In order to better bind to the target, the drug molecules under research often have high fat solubility, which also leads to the decrease of the water solubility of most drugs, which is not conducive to their dissolution and absorption
According to reports, 30% of commercially available drugs and 70% of candidate compounds belong to BCS II drugs (low solubility, high permeability)
Therefore, the problem of increasing and maintaining the apparent solubility of such drugs in the gastrointestinal tract for a long time, thereby improving their absolute bioavailability, needs to be solved urgently
Amorphous solid dispersion (ASD) has attracted much attention in recent years
During the fifteen years from 2005 to 2020, the FDA has approved 25 ASD drugs for marketing
ASD means that the drug is dispersed in a polymer carrier in an amorphous state and at a molecular level, and the amorphous drug is stabilized through the drug-polymer interaction
Since the amorphous drug in a thermodynamically high energy state has higher apparent solubility than its crystal form, its ASD preparation can significantly improve the in vitro dissolution behavior and in vivo absorption of poorly soluble drugs
01 ASD preparation technology comparison Common ASD preparation technology is mainly spray drying method and hot melt extrusion method, but these technologies have their own limitations
Spray drying is the process of dissolving the active pharmaceutical ingredients (APIs) and the auxiliary materials required for the preparation of ASD in a suitable solvent, and then spraying the drug-loading solution into the drying chamber in the form of fine droplets.
In the chamber, the solvent quickly evaporates after being exposed to hot air, which makes the dissolved drug unable to nucleate and grow in a short time, and finally a uniformly dispersed ASD preparation is obtained
It is not difficult to see that spray drying technology needs to take into account the solubility of drugs and polymers in organic solvents, and the solvents used must have suitable volatility
Take the melanoma treatment drug verofenil as an example.
It is difficult to dissolve in conventional organic solvents, but its solubility in dimethylformamide (DMA) exceeds 500 mg/mL.
However, the boiling point of DMA is as high as 166 °C.
Suitable for spray drying technology, residual solvents will also bring potential safety and environmental pollution problems
Hot melt extrusion (HME) refers to the technology of mixing drugs, plasticizers or polymers in a molten state and extruding them to form products at a certain pressure, speed and shape
The key parameters such as melting point, glass transition temperature and component viscosity need to be paid attention to during the preparation of ASD
Hot-melt extrusion technology is not suitable for the preparation of poorly soluble drugs with a melting point higher than 200 ℃ into ASD, because it not only requires higher extruder temperature and lower drug loading, but also takes into account the polymer viscosity and degradation.
The squeezable window of the polymer is not greater than 200 °C
Therefore, in order to solve the problem of ASD preparation, broaden the range of drugs that can be prepared into ASD (such as drugs with high melting point, heat-labile or hard to dissolve in organic solvents), a novel heat generation based on friction and shear force Then the Kinetisol technology for the preparation of ASD has gradually developed
Kinetisol, hot-melt extrusion and spray drying technology applicable drug comparison 02 Introduction to Kinetisol technology The sample mixing chamber of the Kinetisol equipment contains a high-speed rotating shaft with multiple sets of stirring blades attached to the rotating shaft
When the material is put into the sample mixing chamber, the stirring blade rotates with the rotating shaft at a high speed (> 1000 rpm), forcing the materials in the chamber to rub against each other, and collide with the cavity wall and the stirring blade, resulting in strong friction and shearing force, resulting in The temperature in the mixing chamber rises rapidly
The temperature monitoring probe can feed back the temperature of the sample in the mixing chamber in real time and quickly.
After reaching the specified processing temperature, it sends a signal and opens the door at the bottom of the chamber, and the material in the molten state is discharged out of the mixing chamber by centrifugal force
The melt is usually pressed onto a flat disk to maximize the surface area of the sample, and then heat is transferred and quenched
After the sample is cooled, the particle size can be further reduced by sieving or other means to achieve the ideal dissolution and absorption effect
The schematic diagram of the Kinetisol sample mixing chamber is shown in Figure 2
The rotation speed of the stirring blade in Kinetisol technology is an order of magnitude higher than that of hot melt extrusion, and the processing time is an order of magnitude shorter than that of hot melt extrusion, usually less than 20 seconds.
The exposure time of the material under high temperature is usually less than 5 seconds, such as When Kinetisol is used to prepare amorphous solid dispersions of itraconazole, the heating time and amount of heat are significantly lower than that of hot melt extrusion technology, as shown in Figure 3.
Therefore, Kinetisol technology can be used to combine high melting point drugs and thermally unstable components.
And the preparation of materials that are difficult to dissolve in organic solvents into ASD greatly expands the preparation space
Schematic diagram of the sample mixing chamber of Kinetisol Figure 3.
Comparison of the total thermal exposure temperature and time of the system using hot melt extrusion and KinetiSol to prepare itraconazole ASD.
Figure 03 A specific case of using Kinetisol to prepare ASD.
Hydrocortisone) is a short-acting glucocorticoid with a melting point of 220 ℃
Researchers found that when using hot-melt extrusion technology to prepare amorphous hydrocortisone, high temperatures will cause the drug to undergo oxidative degradation
Disperse hydrocortisone in copovidone, and prepare its amorphous solid dispersion by hot-melt extrusion and Kinetisol respectively.
The latter reduces the processing temperature and shortens the residence time during processing (the total time is not More than 30 seconds, stay at a temperature higher than 130 ℃ for 5 seconds), so the prepared hydrocortisone-copovidone amorphous solid dispersion is more stable
Deferasirox (Deferasirox) is an oral iron chelator, mainly used to treat chronic iron overload disease caused by blood transfusion for 2 years and older and chronic iron overload in patients with transfusion-independent thalassemia (NTDT) aged 10 years and older The treatment was first launched in the United States in 2005.
The commercially available products are Exjade® and Jadenu®, with sales of up to 653 million U.
dollars in 2020
Deferasirox is a weakly acidic drug with a melting point of 263 ℃, and its water solubility is pH-dependent.
It has poor solubility in gastric acid (<0.
01 mg/mL, 37 ℃), and its water solubility is only 0.
167 in an environment of pH 7.
mg/mL, the clinically administered dose is as high as 40 mg/kg, and the absorption is poor in about 30% of patients
In order to improve the bioavailability of deferasirox in patients who did not respond to treatment, the researchers used Kinetisol to prepare the drug into a physically stable amorphous solid dispersion
In vitro dissolution experiments showed that with the change of pH value of the dissolution medium (1.
8), the 8 h dissolution amount of deferasirox in Exjade® and Jadenu® was only 25%, while the dissolution amount in ASD was as high as 80%
Beagle dogs’ body absorption data show that deferasirox ASD tablets (Formulation 3011, Formulation 3012) prepared with Kinetisol have a three-fold increase in drug exposure in beagle dogs compared to Exjade® and Jadenu®
Plasma concentration-time curve of Beagle dogs after oral administration of deferasirox ASD tablets (Formulation 3011, Formulation 3012), Exjade? and Jadenu? Vemurafenib is ATP-competitive and reversible BRAF Inhibitor, the standard first-line treatment for patients with BRAF V600E mutation-positive melanoma
Verofenib is a BCS II/IV drug, and its poor water solubility (< 2 μg/mL) makes it difficult to be absorbed.
Therefore, the commercially available verofenib (Zelboraf®) is an amorphous solid prepared by the anti-solvent precipitation method.
Even so, the ASD tablets still have serious food effects and high variability.
Patients need to take 1920 mg of the drug daily, which greatly reduces medication compliance.
Verofenib prepared with Kinetisol technology- Hypromellose acetate succinate amorphous solid dispersion, the rat blood concentration peak (Cmax) and the area under the drug-time curve (AUC0-24h) are 2 times and 2.
5 times that of Zelboraf ?, as shown in Figure 5.
, The bioavailability is further improved compared with the original research agent
Plasma concentration-time curve of Verofenib MBP (Zelboraf?) and KSD suspension (Kinetisol dispersion) in SD male rats.
04 Summary of ASD drugs prepared with Kinetisol technology As the number of poorly soluble drugs increases, How to use preparation methods, such as preparing poorly soluble drugs into amorphous solid dispersions to effectively solubilize and improve their absorption requirements is increasing
Traditional hot melt extrusion and spray drying technologies are limited by melting point, drug thermal stability or solubility, but the new Kinetisol technology fills this gap
Kinetisol technology has proven its ability to handle high melting point, insoluble in organic solvents or thermally unstable drugs and viscous polymers, and its development will further expand the formulation space
Ellenberger, DJ; Miller, DA; Williams, RO, 3rd.
Expanding the Application and Formulation Space of Amorphous Solid Dispersions with KinetiSol(R): a Review.
2018, 19 (5), 1933- 1956.
Ellenberger, DJ; Miller, DA; Kucera, SU; Williams, RO, 3rd.
Improved Vemurafenib Dissolution and Pharmacokinetics as an Amorphous Solid Dispersion Produced by KinetiSol(R) Processing.
2018, 19 (5), 1957-1970.
Jermain, SV; Lowinger, MB; Ellenberger, DJ; Miller, DA; Su, Y.
; Williams, RO, 3rd.
In Vitro and In Vivo Behaviors of KinetiSol and Spray-Dried Amorphous Solid Dispersions of a Weakly Basic Drug and Ionic Polymerdagger.
2020, 17 (8), 2789-2808.