Decoquinate nanoparticle formulations in solid solution form
阅读说明：本技术 固态溶液形式的癸氧喹酯纳米粒子制剂 (Decoquinate nanoparticle formulations in solid solution form ) 是由 王洪星 梁双红 范银洲 黄振平 赵思婷 秦莉 陈小平 于 2019-01-02 设计创作，主要内容包括：公开了一种生产含癸氧喹酯纳米颗粒制剂的固态溶液的热熔挤出方法。包含热熔挤出产品的纳米颗粒的水相均匀且稳定。提供了包含癸氧喹酯固态溶液的组合物,和生产含有癸氧喹酯固体分散体的组合物的热熔挤出方法。此外,提供了包含纳米级癸氧喹酯制剂的固态溶液,其改善了癸氧喹酯的水溶性、增强了癸氧喹酯在消化道的释放,以便于吸收、提高生物利用度以及在肝脏阶段对抗疟疾的功效。(A hot melt extrusion process for producing a solid solution containing decoquinate nanoparticle formulation is disclosed. The aqueous phase comprising the nanoparticles of the hot-melt extruded product is homogeneous and stable. Compositions comprising a decoquinate solid solution, and hot melt extrusion processes for producing compositions containing decoquinate solid dispersions are provided. In addition, solid solutions comprising nanoscale decoquinate formulations are provided that improve the water solubility of decoquinate, enhance the release of decoquinate in the digestive tract for absorption, increase bioavailability, and efficacy against malaria during the hepatic stage.)
1. A composition comprising decoquinate, a hot melt extrudable excipient, and a plasticizer or solubilizer.
2. The composition of claim 1, wherein the composition comprises, on a dry weight basis, 5% to 30% decoquinate, 60% to 90% of a hot melt extrudable excipient, 5% to 10% of a plasticizer or solubilizer.
3. The composition of claim 1 wherein the molecular weight of the decoquinate is 418 g/mole.
4. The composition of claim 1, wherein the hot-melt extrudable excipient is one of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, vinyl pyrrolidone-vinyl acetate copolymer, hydroxypropyl methylcellulose acetate succinate, and dimethylaminoethyl methacrylate copolymer, or a combination of two or more.
5. A composition according to claim 1, wherein the hydroxypropylmethylcellulose has a molecular weight in the range of 80kDa to 550 kDa.
6. A composition according to claim 1 wherein the hydroxypropyl methyl cellulose acetate succinate has an acetate degree of substitution of from 5% to 14% and a succinate degree of substitution of from 4% to 14%.
7. The composition of claim 1, wherein the dimethylaminoethyl methacrylate copolymer has a weight average molar mass (Mw) of about 47,000 g/mol.
8. The composition of claim 1, wherein the plasticizer is one of polyethylene glycol, poloxamer, polyoxyethylene hydrogenated castor oil, polyethylene glycol glyceryl laurate, polyethylene glycol glyceryl stearate, or a combination of two or more.
9. The composition of claim 1, wherein the solubilizing agent is one of polyethylene glycol, poloxamer, polyoxyethylene hydrogenated castor oil, polyethylene glycol glyceryl laurate, polyethylene glycol glyceryl stearate, or a combination of two or more thereof.
10. The composition of claim 1, wherein the polyethylene glycol has a molecular weight ranging from 2000 to 8000 g/mol.
11. The composition according to claim 1, wherein the poloxamer is poloxamer 188.
12. A high temperature heating process for preparing the composition of any one of claims 1-11, comprising the steps of mixing decoquinate with a hot melt extrudable excipient, plasticizer or solubilizer to form a mixture; processing the mixture in a twin screw extruder having a plurality of temperature zones at a hot melt temperature below the degradation temperature of decoquinate; and extruding the mixture to form an extrudate, wherein the decoquinate in the extrudate is in a solid solution state.
13. The method of claim 12, wherein processing the mixture is performed in a hot melt extruder at a hot melt temperature of 50 to 200 ℃, preferably 120 to 180 ℃.
14. The production method according to claim 13, wherein the hot-melt extruder is a twin-screw extruder, wherein the screw rotation speed is 15 to 300rpm, more preferably 25 to 150 rpm.
15. The method of claim 12, wherein the mixture is processed in a twin screw extruder to form an extrudate, wherein the extrudate is in a solid dispersion state or a solid solution state, preferably a solid solution.
16. The method of claim 12, wherein the solid solution provides an active therapeutic agent that can be further formulated into a solid oral dosage form for in vivo delivery of the therapeutic agent for prevention or treatment of malaria infection or other parasitic diseases or conditions.
17. Use of a composition according to any one of claims 1-11 for the preparation of a pharmaceutical preparation for the prevention and/or treatment of a disease caused by plasmodium.
18. The use according to claim 17, wherein the disease is any one or more of: plasmodium vivax, plasmodium falciparum, plasmodium malariae, plasmodium ovale and plasmodium knowlesi, preferably plasmodium vivax, plasmodium falciparum and plasmodium ovale.
Technical Field
The present invention relates to a thermal process in a twin screw extruder which produces extrudates in the form of solid solutions whose composition comprises the antimalarial (antiparasitic) drug Decoquinate (DQ) or other therapeutic drugs such as other antiparasitic drugs. In some embodiments, the solid solution is in the form of a composite comprising the drug, a hot-melt extrudable excipient, and a minor percentage of a plasticizer or solubilizer, based on the weight of the composite. Examples of hot melt extrusion excipients include hydroxypropyl methylcellulose, dimethylaminoethyl methacrylate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, vinyl pyrrolidone/vinyl acetate copolymer. Such solid solutions are intended to release a pharmaceutically active ingredient (API) in vivo as a solid oral formulation to achieve prevention or treatment of malaria infection or other parasitic disease or disorder.
Background
Malaria is a mosquito-borne infectious disease caused by infection with Plasmodium, such as Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum and Plasmodium ovale. Another species of Plasmodium, Plasmodium knowlesi, infects humans and monkeys. Malaria is usually transmitted by infected female anopheles mosquitoes, and the parasites enter human blood (Malaria Fact sheet. No.94.updated March2014, Retrieved28August 2014) with their saliva as they inhale, and mature and multiply in the liver. The majority of malaria patients die from plasmodium falciparum, while malaria caused by plasmodium vivax, plasmodium ovale and plasmodium malariae is generally relatively mild. The mortality rate of severe cases caused by plasmodium falciparum is extremely high, with over 70% being children under the age of 5. In addition, travelers to malaria endemic areas are also susceptible to parasite infections. Plasmodium vivax and plasmodium ovale are closely related, both having unique biological characteristics that form a dormant seed at the liver stage. Dormancy is a form of occult in the liver that can lead to recurrence of malaria in humans.
After infection of humans, primates and rodents by plasmodium, the first 48h proliferate in the liver (pre-erythrocytic stage) and the later stage proliferate in erythrocytes. Artemisinin is the most commonly used first-line antimalarial drug used as a core drug in Artemisinin Combination Therapy (ACT). It and most classical antimalarial drugs such as chloroquine and quinine act on the red blood cell stage of the malaria parasite, but do not inhibit the growth of the parasite in the liver stage. In addition, the problem of resistance of plasmodium to antimalarial drugs has arisen worldwide. For example, chloroquine-resistant plasmodium falciparum has spread to most malaria sites, and artemisinin-resistant plasmodium has become a problem in parts of southeast asia. ("Malaria Fact sheet N ° 94". WHO. March2014.Retrieved28August 2014). The widespread resistance of Plasmodium to chloroquine and sulfadoxine/pyrimethamine, as well as the resistance presented by the artemisinin component of ACT, have become critical challenges for the control of malaria (Ariel, f.et al, american marker of artemisinine-resistant plasma falciparum malaria, Nature 2014,505: 50-55). The dormant seeds generated by plasmodium vivax and plasmodium ovale infections during quiescent liver phase also make malaria difficult to control. Primaquine is an antimalarial drug used in the liver stage, but has serious side effects. The medicine can cause acute hemolytic anemia in patients with glucose 6-phosphate dehydrogenase deficiency (G6PDD) tendency. Malaron (a Chinese character of 'Mailuo')Is a mixed preparation of atovaquone and proguanil and is also an antimalarial drug used in the liver stage, but the price is high, and most patients are difficult to bear. Therefore, there is a need to develop new, highly effective and reasonably priced low-toxicity antimalarial drugs, especially antimalarial drugs that are effective in the hepatic phase and are non-resistant, to better protect susceptible populations.
Decoquinate (DQ, CAS No.18507-89-6) was found to exhibit potent inhibitory and killing effects on Plasmodium in both in vivo and in vitro experiments (Meister, S.et al, Imaging of Plasmodium lift stages driven next-generation anti-microbial drug discovery, Science 2011; 334: 1372-7). It has efficacy on both Liver and blood stage Plasmodium, so DQ has more obvious advantages than the existing antimalarial drugs in preventing and treating clinical symptoms, reducing transmission and reducing Drug resistance possibility (da Cruz, fp.et al, Drug discovery targeted at plasma live bacteria sites identify a patent multiple cause antibacterial Drug, j infection Dis 2012,205(8): 1278-. It acts on and inhibits the cytochrome bc1 complex of plasmodium mitochondria without affecting the mammalian respiratory chain. Decoquinate has proven safe in animal toxicology as a veterinary drug and nanoparticle form (Wang, H.et al, Nanoparticulate formulations of decoquinate antibacterial efficacy against bacteria infections in mice, Nanomedicine: Nanotechnology, Biology, Medicine 2014,10: 57-65). Chloroquine-resistant malaria parasites are not resistant to them (CN104906044A [2015]: adecomsonate nano-formation and identity preparation and application; da Cruz, FP. Et al., Drug Screen Targeted at plasmid proteins identities a Potent Multi antibiotic Drug J InfeDisct (2012),205(8): 1278-1286). Decoquinate has great potential to become an antimalarial drug. However, the important point for the development of decoquinate as an oral antimalarial drug for clinical use is to solve the problem of solubility; meanwhile, oral formulations require that decoquinate be efficiently absorbed in the body by the small intestine, so that the compound becomes available and active in the body.
The Hot Melt Extrusion (HME) method has significant advantages in solving the problem of insolubility of small molecule compounds by using the controllable temperature of each screw section, low melting point excipients, efficiency of physical interaction of drug components, mechanical action during processing, etc. Nevertheless, the selection of excipients suitable for the API and the process parameters suitable for the formulation of the composition are indispensable for obtaining a hot-melt extruded product which allows the homogeneous dispersion and stabilization of the poorly soluble compounds present in the aqueous phase before they reach the intestinal tract and are absorbed.
When the Active Pharmaceutical Ingredient (API) is homogeneously dispersed in another solid excipient in a crystalline or amorphous particulate state, a solid dispersion is obtained. If the API is molecularly dissolved in a solid matrix composed of excipients, the formulation is a true solid solution. In the case of true solid solutions, the formulations are thermodynamically stable because the API and excipients are completely miscible and are readily miscible throughout the range of components. However, in most cases, the API and excipients are miscible only to a limited extent, resulting in other forms of solid solutions and dispersions, where various destabilizing factors are encountered. Because there is no driving force to dissolve the API that diffuses to the surface of the supersaturated solid solution, the API that was initially dissolved in the supersaturated solid solution may precipitate over time. The particle size distribution of API particles in solid dispersions becomes larger over time at the expense of smaller particles being dissolved (ostwald ripening). The number of small particles of API in the suspension gradually decreased, while the larger particles continued to increase. The API dispersed in the amorphous particles is also thermodynamically unstable and may crystallize over time.
Disclosure of Invention
A high temperature heating process for preparing a solid solution formulation containing a pharmacologically active agent comprises the steps of mixing decoquinate with a hot melt extrudable excipient, a plasticizer or solubilizer to form a mixture. Processing the mixture is carried out in a twin screw extruder having a plurality of temperature zones, each melting temperature being below the degradation temperature of the decoquinate. Extruding the mixture to form an extrudate, wherein the decoquinate is in a solid solution state in the extrudate. The solid solution provides an active therapeutic agent and may further be formulated into a solid oral dosage form for in vivo release of the therapeutic agent for the prevention or treatment of malaria infection or other parasitic disease or disorder.
The invention provides a composition for hot melt extrusion, wherein the composition comprises 5-30% decoquinate, 60-90% hot melt extrudable excipient, and 5-10% plasticizer or solubilizer calculated by dry weight.
In one embodiment, the hot-melt extrudable excipient is hydroxypropyl methylcellulose (AFFINISOL)TMHPMCHME), hydroxypropyl methylcellulose acetate succinate (AFFINISOL)TMHPMCAS), dimethylaminoethyl methacrylate copolymer
In another embodiment, AFFINISOLTMHPMC HME is a commercial product designed to improve the solubility of API and inhibit the recrystallization of API, with hydroxypropyl methylcellulose being less hygroscopic as a carrier for solid solutions of API than other commercial polymeric carriers for hot melt extrusion. AFFINISOLTMHPMCAS is a soluble high molecular polymer that helps optimize solubility by maintaining the stability of the solid dispersion and inhibiting crystallization of the API. Methyl acrylate Polymer (A)
In another specific embodiment, the polyethylene glycol is polyethylene glycol 8000, polyethylene glycol 6000, or polyethylene glycol 4000. Polyethylene glycol acts as a plasticizer, lowering the melting temperature during melting, thereby reducing the likelihood of decomposition of the decoquinate. In addition, polyethylene glycol can also increase the dissolution rate of the active ingredient decoquinate (PCT150162 PPC).
In another embodiment, the plasticizer is poloxamer 188 (b)P188), 
In addition, the polymeric materials used in the present invention may have thermoplastic behavior, be thermally stable at high temperatures, be non-toxic, and be solubilized. The solubilizing agent of choice in the present invention is a formulation excipient designed for hot melt extrusion processing and Generally Recognized As Safe (GRAS) in clinical use.
The present invention provides a hot melt extrusion preparation process for processing a hot melt extrusion composition in which a solid solution of decoquinate is produced.
The invention also provides application of the decoquinate solid solution as a pharmaceutical preparation in preventing and/or treating diseases caused by plasmodium.
Preferably, the disease is one or more of plasmodium malariae malaria caused by plasmodium vivax, plasmodium falciparum, plasmodium malariae, plasmodium ovale and plasmodium knowlesi.
The decoquinate solid solution can be processed into oral preparations such as tablets, granules and capsules according to requirements.
Drawings
FIG. 1 shows the thermogravimetric analysis of the hot melt extrudate (F8) prepared in example 8. Decoquinate hardly changes below 250 ℃ and starts to be degraded gradually only in the temperature range of 250-350 ℃.
FIG. 2 is a Differential Scanning Calorimetry (DSC) chart of a hot melt extrudate containing decoquinate. Sample preparation samples were prepared as prescribed in example 8, but 3 different batches of scale-up preparations, as opposed to the physical mixture of decoquinate and adjuvants in the prescription of example 8 at ambient temperature.
FIG. 3 shows an X-ray diffraction analysis of a hot melt extruded composition. The sample was the same as in figure 2(DSC) (example 8), with the pure drug substance decoquinate on the right. Note that in the Y-coordinate, the peaks for the 3 different batches of scale-up prepared samples were low relative to the physical mixture and the drug substance decoquinate prescribed in example 8.
Fig. 4 shows a comparison of the in vitro dissolution rates of the decoquinate solid solutions prepared in example 1 and example 2. As described in the dissolution test method, the dissolution media used in the experiments contained 0.1N HCl and 10mM SDS, all experiments using the dissolution media unless otherwise stated.
Figure 5 shows a comparison of the in vitro dissolution rates of the solid solutions of decoquinate formulated in examples 3 and 4 prepared by hot melt extrusion techniques, the dissolution media being identical to that used in figure 4.
FIG. 6 shows a comparison of the in vitro dissolution rates of the solid solutions of decoquinate formulated in examples 3 and 4 using hot melt extrusion techniques, with the dissolution medium being phosphate buffered saline pH 6.8.
Figure 7 shows a comparison of the in vitro dissolution rates of the solid solutions of decoquinate formulated in examples 7 and 8 prepared by hot melt extrusion techniques, the dissolution media being identical to that used in figure 4.
FIG. 8 shows a comparison of the in vitro dissolution rates of solid solutions of decoquinate formulated in examples 7 and 8 using hot melt extrusion techniques, with the dissolution medium being phosphate buffered saline pH 6.8.
Figure 9 shows a comparison of the in vitro dissolution rates of the solid solutions of decoquinate formulated in examples 9 and 10 prepared by hot melt extrusion techniques, the dissolution media being identical to that used in figure 4.
Figure 10 shows a comparison of the in vitro dissolution rates of the solid solutions of decoquinate formulated in examples 5, 6, 9, 12 and 13 prepared by hot melt extrusion techniques, the dissolution media being identical to that used in figure 4.
Figure 11 shows a comparison of the in vitro dissolution rates of the solid solutions of decoquinate formulated in examples 14 and 15 prepared by hot melt extrusion techniques, the dissolution media being identical to that used in figure 4.
FIG. 12 is a pharmacokinetic study of the sample of example 8(F8) in Sprague Dowley (Sprague Dawley) rats. F8 hot-melt extrusion nanometer preparation is administrated by stomach irrigation, and LC-MS is used for detecting the concentration of decoquinate in blood; the ordinate represents the concentration of decoquinate in blood, and the abscissa represents the blood collection time.
FIG. 13 high performance liquid chromatogram of decoquinate in the sample prepared in example 8 (F8). The chart shows that decoquinate molecules are still complete after the hot-melt extrusion preparation process, and the peak type and the retention time in the chromatogram are not changed.
FIG. 14 high performance liquid chromatogram of decoquinate standard. Dissolving the standard substance with anhydrous ethanol, diluting to appropriate concentration range, and detecting decoquinate peak type and retention time by established high performance liquid chromatography.
FIG. 15 high performance liquid chromatogram of decoquinate standards after being placed in a pH1.2 solution for 2 days. The sample was dialyzed against distilled water, diluted and assayed by established methods. After being treated by strong acid solution, the peak type and the retention time of the main peak of the pure decoquinate are changed.
FIG. 16 is a high performance liquid chromatogram of a sample of preparation example 8(F8) after being placed in a solution at pH1.2 for 10 days by hot melt extrusion technique. Samples were dialyzed, diluted and tested by established HPLC methods. The HPLC profile showed that the peak pattern and residence time of decoquinate was not detectable by HPLC after the hot melt extrusion solid solution was treated with a strong acidic solution.
FIG. 17 is a high performance liquid chromatogram of a sample of preparation example 8(F8) after being placed in a solution at pH9.0 for 10 days by hot melt extrusion technique. Samples were dialyzed, diluted and tested by established HPLC methods. The HPLC profile indicated that the peak pattern and residence time of decoquinate was not detectable by HPLC after treatment of the hot melt extruded solid solution with an alkaline solution.
FIG. 18 shows the stability of samples prepared using the hot melt extrusion method, formulated as example 8(F8) and example 15 (F15). The product from the hot melt extruder is exposed to room temperature, automatically dried, cooled to a solid, then ground to a powder, and dissolved in an aqueous solution to form a suspension. After the suspension was left at room temperature for 24 hours, each sample was sampled and the particle size was measured after dilution with distilled water, and the results are shown in table 4; samples F8 and F15 were dissolved in PBS (pH7.4) and normal saline (weakly acidic), stored at room temperature for more than 12 months, and the stability of the particles in the solution was periodically observed.
Detailed Description
The invention discloses a high temperature heating process for preparing a solid solution containing a pharmacologically active agent, which comprises the step of mixing decoquinate with an excipient capable of hot-melt extrusion and a plasticizer or solubilizer to prepare a mixture.
Decoquinate and other antiparasitics
The oral formulation compositions of the present invention comprise an antiparasitic agent, such as decoquinate or a mixture of such agents.
Decoquinate (DQ), a chemically synthesized (hydroxy) quinolone compound named 4-hydroxyquinoline (ethyl-6-decyloxy-7-ethoxy-4-hydroxyquinoline-3-carboxylate), CAS No.18507-89-6, molecular weight 418g/mol, molecular formula C25H35NO5. The corresponding chemical structural formula of decoquinate is as follows:
the decoquinate structure has a secondary amine functional group, can be used in a free base form or prepared into a preparation, and can also be used for preparing pharmaceutically acceptable salts. Also, decoquinate in anhydrous or various hydrate forms and salts thereof are also within the scope of the present invention.
The invention provides a composition for hot melt extrusion, wherein the composition comprises 5 to 30 percent of decoquinate, 60 to 90 percent of hot melt extrudable excipient and 5 to 10 percent of plasticizer or solubilizer on a dry weight basis.
In one embodiment, the polymeric carrier material is hydroxypropyl methylcellulose (AFFINISOL)TMHPMCHME), hydroxypropyl methylcellulose acetate succinate (AFFINISOL)TMHPMCAS), dimethylaminoethyl methacrylate copolymer(s) ((R)
In another embodiment, the hydroxypropyl methylcellulose (AFFINISOL) isTMHPMC HME) is a commercial product aimed at improving the solubility of API and inhibiting the recrystallization of API, as a carrier for API solid solutions, which is less hygroscopic than other polymeric carriers used for hot melt extrusion; the three subtypes can be used as solid dispersing agents of decoquinate regardless of the dissolution rate and the dissolution rate of hot-melt extrusion products. Hydroxypropyl methylcellulose acetate succinate (AFFINISOL)TMHPMCAS) is a soluble high molecular weight polymer that helps optimize the solubility enhancement by maintaining the stability of the solid dispersion and inhibiting crystallization of the API; the number of acetate and succinate groups in the polymer molecule can be divided into three subtypes, and manufacturers in different countries have production (Table 3). The effect of different subtypes of HPMCAS on the solubility and stability of decoquinate solid dispersions was examined and compared. Although in vitro solubility experiments, the effect on the drug dissolution rate in solid dispersions wasVA64 and
In another embodiment, the polyethylene glycol is polyethylene glycol 8000, polyethylene glycol 6000, or polyethylene glycol 4000. Polyethylene glycol acts as a plasticizer, lowering the melting temperature during melting, thereby reducing the likelihood of degradation of the decoquinate. In addition, the polyethylene glycol can improve the dissolution rate of the active ingredient decoquinate and promote the release and absorption of the API in the digestive tract.
In another embodiment, the plasticizer is poloxamer 188P188),
The present invention provides a method for preparing a composition for hot melt extrusion in which a solid solution of decoquinate is produced.
In a particular embodiment, the hot-melt extrusion (HME) is carried out in a hot-melt extruder, wherein the composition as described above is mixed and rolled in a parallel co-rotating twin-screw extruder, wherein the components of the composition are mixed in a horizontally segmented barrel and in the molten state, wherein each section provided with a screw has a predetermined temperature, extruded through the twin-screw extruder and shaped by means of a die, the extruded material, after being automatically cooled at room temperature, giving a solid mixture in the form of a strand or in another shape (depending on the die); and shearing and crushing the strip-shaped solid mixture to obtain the powdery decoquinate solid solution.
In a preferred embodiment, the hot melt extrusion temperature is 5-200 ℃, preferably 120-180 ℃; the screw rotation speed of the hot-melt extruder is 15 to 300rpm, preferably 25 to 150 rpm.
In the process of preparing the decoquinate solid solution, the melting temperature is required to be adjusted according to the components of the raw materials, so that the active component decoquinate and the auxiliary materials can be effectively mixed at the molecular level, and the thermal decomposition of the decoquinate and the auxiliary materials is avoided.
In general, solid materials can have both crystalline and amorphous forms, with the temperature at which the crystals begin to melt being referred to as the melting point (Tm). Melting point is the temperature at which a substance changes from a solid to a liquid (melt), often denoted as Tm. Organic compounds generally have a fixed melting point, i.e. the change between the two phases solid-liquid is very sensitive under a certain pressure. The melting point range of a pure substance from a solid state to a liquid state is generally narrow, but when an organic compound is mixed with other substances, the melting point decreases and the melting point range widens. The melting point of decoquinate is 242-246 ℃. The present invention designs a specific composition such that when decoquinate is mixed and melted with excipients (e.g., hot melt extrudable excipients, plasticizers, etc.), it can be converted into a liquid state at a temperature significantly lower than its own melting point, thereby reducing the possibility of thermal decomposition of decoquinate (fig. 14), thus facilitating the retention of its original structure and pharmacodynamic activity.
In the process of preparing the decoquinate solid solution, the chemical structure of the active ingredient decoquinate is kept unchanged, and the pharmacodynamic activity of the active ingredient decoquinate is intact; in some embodiments, the extruded decoquinate solid solution product is uniformly suspended in an aqueous medium, the suspension remaining stable without the appearance of cloudy, floating, and precipitated material for at least one week; in addition, the release rate and the dissolution rate of the decoquinate prepared in the HME product are both obviously improved, and animal experiments show that the bioavailability and the antimalarial activity of the decoquinate are also obviously improved.
The invention provides application of a solid solution of decoquinate obtained by using an HME preparation method as a pharmaceutical preparation for preventing and/or treating diseases caused by plasmodium.
Preferably, the disease is one or more of malaria caused by plasmodium vivax, plasmodium falciparum, plasmodium malariae, plasmodium ovale and plasmodium knowlesi.
The decoquinate solid solution can be processed into oral preparations such as tablets, granules and capsules according to requirements.
The hot-melt extrusion technology adopted by the invention can prepare the active pharmaceutical ingredients into solid solution, wherein the decoquinate is melted and forms a formula in the excipient capable of being hot-melt extruded, so that the decoquinate in a solid dissolved state is generated and stabilized; in the present invention, excipients suitable for decoquinate and the operating parameters of the hot melt extruder suitable for producing such solid solutions are selected to optimize conditions and form stable solid solutions.
The HPMCAS produced by the dow chemical manufacturer in the united states is classified into three subtypes 912, 716 and 126 according to the number of acetate and succinate in the molecule, and the same corresponding products produced by other manufacturers (e.g., japan shin-over chemistry and asia-kalant additives limited, uk) are named L, M and H. These cellulose-based polymers are used in spray-drying techniques for the preparation of formulations of poorly soluble compounds, but exhibit inconsistent physicochemical properties in terms of improved solubility and formulation stability when hot-melted with compounds including itraconazole (weakly basic), ezetimibe (neutral), felodipine (weakly acidic). The subtype 126 or subtype H polymer molecules in HPMCAS contained the most acetate substitutions, and when used in the hot melt extrusion process to prepare decoquinate solid solutions, it was better than the other two subtypes (HPMCAS 912 or 716, or L or M), because of its best effect in solubilizing and stabilizing the formulation (Table 3). The solid decoquinate solution prepared above is suspended in an aqueous mediumIn texture, the formed suspension is homogeneous and glossy, and is stable and free of precipitation or aggregation within at least 24 hours; comparing two-by-two decoquinate solid solutions containing different subtypes of HPMCAS to find the model AffiniSolTM126 are superior to the other two models of AffiniSolTM912 and AffiniSolTM716。
Table 3 shows AffiniSolTMThe HPMCAS specification, the corresponding manufacturer type, and the role in enhancing decoquinate solubility and stabilizing the formulation.
Table 3 various HPMCAS subtypes used to enhance Decoquinate (DQ) solubility and stabilize the formulation.
Note:
HPMCAS＝AFFINISOLTMhydroxypropyl methylcellulose acetate succinate;
tg ℃ ═ glass transition temperature.
The molten components of the composition are extruded through a shaped outlet and the extrudate is rapidly cooled to form a single solid phase that is stable in storage. Also, the extrusion processing equipment can be suitably modified to control the extrudate shape to be modified for downstream processing into dosage forms. Typically, these extruded materials are ground into powders so that they can be incorporated into conventional oral solid dosage forms, such as tablets or capsules, while maintaining the desired release profile of the drug.
Such decoquinate present in the dispersion can be considered a solid solution. To further improve the dispersion state of decoquinate in the aqueous medium, a suitable substance such as a solubilizer or a plasticizer may also be added to the blend prior to the hot-melt extrusion process. The nano-grade granular decoquinate with improved water solubility can improve the dissolution rate, is beneficial to the absorption of intestinal tracts, and improves the bioavailability and the in-vivo biological activity of the medicine. Thus, the improvement of the water solubility of decoquinate is achieved by the stability of the compound in a well dispersed state, which when suspended in an aqueous medium can be present in the aqueous medium for at least 24h, and can even be present in the aqueous phase stably for more than 12 months. In some solid solution examples, the nanoparticles in suspension may be as small as 200nm or between 200 and 400nm without any further manipulation, such as without high pressure homogenization and sonication intervention.
The invention adopts the hot-melt extrusion technology to prepare the decoquinate solid solution. The inventor selects specific preparation auxiliary materials and specific proportion of main drugs and auxiliary materials, so that the decoquinate can be converted into liquid at the temperature lower than the melting point of the decoquinate, and then the decoquinate is mixed and melted with the auxiliary materials such as excipient, plasticizer and the like, the possibility of thermal decomposition of the active ingredient decoquinate is greatly reduced, and the original structure and pharmacodynamic activity of the decoquinate are favorably maintained. In addition, by optimizing the operation parameters of a machine, the active ingredient decoquinate and each auxiliary material can be effectively melted to obtain an extrudate with uniform texture, wherein the bioavailability and the drug effect of the decoquinate are superior to those of a corresponding product prepared by an organic solvent method; compared with an organic solvent method, the hot-melt extrusion method used in the invention is easier to improve the production efficiency, so that the laboratory achievements are more convenient to expand to a pilot-scale test level and an industrialization level, and further the clinical application is promoted.
In order to facilitate understanding of the present invention, examples of the present invention are listed below. It will be appreciated by those skilled in the art that these examples are only for better illustration of the present invention and should not be construed as a specific limitation of the present invention.
The materials and sources thereof used in the following examples
Decoquinate (batch No. 130802, molecular weight: 417.53; Kimbersten pharmaceuticals, Inc., Zhejiang);
propranolol standard (sigma chemicals, china division, usa));
hydroxypropyl methylcellulose (AFFINISOL)TMHPMC HME 15LV, HME 4M; dow chemical company, usa);
hydroxypropyl methylcellulose acetate succinate (AFFINISOL)TMHPMCAS-716, AS-912, AS-126; dow chemical company, usa);
dimethylaminoethyl methacrylate copolymer (A)
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (A)Basf, germany);
vinylpyrrolidone-vinyl acetate copolymer (A)VA64, basf, germany);
poloxamer 188(
lauric acid macrogolglycerides (44/14, Jiafa lion, France);
stearic acid macrogol glyceride (
polyethylene glycol 6000(PEG 6000, Sigma Aldrich, USA).
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