CN113318076B - Ritonavir solid dispersion with solubilizing and crystal inhibiting effects and preparation method thereof - Google Patents
Ritonavir solid dispersion with solubilizing and crystal inhibiting effects and preparation method thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- 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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- 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
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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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
- A61K9/14—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
- A61K9/145—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 compounds
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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
- A61P31/18—Antivirals for RNA viruses for HIV
Abstract
The invention discloses a ritonavir solid dispersion with solubilization and crystal inhibition effects, which is prepared from the following components in percentage by weight: 10-30% of ritonavir, 50-90% of a high-molecular carrier material and 0-33.3% of a surfactant. The solid dispersion is formed by the medicament and the carrier material, so that the medicament can be kept in a high-dispersion state, and ritonavir bulk drugs exist in a microcrystalline state, an amorphous state, a colloid dispersion state or a molecular dispersion state, so that the dispersion degree is high, the dissolution speed of the medicament is accelerated, the absorption of the medicament can be promoted, and the bioavailability is improved.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a ritonavir solid dispersion with solubilizing and crystal inhibiting effects and a preparation method thereof.
Background
Ritonavir (RTV), a Human Immunodeficiency Virus (HIV) protease inhibitor for the treatment of aids, is chemically N- [ (2S, 3S, 5R) -3-hydroxy-5- [ [ (2S) -3-methyl-2- [ [ methyl- [ (2-isopropyl-1, 3-thiazol-4-yl) methyl ] carbamoyl ] amino ] butyryl ] amino ] -1, 6-diphenyl-hex-2-yl ] carbamic acid 5-thiazolylmethyl ester, having the chemical structure shown below:
the product is white powder with molecular formula of C 37 H 48 N 6 O 5 S 2 The molecular weight is 720.95, the melting point is 120-122 ℃, the composite is easy to dissolve in organic solvents such as ethanol, methanol, acetone and the like, is almost insoluble in water and has strong lipophilicity.
Aspartic proteases are human immunodeficiencyRitonavir, a key enzyme for maturation of virus (HIV for short), blocks replication of HIV virus by inhibiting the activity of the protease, thereby preventing HIV virus from spreading in vivo. Because ritonavir is an effective inhibitor of CYP3A liver drug enzyme and can inhibit CYP 3A-mediated biotransformation, ritonavir can be clinically used alone or in combination with other anti-retroviral protease inhibitor drugs for treating AIDS patients. Ritonavir is firstly used in the market as a liquid preparation and a capsule preparation, and then the capsule preparation is withdrawn from the market because drug crystals are easily separated out in the storage process to influence the exertion of the drug effect [1] . Later tablets prepared by hot melt extrusion technology are marketed which can be stored at room temperature without refrigeration and have higher bioavailability than capsules. Ritonavir is often used in combination with other antiviral drugs, i.e., "cocktail therapy", due to problems of drug resistance and toxicity. Ritonavir plays an important role in either first-line or second-line treatment regimens [2] 。
A solid dispersion generally refers to a dispersion system in solid form formed by uniformly dispersing a drug in a carrier in an amorphous state or a molecular state [3] . The technique of uniformly dispersing a drug in a carrier is called a solid dispersion technique. Solid dispersion techniques are often used to improve the dissolution of poorly soluble drugs and to increase bioavailability. The solid dispersion can be classified into quick release type, sustained and controlled release type, and enteric type according to drug release property [4] . Solid dispersions can be classified into eutectic mixtures, solid solutions, glass solutions, coprecipitates, according to the dispersion state of the drug. The concept of solid dispersions was first proposed by Sekiguchi and Obi in 1961 [5] . When the insoluble drug and the water-soluble material (urea) are prepared into the sulfathiazole solid dispersion by a melting method, the dissolution of the sulfathiazole is improved, and the absorption rate of the drug is obviously higher than that of the simple sulfathiazole. Urea and sugars were the first crystalline carrier materials used, and the dispersions prepared from crystalline carriers were the first generation solid dispersions [6] . Later decades of development have led to the appearance of five generations of products, each generation of solid dispersions having different properties.
Solid dispersions are generally composed of two main components, a drug substance and a carrier. When the raw material drugs are fixed, the type and the amount of the carrier have important influence on the physicochemical property and the drug effect of the solid dispersion. The solid dispersion carrier includes water soluble carrier, enteric carrier, and insoluble carrier [7] . The most used of these are water-soluble carriers, including polyvinylpyrrolidone (PVP) [8] For example, PVP K30, the carrier is an amorphous polymer, is easy to form hydrogen bonds with raw material medicines, has higher viscosity and stronger crystal inhibition capability; vinylpyrrolidone-vinyl acetate copolymer (PVP VA) [9] Such as PVP VA64, the carrier has low hygroscopicity, and the solid dispersion stability is improved, so that the carrier can be used for replacing PVP; polyethylene glycols (PEG) [10] For example, PEG 4000 and PEG 6000 have the advantages of low melting point, easy dissolution in organic solvents and the like; surfactants, such as Poloxamer188 (Poloxamer188) [11] Poloxamer407 (Poloxamer407) [12] Sodium Dodecyl Sulfate (SDS) [13] Polysorbate 80(Tween 80) [14] . The enteric carrier is hydroxypropyl methylcellulose phthalate (HPMCP) [15] Hydroxypropyl methylcellulose acetate succinate (HPMCAS) [16] And polyacrylic resins (Eudragit L and Eudragit S) [17] . HPMCAS has amphipathy, pH dependence and strong crystallization inhibiting capability, can maintain the supersaturation degree of a medicament for a long time and prevent the medicament from recrystallizing, but has limited medicament solubilizing capability and possibly influences the bioavailability of the preparation. HPMCAS can be divided into three H, M, L types according to the content of succinyl and acetyl [18] . The insoluble carrier mainly comprises Ethyl Cellulose (EC) [19] And polyacrylic resins (Eudragit RL and Eudragit RS) [20] 。
With the insight into the mechanism of solid dispersion stability and solubility enhancement, binary solid dispersions of a single polymer have encountered bottlenecks and ternary solid dispersions have been developed in which a third component (e.g., a surfactant) is added to the binary solid dispersion to improve the properties of the solid dispersion. The ternary solid dispersion is a dispersion system formed by dispersing the medicine in two auxiliary materials. The ternary solid dispersion has the advantages of improving the processability of materials, improving the dissolution and bioavailability and enhancing the stability of the medicament by combining auxiliary materials with different properties [21] 。
One of the keys to preparing ternary solid dispersions is to select suitable excipients, and in addition to drugs and polymers, the third component added is often additives such as surfactants and plasticizers. The surfactant and the plasticizer can be used for increasing the solubility of the drug so as to improve the dissolution behavior of the drug or reducing the glass transition temperature of a system so that the solid dispersion is easier to process [22] . Common surfactants and plasticizers are Sodium Dodecyl Sulfate (SDS), Tween 80(Tween 80), Poloxamer (Poloxamer), polyoxyethylene hydrogenated castor oil (castor oil) (N, N-butyl-N-propyl-L-butyl-N-butyl-ethyl (methyl-N-ethyl-N-butyl-ethyl (methyl-N-butyl-ethyl) and N-butyl-ethyl-N-butyl-ethyl-methyl-ethyl (N-propyl-ethyl) and N-propyl-ethyl-propyl-methyl-propyl-ethyl-propyl-ethyl-propyl-ethyl-propyl-ethyl-propyl-ethyl-propyl-ethyl alcohol (ethyl) as surfactant and plasticizer
RH 40/60), vitamin E polyethylene glycol succinate (TPGS), triethyl citrate (TEC), and the like. It is noteworthy that the better solubilization of surfactants does not necessarily translate into higher permeability and bioavailability, and in fact surfactants may cause recrystallization of the drug by increasing solubility and decreasing surface tension of crystal growth, which is not conducive to maintaining supersaturation. In summary, surfactants need to be used with caution and different surfactants have different effects on the properties of the solid dispersion.
Disclosure of Invention
The invention mainly aims to provide the ritonavir solid dispersion with solubilization and crystal inhibition effects and the preparation method thereof, so that the dissolution amount of ritonavir in a medium is greatly improved, the bioavailability of the ritonavir is further improved, and the drug effect is ensured; and meanwhile, the in-vitro and in-vivo recrystallization phenomenon of the ritonavir is inhibited, and the stability of the solid dispersion is improved.
The invention provides a ritonavir solid dispersion with solubilization and crystal inhibition effects and a preparation method thereof, wherein the ritonavir solid dispersion is prepared from the following components in percentage by weight: 10-30% of ritonavir, 50-90% of a high-molecular carrier material and 0-33.3% of a surfactant.
The ritonavir solid dispersion, wherein the ratio of ritonavir: high-molecular carrier material: the surfactant is 1:4: 1.
The ritonavir solid dispersion can be prepared by a solvent method, and comprises the following steps: weighing ritonavir bulk drug, high molecular carrier material and surfactant according to the prescription amount respectively, uniformly mixing to obtain a physical mixture, adding 15mL of methanol, carrying out vortex, carrying out ultrasonic dissolution, placing in a forced air drying oven at 60 ℃ for 6 hours, and scraping to obtain the ritonavir solid dispersion.
The ritonavir solid dispersion is characterized in that the high-molecular carrier material is one of hydroxypropyl methylcellulose acetate succinate HF type, hydroxypropyl methylcellulose acetate succinate LF type, hydroxypropyl methylcellulose acetate succinate MF type, povidone PVP K30, hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose E15.
The ritonavir solid dispersion is characterized in that the preferable high-molecular carrier material is hydroxypropyl methylcellulose succinate HF type.
The ritonavir solid dispersion is characterized in that the surfactant is one of Tween 80, span 20 and sodium dodecyl sulfate.
The ritonavir solid dispersion is characterized in that the preferable surfactant is sodium dodecyl sulfate.
The ritonavir solid dispersion is characterized in that the crystal inhibiting effect of the polymer can last for at least 2 hours; and the dissolution rate within 30min can reach more than 90% under the condition of pH 6.8.
Compared with the prior art, the invention has the characteristics and beneficial effects that:
1. the ritonavir solid dispersion solid preparation provided by the invention has the advantages that the drug and the carrier material form the solid dispersion, so that the drug can be kept in a high-dispersion state, and the ritonavir bulk drug exists in a microcrystalline state, an amorphous state, a colloid dispersion state or a molecular dispersion state, so that the ritonavir solid dispersion solid preparation has a large dispersion degree, the dissolution speed of the drug is accelerated, the absorption of the drug can be promoted, and the bioavailability is improved.
2. The polymer carrier material such as hypromellose succinate (HPMCAS) carrier used in the invention has excellent effect of inhibiting crystallization, solves the problem that crystallization is generated after dissolving out solid dispersion prepared by using carrier materials such as copovidone and the like, and the prepared solid dispersion has low hygroscopicity and high stability.
3. The surfactant such as Sodium Dodecyl Sulfate (SDS) surfactant applied by the invention has excellent solubilization effect, and the ritonavir solid dispersion has better dissolution rate, can greatly improve the dissolution amount in an insoluble medium, and further improves the bioavailability, thereby ensuring the drug effect.
Drawings
FIG. 1 dissolution curves of RTV/HPMCAS-HF (HF)/SDS solid dispersions in different ratios in media with pH 6.8;
figure 2 dissolution curves of RTV/HPMCAS-HF solid dispersions in different ratios in pH 6.8 medium;
FIG. 3 solubilization of RTV by different polymers;
FIG. 4 solubilization of RTV by different surfactants;
FIG. 5 the solubilizing effect of HPMCAS-HF (HF)/SDS at different concentrations and combinations on RTV;
FIG. 6 shows the crystal inhibiting effect of different polymers on RTV;
FIG. 7 shows the crystal inhibiting effect of HPMCAS-HF (HF)/different epi-active binary systems on RTV;
FIG. 8 shows the crystal inhibiting effect of different ratios of HPMCAS-HF (HF)/SDS on RTV;
FIG. 9DSC images of RTV, HPMCAS-HF, SDS, RTV/HPMCAS-HF/SDS physical mixture, RTV/HPMCAS-HF/SDS solid dispersion;
fig. 10 dissolution of reference formulation RS, physical mixture PM, solid dispersion SD in pH 6.8 medium;
figure 11 plasma concentration-time curves of RTV after gavage in reference formulation RS, physical mixture PM, solid dispersion SD rats.
Detailed Description
The invention is further described with reference to the following figures and detailed description. It is to be understood that the following description is only for the purpose of illustrating the present invention and is not to be taken as limiting the scope thereof. Unless otherwise specified, the contents of the respective components used below are weight percent contents.
In the embodiment of the invention, the dissolution of the ritonavir solid dispersion is determined according to a paddle method in dissolution determination method of Chinese pharmacopoeia 2015 year edition, a dissolution medium is phosphate buffer solution (500mL) with pH 6.8, the rotating speed is 75rpm, samples are respectively taken at 15min, 30min, 60 min, 90 min, 120 min and 180min, 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.
Example 1: the solvent method is used for preparing the RTV ternary solid dispersion. Weighing a certain amount of RTV raw material medicine, HPMCAS-HF and SDS, wherein the ratio of RTV/HPMCAS-HF/SDS is 1:4.5: 0.5. Mix well, add 15mL of methanol, vortex, and dissolve with sonication. And (3) placing the mixture in a 60 ℃ forced air drying oven for 6 hours, scraping the mixture for standby, and using the mixture for in-vitro dissolution experiments.
Example 2: the solvent method is used for preparing the RTV ternary solid dispersion. Weighing a certain amount of RTV raw material medicine, HPMCAS-HF and SDS, wherein the ratio of RTV/HPMCAS-HF/SDS is 1:4: 1. Mix well, add 15mL of methanol, vortex, and dissolve with sonication. And (3) placing the mixture in a 60 ℃ forced air drying oven for 6 hours, scraping the mixture for standby, and using the mixture for in-vitro dissolution experiments.
Example 3: the solvent method is used for preparing the RTV ternary solid dispersion. Weighing a certain amount of RTV raw material medicine, HPMCAS-HF and SDS, wherein the ratio of RTV/HPMCAS-HF/SDS is 1:3.5: 1.5. Mix well, add 15mL of methanol, vortex, and dissolve with sonication. And (3) placing the mixture in a 60 ℃ forced air drying oven for 6 hours, scraping the mixture for standby, and using the mixture for in-vitro dissolution experiments.
Example 4: the solvent method is used for preparing the RTV ternary solid dispersion. Weighing a certain amount of RTV raw material medicine, HPMCAS-HF and SDS, wherein the ratio of RTV/HPMCAS-HF/SDS is 1:3: 2. Mix well, add 15mL of methanol, vortex, and dissolve with sonication. And (3) placing the mixture in a 60 ℃ forced air drying oven for 6 hours, scraping the mixture for standby, and using the mixture for in-vitro dissolution experiments.
Comparative example 1: the solvent method is used for preparing the RTV binary solid dispersion. Weighing a certain amount of RTV raw material medicine and HPMCAS-HF, wherein the ratio of RTV to HPMCAS-HF is 1: 5. Mix well, add 15mL of methanol, vortex, and dissolve with sonication. And (3) placing the mixture in a 60 ℃ forced air drying oven for 6 hours, scraping the mixture for standby, and using the mixture for in-vitro dissolution experiments.
The dissolution results of examples 1 to 4 and comparative example 1 show (fig. 1) that the dissolution effect of the RTV solid dispersion is the best when HPMCAS-HF: SDS 4: 1. Namely, the optimum formula for preparing the RTV solid dispersion by a solvent method is RTV HPMCAS-HF SDS-1: 4:1, and the dissolution of the RTV/HPMCAS-HF/SDS ternary solid dispersion is superior to that of the RTV/HPMCAS-HF binary system solid dispersion.
Comparative example 2: the RTV binary solid dispersion is prepared by a hot-melt extrusion method. The RTV bulk drug and HPMCAS-HF are uniformly mixed in a ratio of 1:9 (RTV ratio is 10%) to obtain a physical mixture. Adding into a hot-melt extruder, setting the extrusion temperature at 140 ℃ and the rotation speed at 30rpm, extruding, cooling and molding the extrudate, grinding, sieving with a 80-mesh sieve, and storing for later use for in-vitro dissolution experiments.
Comparative example 3: in contrast to comparative example 2, the RTV drug and HPMCAS-HF were mixed homogeneously in a ratio of 2:8 (RTV ratio of 20%).
Comparative example 4: unlike comparative example 2, the RTV drug substance and HPMCAS-HF were mixed uniformly at a ratio of 3:7 (RTV ratio 30%).
The dissolution results of comparative examples 2 to 4 show (FIG. 2) that the lower the RTV ratio, the better the dissolution effect, and that the dissolution rate decreases with increasing RTV ratio. This is probably because when the RTV ratio is high, the RTV becomes high in concentration at the solid-liquid interface layer with the dissolution of HPMCAS-HF, and crystallization occurs, further hindering the release of the drug.
Comparative example 5: 50mL (pH 6.8) of each of the polymer solutions prepared with 0.5mg/mL of PVP K30, VA64, HPMC E5, HPMC E15, HPMCAS-LF, HPMCAS-MF and HPMCAS-HF were prepared; 3mg/mL solutions of Span 20, Tween 80, SDS each 50mL (pH 6.8); 50mL of HPMCAS-HF/SDS mixed solution with different concentrations and proportions (pH 6.8) respectively. Adding excessive RTV raw material powder, performing ultrasonic treatment for 30min, and shaking for 24 hr (37 deg.C, 150 rpm). The RTV concentration was analyzed by filtration through a 0.45 μm filter and HPLC injection.
Comparative example 5 contains results (FIGS. 3-5) showing that the solubility of RTV is not significantly improved by the addition of the respective polymer adjuvants to a medium having a pH of 6.8, i.e.the respective polymers have a general solubilizing effect on RTV with little difference. The surfactant has a certain effect on improving the solubility of RTV, wherein the solubilization effect of SDS is most remarkable. The HPMCAS-HF with different concentrations has little difference on the solubilization effect of RTV and weaker solubilization effect; the solubilization effect of SDS is stronger than that of HPMCAS-HF, and as the concentration of SDS increases, the solubility to RTV increases. It is to be noted that, when HPMCAS-HF is added to SDS, the solubility decreases, and the more HPMCAS-HF is added, the more the solubility decreases, which may be that the added HPMCAS-HF occupies a part of micelles formed by SDS, resulting in a decrease in the solubilizing effect for RTV. Therefore, a suitable HPMCAS-HF/SDS ratio is crucial for the solubilization and crystallization-inhibiting effect of the solid dispersion.
Comparative example 6: 50mL (pH 6.8) of each of polymer solutions of 0.5mg/mL of PVP K30, PVP VA64, HPMC E5, HPMC E15, HPMCAS-LF, HPMCAS-MF and HPMCAS-HF was prepared. RTV organic solution (20mg/mL) 250. mu.L was added, stirred at 37 ℃ and 150rpm, sampled at specific time points, filtered through 0.45 μm filter and analyzed by HPLC injection for RTV concentration.
Comparative example 6 contains the results that (FIG. 6) the crystal inhibition effect is the best with HPMCAS-HF, and RTV can be kept at a higher concentration for a long time; the HPMCAS-MF, the HPMC E5, the HPMC E15 and the HPMCAS-LF also have certain crystal inhibition effects, and the crystal inhibition effects of the four are close to each other; and PVP K30 and PVP VA64 have weak crystal inhibition effect.
Comparative example 7: 50mL (pH 6.8) of each solution of HPMCAS-HF/SDS, HPMCAS-HF/Tween 80 and HPMCAS-HF/Span 20 is prepared, wherein the RTV accounts for 16.7%, and the HPMCAS-HF/surfactant accounts for 4.5: 0.5. RTV organic solution (20mg/mL) 250. mu.L was added, stirred at 37 ℃ and 150rpm, sampled at specific time points, filtered through a 0.45 μm filter and analyzed by HPLC injection for RTV concentration.
The comparative example 7 contains test results (FIG. 7) showing that the crystal inhibition effect of HPMCAS-HF on RTV is improved after SDS is added; adding Tween 80, wherein the crystal inhibition effect of HPMCAS-HF on RTV is not changed; compared with SDS and Tween 80, the addition of Span 20 reversely reduces the crystal inhibition effect of HPMCAS-HF on RTV.
Comparative example 8: 50mL of each of the solutions of HPMCAS-HF and SDS at different ratios (4.5:0.5, 4:1, 3.5:1.5, 3:2) was prepared, and the control was HPMCAS-HF solution without SDS. RTV organic solution (20mg/mL) 250. mu.L was added, stirred at 37 ℃ and 150rpm, sampled at specific time points, filtered through a 0.45 μm filter and analyzed by HPLC injection for RTV concentration.
Comparative example 8 contains test results (FIG. 8) showing that the crystal-inhibiting effect of HPMCAS-HF on RTV increases and then decreases with increasing SDS proportion. When HPMCAS-HF and SDS are 4:1, the crystal inhibition effect on RTV is the best. This is probably because the appropriate proportion of HPMCAS-HF and SDS assemble into a complex, affecting the solubility and crystallization inhibition of RTV.
Comparative example 9: respectively weighing 3-5mg of RTV bulk drug, HPMCAS-HF, SDS, RTV/HPMCAS-HF/SDS (1:4:1) Physical Mixture (PM) and RTV/HPMCAS-HF/SDS (1:4:1) Solid Dispersion (SD). Uniformly placing in an aluminum pan, carrying out DSC detection, and heating up at a rate of 10 ℃ for min -1 The scanning range is 30-140 ℃.
Comparative example 9DSC results (FIG. 9) show that RTV exhibits a sharp and single endothermic peak at about 124 deg.C, indicating that RTV is crystalline. SDS showed an endothermic peak at about 110 ℃ which is consistent with literature reports. For the RTV/HPMCAS-HF/SDS ternary solid dispersion, the endothermic peak of RTV at around 124 ℃ disappeared, and only a weak endothermic peak at 110 ℃ attributed to SDS was observed, indicating that RTV exists in an amorphous state in the solid dispersion. In the physical mixture, the endothermic peak of RTV still exists, which indicates that the RTV exists in the physical mixture as crystals.
Comparative example 10: weighing a Physical Mixture (PM) of RTV/HPMCAS-HF/SDS (1:4:1),
Ritonavir tablets (reference formulation, RS), RTV/HPMCAS-HF/SDS (1:4:1) Solid Dispersions (SD) several (each containing 50mg of RTV) were used for in vitro dissolution experiments.
Comparative example 10 dissolution test results (fig. 10) show that the dissolution rate of SD is high in a medium with pH 6.8, and the drug concentration can be maintained at a high level for a long time without significant crystallization tendency. The dissolution rate of the reference preparation is not as high as SD, and the concentration of the medicine after dissolution is gradually reduced, which shows that the crystal inhibition effect of the auxiliary materials of the reference preparation is weaker. The physical mixture has a low dissolution rate because the RTV exists in the physical mixture in a crystalline state.
Experimental example 1: weighing a Physical Mixture (PM) of RTV/HPMCAS-HF/SDS (1:4:1),
Ritonavir tablets (reference formulation, RS), RTV/HPMCAS-HF/SDS (1:4:1) Solid Dispersions (SD) several (each containing RTV 20mg) were prepared into homogeneous suspensions by adding 10mL of physiological saline. 18 female SD rats (n-6) were selected, weighing around 200g, and were randomly assigned on average into three groups (six per group) for numbering. Fasted for 12h before dosing and water was freely available throughout the experiment. The rat is subjected to intragastric administration at a dose of 10mg/kg, and after administration, the blood is taken for 5min, 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h and 24h, 0.5mL of blood is taken from the fundus venous plexus of the rat and is put into a heparinized centrifuge tube, then 5000 revolutions and centrifugation are carried out for 5 minutes, 0.2mL of blood plasma is taken into a 1.5mL centrifuge tube, and the RTV concentration in the blood plasma is determined after treatment.
Experimental example 1 results of pharmacokinetic experiments (FIG. 11) show that different preparations have different peak-reaching times, PM reaches a peak in about 2 hours, RS reaches a peak in about 4 hours, and SD reaches a peak in about 5 hours. The blood concentration of PM is lower, and the PM rapidly decreases after reaching the peak, which indicates that the release and absorption effects of the PM are general. RS has a high blood concentration, but also has a problem of short maintenance time at the peak of the drug concentration. SD not only has higher blood concentration, but also can maintain the peak of the drug concentration for a long time, which indicates that the release and absorption effects of the drug are better. The main pharmacokinetic parameters are shown in Table 1, SD, RS, and PM, T max The difference of (A) is not statistically significant, C max There was a significant difference in AUC. The MRT is significantly different from the MRT, and the SD time is longest, which indicates that the SD medicament has the longest effective action time. AUC of SD (0-t) The highest indicates that the preparation absorbs better in vivo, while the AUC of PM (0-t) Lower, probably due to lower drug release levels. The above results indicate that RTV is the most bioavailable in SD.
TABLE 1 pharmacokinetic parameters of RTV after gavage in rats
Each value represents the mean±S.D.(n＝6).
* P<0.05compared to PM.
# P<0.05compared to SD.
The above examples of the present invention are merely illustrative and not restrictive of 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. Obvious changes and modifications of the present invention are also within the scope of the present invention.
Claims (2)
1. The ritonavir solid dispersion with the effects of solubilization and crystal inhibition is prepared from ritonavir, a high-molecular carrier material, namely hydroxypropyl methylcellulose acetate succinate HF type, and a surfactant, namely sodium dodecyl sulfate, wherein the ritonavir: high-molecular carrier material: the weight ratio of the surfactant is 1:4: 1.
2. The process for the preparation of ritonavir solid dispersion according to claim 1 wherein the process is a solvent process comprising the steps of: weighing ritonavir bulk drug, high molecular carrier material and surfactant according to the prescription amount respectively, uniformly mixing to obtain a physical mixture, adding 15mL of methanol, carrying out vortex, carrying out ultrasonic dissolution, placing in a 60 ℃ forced air drying oven for 6 hours, and scraping to obtain the ritonavir solid dispersion.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20050048112A1 (en) * | 2003-08-28 | 2005-03-03 | Jorg Breitenbach | Solid pharmaceutical dosage form |
| WO2008067164A2 (en) * | 2006-11-15 | 2008-06-05 | Abbott Laboratories | Solid pharmaceutical dosage formulations |
| US20110207660A1 (en) * | 2008-08-07 | 2011-08-25 | Schering Corporation | Pharmaceutical formulations of an hcv protease inhibitor in a solid molecular dispersion |
| WO2011141192A1 (en) * | 2010-05-10 | 2011-11-17 | Evonik Röhm Gmbh | Pharmaceutical dosage form comprising one or more antiretroviral active ingredients |
| EP2564832A1 (en) * | 2011-08-29 | 2013-03-06 | Hexal AG | Solid dosage form of HIV protease inhibitors |
| CN108186578A (en) * | 2018-03-27 | 2018-06-22 | 聊城大学 | A kind of preparation method of Ritonavir solid dispersions |
| EP3569225A1 (en) * | 2018-05-18 | 2019-11-20 | Pharmaceutical Oriented Services Ltd | Solid dispersion containing ritonavir |
| CN111467344B (en) * | 2019-01-24 | 2021-07-16 | 沈阳药科大学 | Lacidipine solid dispersion and preparation method thereof |
| US20210128536A1 (en) * | 2019-11-01 | 2021-05-06 | Dispersol Technologies, Llc | Weakly basic drug and ionic polymer pharmaceutical formulations and methods of formation and administration thereof |
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