CN113081970A - Cyclosporine solid dispersion and preparation method of tablet thereof - Google Patents
Cyclosporine solid dispersion and preparation method of tablet thereof Download PDFInfo
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
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- A61P37/00—Drugs for immunological or allergic disorders
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Abstract
The invention discloses a ciclosporin solid dispersion and a preparation method of tablets thereof, wherein the solid dispersion is prepared by ciclosporin serving as an active ingredient and a hydrophilic carrier polyvinylpyrrolidone PVP K12. The solid dispersion is prepared by hot-melt extrusion technology, and the cyclosporine exists in the solid dispersion in an amorphous state. The hydrophilic carrier can greatly improve the dissolution rate of the cyclosporine, has good effect of inhibiting crystallization, and can maintain the supersaturated state of the cyclosporine, thereby improving the bioavailability and reducing adverse reactions.
Description
Technical Field
The invention relates to a preparation method, in particular to a ciclosporin solid dispersion and a preparation method of a tablet thereof.
Background
Cyclosporine is a neutral cyclic polypeptide consisting of 11 lipophilic amino acids, known in the english name Cyclosporine a, and known by the chemical name [ (E) (2S,3R,4R) -3-hydroxy-4-methyl-2- (methylamino) -6 octenoyl ] -L-2 aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-valyl, having the following structural formula:
cyclosporin (CsA) is a potent immunosuppressant and can prolong the survival time of allografts such as skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung in animals. CsA has been shown to suppress certain humoral immunity and to a greater extent cell-mediated immune responses, such as allograft rejection, delayed-type hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis and the relationship of various animal organ transplants to host disease. The effectiveness of CsA results from the specific and reversible inhibition of G in the cell cycle0And G1Immunocompetent lymphocytes of stage wherein T lymphocytes are preferentially suppressed. While T suppressor cells may also be inhibited, Thelper cells are the primary target, while CsA also inhibits the production and release of lymphokines, including interleukin-2.
The cyclosporine is white or quasi-white powder, and has no odor and taste. The compound is very soluble in methanol, ethanol or acetonitrile, is soluble in ethyl acetate, is soluble in acetone or ether, is almost insoluble in water, belongs to BCS II medicines with low solubility and high permeability in a biological and pharmaceutical classification system, and is an effective method for improving the bioavailability of the medicines. The ciclosporin oral preparation widely used in clinic is ciclosporin soft capsuleIs a cyclosporine self-microemulsifying preparation, can form a nano-emulsion in the gastrointestinal tract, and has the effect of improving the bioavailability of CsA.The formulation comprises DL-alpha-tocopherol, a high proportion of ethanol, propylene glycol, corn glycerides andRH40, whereinRH40 causes allergic reaction and generates nephrotoxicity to the organism, and the existence of ethanol in the prescription also has adverse effect on the stability of the medicine. Therefore, there is a need to find alternative formulations to improve the bioavailability of cyclosporin.
Other commonly used methods for improving the bioavailability of poorly soluble drugs include nano drug delivery systems, liposomes, drug salt formation and solid dispersion techniques, etc. At present, insoluble drugs are prepared into solid dispersion by utilizing high water-soluble carrier materials, so that the effects of improving the solubility of the drugs and accelerating the dissolution speed of the drugs are outstanding, and the insoluble drugs are increasingly and widely concerned and applied. The existing methods for preparing the cyclosporine solid dispersion comprise a solvent method, a solvent-melting method, a spray drying method, a freeze drying method and the like, while a hot-melt extrusion technology is often used for preparing the chemical small-molecule drug solid dispersion with better thermal stability, and the application in polypeptide drugs (such as cyclosporine) is rare.
Disclosure of Invention
The main purpose of the invention is to prepare the solid dispersion and the tablet of the insoluble drug cyclosporine, so as to improve the release amount of the insoluble drug cyclosporine in a dissolving medium, simultaneously maintain the supersaturated state of an amorphous drug solution, inhibit the recrystallization phenomenon, further improve the bioavailability of the amorphous drug solution and ensure the drug effect.
The invention provides a cyclosporine solid dispersion, wherein the solid dispersion is prepared from the following components in percentage by weight: cyclosporine/polyvinylpyrrolidone (PVP K12) 1:2 to 1: 9;
preferably, the preparation method of the solid dispersion is a hot-melt extrusion technology, and comprises the following steps: weighing cyclosporine bulk drug and carrier material PVP K12 according to the prescription amount respectively, premixing, adding into a double-screw hot-melt extruder, melting at high temperature and extruding, cooling, crushing and sieving with a 80-mesh sieve to obtain the cyclosporine solid dispersion.
Preferably, the temperature of the screw hot-melt extruder is set to 140 ℃, 150 ℃ and 160 ℃, and the screw rotation speed is 30 revolutions per minute.
A preparation method of cyclosporine solid dispersion tablet comprises mixing the obtained cyclosporine solid dispersion with microcrystalline cellulose as filler, croscarmellose sodium as disintegrant and silica gel/magnesium stearate as lubricant, and tabletting by direct powder tabletting method to obtain tablet.
Preferably, the mass ratio of the cyclosporine solid dispersion to the filler is 150:118, the mass percent of the disintegrant is 10%, and the mass percent of the lubricant is 0.67%.
Compared with the prior art, the invention has the characteristics and beneficial effects that:
1. according to the cyclosporine solid dispersion provided by the invention, the drug is highly dispersed in the polymer carrier in an amorphous or molecular state, so that the dissolution speed of the drug is accelerated, the recrystallization behavior of the drug is inhibited, the in-vivo absorption of the drug is finally promoted, and the bioavailability is improved.
2. The polymer carrier PVP K12 applied by the invention can solubilize and has good recrystallization inhibition effect, so that the drug solution can maintain the supersaturated state.
3. Compared with the pure amorphous drug, the ciclosporin solid dispersion tablet provided by the invention has the advantages of good in-vitro dissolution effect, high in-vivo blood concentration and obvious drug effect. The method has the advantages of simple preparation process, low energy consumption, no solvent residue, no other impurities introduced in the whole process, and easy realization of continuous production.
Drawings
FIG. 1 crystallization inhibition of supersaturated solutions of cyclosporin by different polymers.
Figure 2 in vitro dissolution curves of solid dispersions prepared at an extrusion temperature of 140 ℃ with cyclosporin drug substance.
FIG. 3 in vitro dissolution curves of the solid dispersion prepared at an extrusion temperature of 150 ℃ with a cyclosporin drug substance.
Figure 4 in vitro dissolution profiles of the solid dispersion prepared at an extrusion temperature of 160 ℃ with cyclosporine drug substance.
FIG. 5 DSC spectra of cyclosporin A.s.raw materials, excipients, physical mixture and solid dispersion.
Figure 6 in vitro dissolution profiles of solid dispersion tablets with cyclosporin bulk drug in pH 1.2 medium.
Figure 7 in vitro dissolution profiles of solid dispersion tablets with cyclosporin bulk drug in pH 6.8 medium.
Figure 8 in vitro dissolution profiles of solid dispersion tablets with cyclosporin bulk drug in pH 7.4 medium.
FIG. 9 in vivo pharmacokinetic profiles of cyclosporin solid dispersion tablets with cyclosporin bulk drug.
Detailed Description
The invention is further described with reference to the following figures and detailed description. The following description is given for the purpose of explanation and not limitation. Unless otherwise specified, the contents of the respective components used below are weight percent contents.
In the embodiment of the invention, the dissolution rate of the cyclosporine solid dispersion and the tablet thereof is determined according to a paddle method in dissolution rate determination methods of Chinese pharmacopoeia 2015 edition, a dissolution medium is phosphate buffer solutions (900mL) containing 0.1% SDS and having different pH values, the rotating speed is 100rpm, the samples are respectively sampled at 5min, 10min, 15min, 30 min, 45min, 60 min, 90 min and 120min, the drug concentration is determined by an HPLC method after timely filtration, the cumulative drug release amount at each time point is calculated, and a dissolution curve is drawn.
Earlier researches show that the crystal inhibiting polymer with good effect mainly comprises amphiphilic hydroxypropyl methyl acetate succinate (HPMCAS) and novel carrier auxiliary materialsThe crystal-inhibiting effect is often dependent on the surfactant function and the hydrogen bond donor function. In addition, Hypromellose (HPMC) and the like can effectively prevent molecules of insoluble drugs from colliding with each other due to the high viscosity characteristic, and therefore, the hypromellose also has a certain crystallization inhibiting effect. However, the carrier has a very limited effect of improving the solubility of the drug due to the limitation of the solubility of the carrier; or because of the pH dependence of the carrier, the dissolution rate of the obtained solid dispersion also has the pH dependence characteristic, and the absorption site of the medicament is limited.
Experimental example 150 mL of each polymer solution (polymers including HPMCAS-LF, HPMCAS-MF,PVP VA64, PVP K12), a quantitative excess of CsA was added separately to the above solutions and blanked, each sample was assayed in duplicate, and then the solubilization of CsA by each polymer was determined under different pH conditions. The measurement conditions were as follows: the temperature is 25 ℃, the rotating speed is 150rpm/min, the shaking table is used for 24h, and the concentration of CsA is measured by a UV method.
The results are shown in Table 1, in which PVP K12,And PVP VA64, while HPMCAS-LF and HPMCAS-MF have almost no solubilizing effect. It can also be seen that the solubility behavior of CsA is not pH dependent.
TABLE 1
Experimental example 2A proper amount of CsA drug is weighed and dissolved in a minimum amount of organic solvent (3.5 mL of methanol) to form a uniform supersaturated solution to be crystallized, which is used for simulating a supersaturated drug system of CsA. 70mg of each polymer is weighed and added with 700mL of medium with pH 6.8 to prepare a solution with the concentration of 100 mu g/mL, and the solution is duplicated in parallel and used as a blank control. The supersaturated drug solution was added to the above polymer solution, and the experiment was carried out by the slurry method at 37 ℃ and 50 rpm/min. 4mL of the solution was sampled at different sampling time points, and the subsequent filtrate was filtered through a 0.45 μm filter, and the absorbance was measured by UV method to calculate the drug concentration.
As shown in FIG. 1, in the blank without polymer, the drug crystallized rapidly within 5min and was always at a low concentration of 10. mu.g/mL for 4 h. The crystal inhibition effect of HPMCAS-MF, HPMCAS-LF and PVP K12 is good, and the solubility effect is poor when the two are enteric carriers, so that the CsA solid dispersion is prepared by using the hydrophilic polymer PVP K12 as the carrier.
Example 1 cyclosporin and PVP K12 were mixed uniformly in a ratio of 1:2 to prepare a physical mixture, the extrusion temperature was set at 140 ℃, the rotation speed was 30rpm, after the temperature was raised to a set value and stabilized, the physical mixture was added at a constant speed to obtain a ribbon-like extrudate, which was cooled, pulverized and sieved through a 80-mesh sieve to obtain a cyclosporin solid dispersion powder for in vitro dissolution experiments.
Example 2 unlike example 1, cyclosporin was mixed with PVP K12 in a ratio of 1: 3.
Example 3 unlike example 1, cyclosporin was mixed with PVP K12 in a ratio of 1: 5.
Example 4 unlike example 1, cyclosporin was mixed with PVP K12 in a ratio of 1: 7.
Example 5 unlike example 1, cyclosporin was mixed with PVP K12 in a ratio of 1: 9.
The experimental results are as follows: the dissolution results of examples 1-5 are shown in FIG. 2: at 140 ℃, the solid dispersions with drug loading of 1:2 and 1:3 are slowly dissolved out, and the drug dissolution rates with drug loading of 1:5, 1:7 and 1:9 are not greatly different, so that the solid dispersions can be quickly dissolved out and maintained at a higher level.
Example 6 cyclosporin and PVP K12 were mixed uniformly in a ratio of 1:2 to prepare a physical mixture, the extrusion temperature was set at 150 ℃, the rotation speed was 30rpm, after the temperature was raised to a set value and stabilized, the physical mixture was added at a constant speed to obtain a ribbon-like extrudate, which was cooled, pulverized and sieved through a 80-mesh sieve to obtain a cyclosporin solid dispersion powder for in vitro dissolution experiments.
Example 7 unlike example 6, cyclosporin was mixed with PVP K12 in a ratio of 1: 3.
Example 8 unlike example 6, cyclosporin was mixed with PVP K12 in a ratio of 1: 5.
Example 9 unlike example 6, cyclosporin was mixed with PVP K12 in a ratio of 1: 7.
Example 10 unlike example 6, cyclosporin was mixed with PVP K12 in a ratio of 1: 9.
The experimental results are as follows: the results of the dissolution tests for examples 6-10 are shown in FIG. 3: under the condition of 150 ℃, the solid dispersions with different drug loading ratios all reach more than 80 percent in 45min, and the early-stage drug release is faster when the drug loading ratios are 1:5 and 1: 7.
Example 11 cyclosporin and PVP K12 were mixed uniformly in a ratio of 1:2 to prepare a physical mixture, the extrusion temperature was set at 160 ℃, the rotation speed was 30rpm, after the temperature was raised to a set value and stabilized, the physical mixture was added at a constant speed to obtain a ribbon-like extrudate, which was cooled, pulverized and sieved through a 80-mesh sieve to obtain a cyclosporin solid dispersion powder for in vitro dissolution experiments.
Example 12 unlike example 11, cyclosporin was mixed with PVP K12 in a ratio of 1: 3.
Example 13 unlike example 11, cyclosporin was mixed with PVP K12 in a ratio of 1: 5.
Example 14 unlike example 11, cyclosporin was mixed with PVP K12 in a ratio of 1: 7.
Example 15 unlike example 11, cyclosporin was mixed with PVP K12 in a ratio of 1: 9.
The experimental results are as follows: the results of the dissolution experiments of examples 11-15 are shown in FIG. 4: when the extrusion temperature is 160 ℃, the drug is quickly dissolved out when the drug loading ratio is 1:7 and 1:9, the drug release reaches over 90 percent within 10min, and the drug release reaches the maximum at 45 min.
Based on the results of examples 1 to 15, it can be seen that the drug dissolution effect is better when the drug loading ratio is smaller and the temperature is higher. However, the preparation of the preparation product is not facilitated when the using amount of the carrier is too large, and the decomposition of the drug or the carrier can be caused due to the too high temperature of hot-melt extrusion, so that the CsA solid dispersion is prepared at 140 ℃ and in a ratio of 1:5, and the form of the CsA solid dispersion is characterized.
Example 16 a small amount of cyclosporin a.i., raw material drug, PVP K12 as an excipient, the physical mixture, and the solid dispersion powder were each subjected to differential scanning calorimetry to determine the crystal structure of the drug and the excipient, and to analyze whether there was an interaction between the two.
As shown in fig. 5, the cyclosporine drug substance has an endothermic peak at 127 ℃, a weak endothermic peak is also observed in the physical mixture at this temperature due to the solid-liquid phase transition, while no endothermic peak is observed in the solid dispersion at this temperature, probably because the interaction between cyclosporine and PVP K12 prevents the solid-liquid phase transition due to the high dispersion of cyclosporine in amorphous form.
Example 17 direct powder compression method cyclosporin solid dispersion tablets were prepared.
The prescription design is shown in table 2:
TABLE 2
Weighing 1500mg of cyclosporine solid dispersion (CsA-ASDs) powder, 1180mg of microcrystalline cellulose (MCC), 300mg of croscarmellose sodium (CCMC-Na), 5mg of aerosil and 15mg of magnesium stearate according to the prescription amount, uniformly mixing, and pressing the prescription into tablets by adopting a direct powder tabletting method, wherein the marked amount of each tablet is cyclosporine 25 mg.
Example 18 an in vitro dissolution experiment was performed in a medium of pH 1.2 using the tablet prepared in example 17 and cyclosporine drug powder as a control.
As shown in FIG. 6, the dissolution speed of the solid dispersion tablet is higher, the cumulative release amount can reach more than 80% in 15min and slowly approaches to stability, and the dissolution of the ciclosporin bulk drug powder is relatively slow.
Example 19 an in vitro dissolution experiment was performed in a medium of pH 6.8 using the tablet prepared in example 17 and cyclosporine drug powder as a control.
As shown in fig. 7, the solid dispersion tablet can realize rapid drug release, the drug release amount reaches the maximum within 10min and is always maintained at more than 80%, and the release amount of the cyclosporine bulk drug cannot reach 80% within 2 h.
Example 20 an in vitro dissolution experiment was performed in a medium of pH 7.4 using the tablet prepared in example 17 and cyclosporine drug powder as a control.
As shown in fig. 8, the release amount of the solid dispersion tablet reaches 90% within 15min, and is always maintained at 85% or more within 2h, in contrast, the maximum drug release amount of the cyclosporine drug substance is only 60%.
Example 21 the tablets prepared in example 17 were ground and pharmacokinetic experiments were performed in Sprague-Dawley male rats using cyclosporin bulk drug powder as a control, and rats were administered solid dispersion tablet powder and a physiological saline suspension of cyclosporin bulk drug powder at the same dose as cyclosporin in an intragastric manner, respectively.
As shown in fig. 9, it can be seen that the blood concentration of rats in the solid dispersion tablet group is significantly higher than that of the raw medicinal materials, which indicates that the absorption behavior of the medicament in vivo is significantly improved and the bioavailability in vivo is improved after the cyclosporin is prepared into the solid dispersion tablet.
It should be understood that the above-described embodiments of the present invention are only examples for illustrating the present invention, and are not intended to limit the specific embodiments of the present invention. It will be apparent to those skilled in the art that other variations and modifications can be made on the above examples. Not all embodiments are exemplified in detail herein. All obvious changes and modifications of the present invention are within the scope of the present invention.
Claims (5)
1. The cyclosporine solid dispersion is characterized by being prepared from the following components in percentage by weight: cyclosporine/polyvinylpyrrolidone (PVP K12) 1:2 to 1: 9.
2. The cyclosporin solid dispersion of claim 1, wherein the solid dispersion is prepared by a hot-melt extrusion process comprising the steps of: weighing cyclosporine bulk drug and carrier material PVP K12 according to the prescription amount respectively, premixing, adding into a double-screw hot-melt extruder, melting at high temperature and extruding, cooling, crushing and sieving with a 80-mesh sieve to obtain the cyclosporine solid dispersion.
3. A cyclosporin solid dispersion according to claim 2 wherein the temperature of the twin-screw hot-melt extruder is set at 140 ℃, 150 ℃ or 160 ℃ and the screw speed of the hot-melt extruder is 30 rpm.
4. A process for preparing a cyclosporin solid dispersion tablet, which comprises mixing the cyclosporin solid dispersion of any one of claims 1 to 3 with microcrystalline cellulose as a filler, croscarmellose sodium as a disintegrant, and aerosil/magnesium stearate as a lubricant, and tabletting by a powder direct tabletting method to obtain the tablet.
5. The process for producing a cyclosporin solid dispersion tablet according to claim 4, wherein the ratio by mass of the cyclosporin solid dispersion to the filler is 150:118, the disintegrant is 10% by mass, and the lubricant is 0.67% by mass.
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