CN116159023A - Atorvastatin suspension with high bioavailability and preparation method thereof - Google Patents

Atorvastatin suspension with high bioavailability and preparation method thereof Download PDF

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Publication number
CN116159023A
CN116159023A CN202310218800.XA CN202310218800A CN116159023A CN 116159023 A CN116159023 A CN 116159023A CN 202310218800 A CN202310218800 A CN 202310218800A CN 116159023 A CN116159023 A CN 116159023A
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suspension
atovaquone
atorvastatin
excipient
highly bioavailable
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Chinese (zh)
Inventor
郝天云
张慧桢
王贝贝
刘新湘
毛亮
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Shanghai STA Pharmaceutical R&D Ltd
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Shanghai STA Pharmaceutical R&D Ltd
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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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses an atorvastatin suspension with high bioavailability and a preparation method thereof, wherein the atorvastatin suspension with high bioavailability comprises atorvastatin, an excipient and a dispersion medium, the atorvastatin suspension with high bioavailability is prepared by the atorvastatin and the excipient through a nano process, and the excipient is a suspending carrier, a wetting agent or a combination of the suspending carrier and the wetting agent. The invention has better solubility and faster dissolution rate, improves pharmacokinetics, enhances the bioavailability of the atovaquone, and has the advantages of high drug loading and low toxic and side effects.

Description

Atorvastatin suspension with high bioavailability and preparation method thereof
Technical Field
The invention relates to the technical field of thermal analysis equipment, in particular to an atovaquone suspension with high bioavailability and a preparation method thereof.
Background
Atovaquone is a compound with significant antimalarial activity, with antimalarial activity. For the genus plasmodium, its site of action is the cytochrome bcl junction (junction III). Atovaquone can reversibly bind to 11500Da molecular groups on polypeptides. Dihydroorotate dehydrogenase is an important enzyme in pyridine biosynthesis, and is linked to mitochondria via coenzyme Q for electron transfer, and atovaquone inhibits pyridine synthesis by inhibiting electron transfer. Some metabolic enzymes are involved in mitochondrial electron transfer via coenzyme Q, and the inhibition of electron transfer by atovaquone actually inhibits the activity of these enzymes and inhibits the function of mitochondrial complex III. Atorvastatin is used as a better antimalarial drug, can destroy the normal operation of mitochondria in plasmodium within a few minutes after administration, cuts off the energy source in the plasmodium to cause death of the plasmodium, and is also suitable for oral treatment of mild to moderate Karsch pneumonia AIDS patients which cannot tolerate SMZ-TMP.
The atovaquone is insoluble in water, the solubility of the atovaquone in water at normal temperature is only 1 mug/mL, the commercial preparation of the atovaquone is a common tablet at present, and the preparation contains 100mg and 250mg specifications, has higher specification, and is easy to cause obvious side effects such as gastrointestinal dysfunction, liver dysfunction, skin allergy and the like. Therefore, it is very significant to improve the oral bioavailability of atovaquone and further improve the drug effect.
There is a need in the art for a novel agent or intermediate for atovaquone that improves pharmacokinetics and increases bioavailability of an oral drug of atovaquone, thereby improving efficacy and slowing down side effects.
Disclosure of Invention
In order to solve the technical problems, the invention provides a high-bioavailability atorvastatin suspension, which comprises atorvastatin, an excipient and a dispersion medium, wherein the high-bioavailability atorvastatin suspension is prepared by processing the atorvastatin and the excipient through a nano process, and the excipient is a suspending carrier, a wetting agent or a combination of the suspending carrier and the wetting agent.
Specifically, the concentration of the atorvastatin in the atorvastatin suspension with high bioavailability is 10mg/mL-200mg/mL.
Preferably, the concentration of the atorvastatin in the high-bioavailability atorvastatin suspension is 50mg/mL-100mg/mL.
Specifically, the suspending carrier is one or a combination of more of polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyvinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, vitamin E polyethylene glycol 1000 succinate, sodium carboxymethyl starch, sodium crosslinked carboxymethyl cellulose, crospovidone and sodium carboxymethyl cellulose, and the weight ratio of the suspending carrier in the atovaquone suspension is 0.1-0.2%.
Preferably, the suspending carrier is a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose, wherein the weight ratio of polyvinylpyrrolidone in the atorvastatin suspension is 0.1% -0.2%, and the weight ratio of hydroxypropyl methylcellulose in the atorvastatin suspension is 0.1% -0.2%.
Specifically, the wetting agent is one or a combination of more of sodium dodecyl sulfate, poloxamer, polysorbate-80 and sodium alginate, and the weight ratio of the wetting agent in the atovaquone suspension is 0.05-1%.
Preferably, the wetting agent is sodium dodecyl sulfate, and the weight ratio of the sodium dodecyl sulfate in the atovaquone suspension is 0.05-1%.
Specifically, the dispersion medium is water.
In particular, the mode of administration of the suspension of atovaquone with high bioavailability is oral administration.
The invention also provides a preparation method of the atorvastatin suspension with high bioavailability, which adopts a medium milling method to prepare the atorvastatin suspension, and the preparation method comprises the following steps:
s1, adding an excipient into a dispersion medium, and uniformly stirring by using magnetic force to obtain an excipient aqueous solution;
s2, adding the atovaquone bulk drug into the excipient aqueous solution, and uniformly stirring by using magnetic force to obtain an atovaquone crude suspension;
s3, transferring the crude suspension of the atovaquone into a grinding cavity of a nano grinder, adding a grinding medium, and grinding to obtain the suspension of the atovaquone.
Specifically, the grinding medium is one of glass beads, steel balls and zirconium silicate beads, the particle size of the grinding medium is 0.2-0.8mm, the volume ratio of the atovaquone crude suspension to the grinding medium is 1:2-1:4, the rotating speed of the nano grinding machine is set to 1500-4500rpm, the grinding time is 0.25-4.5h, and the grinding temperature is 10-30 ℃.
Compared with the prior art, the invention has the beneficial effects that:
1. the suspension of the atovaquone with high bioavailability is milled by a nano mill, the indissolvable drug atovaquone is prepared into an orally taken nano suspension drug, and the viscosity of a dispersion medium is increased and the hydrophilicity of drug particles is increased by adding a suspending carrier and a wetting agent, so that the drug has better solubility and faster dissolution rate, the pharmacokinetics is improved, the bioavailability of the atovaquone is enhanced, and the preparation has the advantages of high drug loading capacity and low toxic and side effects, thereby being beneficial to developing a drug preparation with higher safety;
2. the preparation method of the atovaquone suspension with high bioavailability provided by the invention has the advantages of simple preparation process, strong operability and stable process, and the prepared nanocrystals have narrow particle size distribution, so that the preparation method is beneficial to the development of experiments or further preparation of dosage forms.
Drawings
Fig. 1 is a graph of blood concentration versus time for a suspension of atovaquone provided by the present invention in example 1.
Detailed Description
The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. Materials, instruments, reagents and the like used in the following examples are commercially available unless otherwise specified. The technical means used in the examples, unless otherwise specified, are conventional means well known to those skilled in the art.
The structures, proportions, sizes, etc. shown in the drawings are shown only in connection with the present disclosure, and therefore, it should be understood and appreciated by those skilled in the art that the present disclosure is not limited to the specific terms or arrangements disclosed herein, but rather, any structural modifications, proportional changes, or dimensional adjustments, which may be made without departing from the spirit or scope of the present disclosure, should be construed as falling within the spirit or scope of the present disclosure, and the terms such as "upper," "lower," "left," "right," "middle," and "one" etc. are used herein for descriptive purposes only and are not intended to limit the scope of the present disclosure, but rather, the relative changes or modifications thereof should be construed as falling within the scope of the present disclosure without materially altering the teachings.
Example 1 preparation of an atovaquone suspension and pharmacokinetic Studies
1. An atovaquone suspension was prepared as follows:
s1, weighing (0.5) g of hydroxypropyl methyl cellulose, (0.5) g of polyvinylpyrrolidone and (0.2) g of sodium dodecyl sulfate, adding into (100) mL of water, and uniformly stirring by using magnetic force to obtain an excipient aqueous solution;
s2, adding the atorvastatin raw material drug (5) g into the excipient aqueous solution obtained in the previous step, and uniformly stirring by using magnetic force to obtain an atorvastatin crude suspension;
s3, transferring the crude suspension of the atovaquone into a grinding cavity of a nano grinder, adding a grinding medium steel ball, and grinding to obtain the suspension of the atovaquone. Milling conditions are as follows: the volume ratio of the atovaquone crude suspension to the steel balls is 1:2-1:4, the rotating speed of the nano grinder is 2500rpm, the grinding time is 1h, and the grinding temperature is 10-30 ℃.
An atorvastatin suspension having an atorvastatin concentration of (50) mg/mL was prepared.
2. Pharmacokinetic experiments of atorvastatin suspension to facilitate oral absorption
Experimental protocol: SD rats weighing 250-300 g, males, randomly divided into a commercially available tablet group of atovaquone and a suspension group of atovaquone nanocrystals, 6 rats per group, and the two rats were given the following modes of intragastric administration:
atovaquone commercial tablet group: the commercial tablet of atovaquone is ground and then administered alone.
Group of atovaquone nanocrystal suspensions: the suspension of atovaquone prepared in this example was administered.
After oral administration, 0.4mL of blood was taken at 0.5h,1h,2h,4h,6h,12h,24h,48h,72h,96h,120h, and the upper plasma was collected by centrifugation, and the atorvastatin blood concentration was measured, and the area under the drug concentration-time curve and the relative bioavailability were calculated.
Experimental results:
as shown in fig. 1, the plasma concentration-time curve of atovaquone is shown as a function of pharmacokinetic experiment.
The pharmacokinetic parameters corresponding to the commercial tablet set of atovaquone and the suspension set of atovaquone nanocrystals are shown in table 1 below:
table 1: pharmacokinetic parameter results table for two experimental groups
Figure BDA0004115920300000041
In the above table, t 1/2 : biological half-life: t (T) max : peak time; c (C) max : maximum blood concentration; AUC: area under the drug-time curve; RB%: relative bioavailability.
As can be seen from the table above, the oral absorption of the atovaquone can be obviously improved by the oral administration of the suspension of the atovaquone, and the oral administration relative bioavailability of the atovaquone is improved by 1.59 times compared with that of the conventional tablet medicines.
In summary, the above embodiments are only preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, but any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (10)

1. The high-bioavailability atorvastatin suspension is characterized by comprising atorvastatin, an excipient and a dispersion medium, wherein the high-bioavailability atorvastatin suspension is prepared by processing the atorvastatin and the excipient through a nano process, and the excipient is a suspending carrier, a wetting agent or a combination of the suspending carrier and the wetting agent.
2. The highly bioavailable suspension of atorvastatin according to claim 1 wherein the concentration of atorvastatin in the highly bioavailable suspension is 10mg/mL to 200mg/mL.
3. The highly bioavailable suspension of atorvastatin according to claim 1 wherein the concentration of atorvastatin in the highly bioavailable suspension is 50mg/mL to 100mg/mL.
4. The highly bioavailable atorvastatin suspension of claim 1 wherein the suspending vehicle is one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyvinylpyrrolidone vinyl acetate copolymer, polyethylene glycol, vitamin E polyethylene glycol 1000 succinate, sodium carboxymethyl starch, sodium croscarmellose, crospovidone, and sodium carboxymethyl cellulose, wherein the suspending vehicle comprises 0.1% to 0.2% by weight of the atorvastatin suspension.
5. The highly bioavailable suspension of atovaquone of claim 1 wherein the suspending vehicle is a combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose, wherein the weight ratio of polyvinylpyrrolidone in the suspension of atovaquone is between 0.1% and 0.2%, and wherein the weight ratio of hydroxypropyl methylcellulose in the suspension of atovaquone is between 0.1% and 0.2%.
6. The highly bioavailable suspension of atovaquone of claim 1 wherein the wetting agent is a combination of one or more of sodium lauryl sulfate, poloxamer, polysorbate-80, and sodium alginate, wherein the wetting agent comprises 0.05% to 1% by weight of the suspension of atovaquone.
7. The highly bioavailable suspension of atovaquone of claim 1 wherein said wetting agent is sodium lauryl sulfate and wherein said sodium lauryl sulfate comprises from 0.05% to 1% by weight of said suspension of atovaquone.
8. The highly bioavailable suspension of atovaquone of claim 1 wherein the dispersing medium is water.
9. The preparation method of the atovaquone suspension with high bioavailability is characterized in that the atovaquone suspension is prepared by adopting a medium milling method, and the preparation method comprises the following steps:
s1, adding an excipient into a dispersion medium, and uniformly stirring by using magnetic force to obtain an excipient aqueous solution;
s2, adding the atovaquone bulk drug into the excipient aqueous solution, and uniformly stirring by using magnetic force to obtain an atovaquone crude suspension;
s3, transferring the crude suspension of the atovaquone into a grinding cavity of a nano grinder, adding a grinding medium, and grinding to obtain the suspension of the atovaquone.
10. The method for preparing a highly bioavailable suspension of atovaquone according to claim 9, wherein the milling medium is one of glass beads, steel beads, zirconium silicate beads, the particle size of the milling medium is 0.2-0.8mm, the volume ratio of the crude suspension of atovaquone to the milling medium is 1:2-1:4, the rotational speed of the nanomiller is set to 1500-4500rpm, the milling time is 0.25-4.5h, and the milling temperature is 10-30 ℃.
CN202310218800.XA 2023-03-09 2023-03-09 Atorvastatin suspension with high bioavailability and preparation method thereof Pending CN116159023A (en)

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