Tecovirimat (bulk drug powder, 5 mg) as a reference was accurately weighed, and placed in a 100 ml volumetric flask, and the medium for dissolution was added to a final volume of 100 ml, thereby obtaining a reference solution. By high performance liquid chromatography, the peak area of the test solution and the reference solution were measured at 224 nm. The dissolution amounts at different time points was calculated by an external standard method, and the cumulative dissolution curves were plotted.
The dissolution curves were shown in
Experimental method: a suitable amount of Tecovirimat, meglumine, cyclodextrin, a binary composition of Tecovirimat and meglumine (Tecovirimat/meglumine at a weight ratio of 1:2), a binary composition of Tecovirimat and cyclodextrin (Tecovirimat/cyclodextrin at a weight ratio of 1:6), and a ternary composition of Tecovirimat, meglumine and cyclodextrin (Tecovirimat/meglumine/cyclodextrin at a weight ratio of 1:2:6) were dissolved in DMSO-d6 to prepare samples, respectively, and the possible intermolecular interaction was analyzed by 1H NMR spectroscopy.
Experimental result: the NMR spectra were shown in
To sum up, as compared with the prior art, the present invention provides an oral pharmaceutical composition of Tecovirimat, in which the inclusion efficiency of cyclodextrin is enhanced greatly because the addition of an additive makes the drug to be included more easily. The synergistic action of them greatly improves the in vitro dissolution of the poorly soluble drug Tecovirimat, and meanwhile, reduces the amount of cyclodextrin used, and therefore reduces the potential medicament risk. The oral pharmaceutical composition also has the advantages such as simple formulation, low cost, easy operation, stable and controllable quality, and good reproducibility.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201610560206.9 | Jul 2016 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2017/091648 | 7/4/2017 | WO | 00 |
