CN116270690A - Breviscapine-matrine dual drug-loaded co-amorphous substance and application thereof - Google Patents

Breviscapine-matrine dual drug-loaded co-amorphous substance and application thereof Download PDF

Info

Publication number
CN116270690A
CN116270690A CN202310216247.6A CN202310216247A CN116270690A CN 116270690 A CN116270690 A CN 116270690A CN 202310216247 A CN202310216247 A CN 202310216247A CN 116270690 A CN116270690 A CN 116270690A
Authority
CN
China
Prior art keywords
breviscapine
matrine
amorphous
amorphous material
amorphous substance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310216247.6A
Other languages
Chinese (zh)
Inventor
王文苹
尹会云
王皎
董志
金文彬
马燕
王佳丽
丁雄
张文平
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yunnan University of Traditional Chinese Medicine TCM
Original Assignee
Yunnan University of Traditional Chinese Medicine TCM
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yunnan University of Traditional Chinese Medicine TCM filed Critical Yunnan University of Traditional Chinese Medicine TCM
Priority to CN202310216247.6A priority Critical patent/CN116270690A/en
Publication of CN116270690A publication Critical patent/CN116270690A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C07H1/08—Separation; Purification from natural products
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Physiology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Nutrition Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a medicine-medicine co-amorphous substance for co-carrying traditional Chinese medicine active ingredients of breviscapine and matrine, the prescription of the medicine-medicine co-amorphous substance does not contain any auxiliary materials, the preparation method is simple and efficient, no special process or equipment is needed, the cost is low, and the industrialization is easy. The breviscapine-matrine blend powder prepared by the invention is in an amorphous state, can remarkably improve the water solubility of two medicaments simultaneously, improves the in-vitro dissolution performance of the insoluble medicament breviscapine, and is beneficial to further preparation forming and improving the bioavailability.

Description

Breviscapine-matrine dual drug-loaded co-amorphous substance and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a breviscapine-matrine dual drug-loaded co-amorphous substance, a preparation method of the breviscapine-matrine co-amorphous substance and application of the breviscapine-matrine co-amorphous substance in preparing oral solid quick-release preparations and conventional preparations.
Background
The erigeron Breviscapus (BRE) is flavonoid effective component extracted from dried whole plant erigeron breviscapus of Compositae, is representative effective component of erigeron breviscapus, and is a mixture of erigeron breviscapus B (4 ', 5, 6-trihydroxyflavone-7-gluconic acid glycoside) and erigeron breviscapus A (4', 5-dihydroxyflavone-7-gluconic acid glycoside), wherein the content of erigeron breviscapus B is above 95%. Breviscapine has wide pharmacological activity, and especially has definite clinical curative effect on cardiovascular and cerebrovascular diseases. However, the erigeron breviscapus belongs to a biological pharmaceutical IV medicine, and has poor water solubility and fat solubility, low oral bioavailability, rapid elimination in intravenous injection and short half-life period. Therefore, despite the great medicinal potential of breviscapine, the deficiency of physicochemical and pharmacokinetic properties limits the full play of clinical efficacy.
Matrine (MAT) is also called Matrine, and is a pyridine derivative alkaloid using piperidine as matrix, and is mainly extracted from natural plants such as Sophora flavescens ait, sophora tonkinensis S.tonkinensis Gagnep, sophora alopecuroides L, and Sophora davidii Hance. Matrine has wide pharmacological action, can be clinically used for treating various diseases, such as anti-tumor and arthritis treatment, prevention and treatment of kidney diseases, cardiovascular and cerebrovascular system protection, treatment and the like.
One of the most common strategies for improving the solubility and dissolution rate of poorly soluble drugs is to prepare amorphous solid dispersions, and the traditional solid dispersions have the problems that the system is easy to absorb moisture, has crystallization tendency, is difficult to produce in industrial scale-up and the like because the drugs are highly dispersed in a large amount of water-soluble carriers.
The prior art (screening of preparation process of breviscapine solid dispersion) (Tang Ting, etc., chinese medical guide, 19 (24), 2022) discloses a method for preparing breviscapine solid dispersion by taking poloxamer 188 as a carrier and adopting a melting method, wherein the medicine-carrier ratio is 1:5, the medicine loading rate is about 2mg/g, and the existence state of the medicine is unknown. Novel carrier Soluplus ® Application study in preparation of Breviscapine solid Dispersion (Jie Zhongba, university of Guangdong medical science, 2017) discloses a preparation method of a solid dispersion of Breviscapine ® The preparation method of the breviscapine solid dispersion is a carrier, a solvent volatilizing method or a hot-melt extrusion method, wherein the medicine-carrier ratio is 1:9, and the medicine is in an amorphous state. The prior art CN1408392A discloses a formula and a preparation method of a breviscapine dripping pill, which are prepared by taking polyethylene glycol 6000, stearic acid and poloxamer 188 as matrixes and adopting a melting-dripping method, wherein the drug loading is 20-30%. The above prior art adopts a solid dispersion strategy known to those skilled in the art for improving the dissolution and dissolution performance of breviscapine, wherein part of the technology can convert the medicine from a crystalline state to an amorphous state, but a large amount of carriers and auxiliary materials are needed, and the medicine loading amount is limited.
The co-amorphous substance is a single-phase binary system formed by the medicine and another compound through interaction of hydrogen bond, van der Waals force and the like based on the defect of thermodynamic instability of the amorphous medicine, so that all components are uniformly mixed at a molecular level and are in a thermodynamic high-energy state. The co-amorphous material can be used for solving various requirements of insoluble drugs, such as improving solubility, dissolution and bioavailability, improving release characteristics and the like, even adjusting melting point, enhancing compressibility, masking bad smell and the like. The co-amorphous system composed of the two medicines can also produce synergistic pharmacological effects, enhance curative effects, reduce toxic and side effects and adverse reactions caused by single administration, and provide a new idea for combined administration. Thus, drug-drug co-amorphous has become a new technological trend for drug combination, but there is also the possibility that no interaction between the two drugs occurs, but only a simple physical mixture is formed, and thus whether the product is co-amorphous or not is unpredictable.
The prior art CN107501211A discloses a docetaxel-flavone co-amorphous substance, docetaxel, myricetin and naringenin are prepared into the co-amorphous substance, the solubility of the obtained product in an aqueous medium is improved by 2.5-3.1 times compared with that of docetaxel crystals, the characteristic dissolution rate is improved by 5.1-7.1 times, and the oral bioavailability of the product can be remarkably improved. The prior art CN107998112A discloses a co-amorphous substance of curcumin-ursodeoxycholic acid and a preparation method thereof, and the co-amorphous substance prepared by a solvent method or a grinding method can remarkably accelerate the in-vitro dissolution rate of curcumin and improve the apparent permeability coefficient of the curcumin-ursodeoxycholic acid on Caco-2 cells. The prior art CN202110261617 discloses a common amorphous substance containing andrographolide, a preparation method and a pharmaceutical composition thereof, wherein andrographolide, oxymatrine and ferulic acid (or cinnamic acid or p-hydroxy cinnamic acid) are prepared into the common amorphous substance by adopting a solvent method, and the solubility of the andrographolide in the amorphous substance is 1.3-3.7 times of that of corresponding bulk drugs. The prior art CN202011489209 discloses a berberine-silybin co-amorphous substance and preparation and application thereof, wherein berberine (or inorganic salt thereof) and silybin (or derivative thereof) are prepared into the co-amorphous substance, the in-vitro dissolution rate of the berberine in the obtained co-amorphous substance is lower than that of corresponding bulk drugs and physical mixtures, and the dissolution rate of the silybin is obviously improved; after oral administration to mice, the bioavailability of berberine in the co-amorphous form is comparable to that of the physical mixture, whereas the bioavailability of silybin is significantly higher than that of the physical mixture. The prior art CN201910747737 discloses a cefpodoxime proxetil-naringenin co-amorphous substance and a preparation method thereof, and adopts a solvent method to prepare the cefpodoxime proxetil and naringenin co-amorphous substance, which can obviously mask the bitter taste of the cefpodoxime proxetil drug and improve the compressibility of the cefpodoxime proxetil drug, but has no obvious influence on the solubility and the dissolution rate. In addition, the prior art (screening, characterization and evaluation of supermolecular compound based on indissolvable drugs) (Du Shuang, university of Hebei medical science, 2019) discloses a method for preparing bisflurazine-saccharin co-amorphous, bisflurazine-salicylic acid composite salt and bisflurazine-tartrate by using saccharin, salicylic acid and tartaric acid as co-forming substances and adopting a solvent-assisted grinding method, which remarkably improves the solubility of the bisflurazine in 30% ethanol, water and pH4.5 acetate solution.
However, in the prior art described above: (1) The dissolution and dissolution properties of the compound as co-former are not known; (2) The relationship between the formation of the amorphous form and the process is not clear (such as particle size change caused by grinding, or crystal form change caused by dissolution-precipitation, etc.); (3) Generally, the co-amorphous substance has limited effect of improving the solubility of poorly soluble drugs.
The medicine-medicine co-amorphous substance is based on the interaction between the breviscapine and the matrine, does not need to add any carrier or auxiliary materials, and has simple and convenient process and stable product.
Disclosure of Invention
The invention aims to provide a drug-drug co-amorphous substance for co-carrying breviscapine and matrine. The system can form co-amorphous substances without adding any auxiliary materials, the drug loading rate reaches 100%, the cost is greatly reduced, and the dosage of the preparation is reduced.
Another object of the present invention is to provide a co-amorphous system capable of simultaneously and remarkably improving the water solubility of two pharmaceutical components and remarkably improving the in vitro dissolution performance of the poorly soluble component breviscapine, which is simple and convenient to prepare without adding any functional auxiliary materials.
It is another object of the present invention to provide a process for preparing the above drug-drug co-amorphous material.
The invention also aims to provide the application of the drug-drug co-amorphous substance in preparing solid preparations, namely, the co-amorphous substance is used as a preparation intermediate to be further prepared into various quick-release preparations such as dispersible tablets, orally disintegrating tablets, oral instant films, dripping pills and the like, or further prepared into general oral dosage forms such as tablets, granules, capsules, pills, powder and the like, which is beneficial to improving oral absorption and improving clinical application effects.
Specifically, the invention provides the following technical scheme:
a medicine, YAO SHU amorphous, comprises breviscapine and matrine as active ingredients, wherein no functional adjuvants are added, and the molar ratio of breviscapine to matrine is 1:5-5:1.
Preferably, the molar ratio of the breviscapine to the matrine is 1:3-3:1.
More preferably, the molar ratio of the breviscapine to the matrine is in the range of 1:2-2:1.
Most preferably, the molar ratio of the breviscapine to the matrine is 1:1.
The invention also provides a method for preparing the co-amorphous material, namely a solvent evaporation method, a grinding method and a melting method. Preferably, the preparation method is a solvent evaporation method.
The solvent evaporation method is to weigh a proper amount of breviscapine and matrine, completely dissolve in the solvent, uniformly mix, decompress and recycle most of the solvent, naturally volatilize the residual solvent at room temperature, crush and pass through an 80-mesh sieve to obtain the breviscapine-matrine co-amorphous substance. Preferred solvents are methanol and ethanol.
Wherein the grinding method comprises weighing appropriate amount of breviscapine and matrine, placing into container, adding appropriate amount of grinding medium with appropriate size and material, grinding for 3 hr or more, and sieving with 80 mesh sieve to obtain breviscapine-matrine amorphous substance.
The melting method comprises weighing appropriate amount of breviscapine and matrine, heating matrine to molten state, adding breviscapine, mixing, rapidly solidifying in ice bath, pulverizing, and sieving with 80 mesh sieve to obtain breviscapine-matrine amorphous material.
Experiments prove that the co-amorphous substance obtained by the solvent evaporation method has the highest product yield, simple preparation process and optimal water solubility of the obtained product.
The breviscapine-matrine co-amorphous substance provided by the invention has the advantages of simple preparation method, low cost and good reproducibility.
The invention takes the medicine-medicine co-amorphous substance as a preparation intermediate, further prepares various preparations, and is prepared from the co-amorphous substance and pharmaceutic adjuvant.
In summary, the inventors have found through unexpected studies that the co-amorphous form prepared by mixing the components of breviscapine and matrine can produce extremely remarkable water-solubility improving effect, which is far greater than the solubilization effect of a simple mixture of breviscapine and matrine, and is also significantly greater than the solubilization effect of a general solid dispersion. In addition, the in vitro dissolution of the difficultly soluble component breviscapine can be obviously accelerated, and the oral bioavailability of the breviscapine can be enhanced. In addition, any auxiliary materials are not needed in the process of preparing the co-amorphous material, so that the cost is saved, the repeatability is good, and the stability is excellent.
Description of the drawings:
FIG. 1 shows powder X-ray diffraction patterns (A), differential scanning calorimetric patterns (B), fourier transform infrared spectra (C) and polarized micrographs (D) of a mixture of a breviscapine-matrine co-amorphous substance and a physical mixture of breviscapine and matrine crude drugs in example 1.
FIG. 2 is an in vitro dissolution graph (A) (mean.+ -. SD; n=3) of breviscapine-matrine co-amorphous material in water in example 1, wherein B is an in vitro dissolution graph of a sample after being placed at 50 ℃ under 60% RH in a sealed light-shielding condition for 0, 5, 10 days; c is an in vitro dissolution curve of the sample after being placed for 0, 3 and 6 months at 40 ℃ under 75% RH and sealed in dark conditions; d is a powder X-ray diffraction pattern of the sample after being placed for 0, 3 and 6 months at 40 ℃ under 75% RH and sealed in dark conditions.
Fig. 3 shows the disintegration time (a) of the breviscapine-matrine co-amorphous oral instant film of example 5 (< 0.01 compared with the breviscapine bulk drug oral instant film group, # P <0.05 compared with the two pharmaceutical blend oral instant film group) and the in vitro dissolution profile (B) in artificial saliva (mean±sd; n=3).
FIG. 4 shows the in vitro dissolution profile (mean.+ -. SD; n=3) of a breviscapine-matrine co-amorphous and physical mixture prepared by different preparation methods in examples 1, 2, 3 in water.
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is evident that the embodiments described are only some embodiments of the present invention, but not all embodiments.
Detailed Description
Example 1: weighing appropriate amount of breviscapine and matrine (molar ratio of 1:1), completely dissolving in methanol, mixing, recovering ethanol under reduced pressure until the volume is reduced to one tenth, naturally volatilizing the obtained concentrated solution at room temperature, pulverizing, and sieving with 80 mesh sieve to obtain breviscapine-matrine co-amorphous material.
Example 2: weighing appropriate amount of breviscapine and matrine (molar ratio of 1:2), adding zirconia microbeads, continuously grinding for 3 hr, and sieving with 80 mesh sieve to obtain powder.
Example 3: respectively weighing appropriate amount of breviscapine and matrine (molar ratio of 1:5), heating matrine to completely melt, adding breviscapine, stirring for 15min under heat preservation, transferring into ice bath to rapidly solidify, pulverizing, and sieving with 80 mesh sieve to obtain breviscapine-matrine amorphous substance.
Example 4: weighing appropriate amount of breviscapine and matrine (molar ratio of 5:1), completely dissolving in ethanol, mixing, naturally volatilizing solvent at room temperature, pulverizing, and sieving with 80 mesh sieve to obtain breviscapine-matrine co-amorphous material.
Example 5: weighing HPMC E50 (50%) and dispersing in quantitative pure water, soaking and swelling overnight, stirring to obtain gel solution; sequentially taking sorbitol (16%), PEG 400 (12%), low-substituted hydroxypropyl cellulose (5%), citric acid (1%) and aspartame (1%) and adding into 10mL pure water, stirring for fully dissolving or dispersing, and adding the erigeron breviscapus-matrine co-amorphous substance (15%) prepared in example 1 for dissolving; mixing the two liquids under stirring, ultrasonic degassing, slowly and uniformly coating 5mL on a glass plate (5 cm×10cm), and drying in a 55 deg.C drying oven; cutting into 2×2cm after removing the film, and sealing and storing for use.
Example 6: weighing a proper amount (50%) of the breviscapine-matrine co-amorphous substance prepared in example 2 (the molar ratio is 1:2), adding lactose (40%), povidone K30 (5%) and croscarmellose sodium (5%) and fully and uniformly mixing; the erigeron breviscapus-matrine double-drug-carrying dispersible tablet is obtained by adopting a powder direct tabletting process for compression molding.
Example 7: weighing appropriate amount (35%) of breviscapine-matrine co-amorphous material (molar ratio of 5:1) prepared in example 3, adding microcrystalline cellulose (30%), lactose (30%), and crospovidone (5%), and mixing thoroughly; the erigeron breviscapus-matrine co-amorphous tablet is obtained by adopting a powder direct tabletting process for compression molding.
Example 8: weighing appropriate amount (25%) of breviscapine-matrine co-amorphous material prepared in example 4, adding sugar powder (20%), dextrin (50%) and hydroxypropyl methylcellulose (5%), and mixing thoroughly; granulating by dry granulating process; and filling the obtained granules into empty capsules to obtain capsules.
Comparative example 9: weighing a proper amount of breviscapine, completely dissolving in methanol, naturally volatilizing the solvent at room temperature, crushing, and sieving with an 80-mesh sieve to obtain a methanol recrystallization product of the breviscapine; and preparing matrine methanol recrystallization by the same method.
Comparative example 10: weighing a proper amount of breviscapine, and preparing the breviscapine oral instant membrane according to the same preparation method as in example 5; the matrine oral instant membrane is prepared by the same method, and the breviscapine-matrine physical mixture oral instant membrane (namely, the breviscapine and matrine bulk drug are added according to the mol ratio of 1:1).
Example 11: effect of coform selection on Breviscapine solubility
According to example 1, piperine, berberine hydrochloride, coptisine, betaine and oxymatrine were selected as coformers and prepared in the same way instead of matrine, and the rough solubility of each group of products was measured, and the influence of different coformers on the solubility of breviscapine was examined in comparison.
TABLE 1 crude solubility determination of Breviscapine in products from different coformulations (Unit: mg/mL)
Co-forms Piperine Berberine hydrochloride Coptisine Betaine (betaine) Oxymatrine
Solubility of ＜0.1 ＜0.1 ＜0.1 ＜0.1 ＜1
The results in Table 1 show that the solubility of breviscapine in the product obtained is still small when piperine, berberine hydrochloride, coptisine and betaine are used as coformer, and the solubility of matrine oxide is improved by about 10 times when matrine oxide is used as coformer; the invention has obvious superiority in selecting matrine as coform.
Example 12: determination of equilibrium solubility of Breviscapine
Examine the equilibrium solubility of breviscapine in example 1 of the present invention: taking excessive breviscapine raw material and breviscapine-matrine co-amorphous substances respectively, adding appropriate amount of solvent, placing in a constant temperature gas bath table (37deg.C, 120 r/min), shaking 72 h, taking out, immediately centrifuging, collecting supernatant, diluting with corresponding solvent, measuring absorption peak area by HPLC, and calculating equilibrium solubility of breviscapine, and the result is shown in Table 2.
Table 2 equilibrium solubility of breviscapine in different solvents (mg/mL, mean±sd, n=3)
Solvent(s) Breviscapine raw material medicine Breviscapine-matrine co-amorphous material S Co-amorphous material /S Bulk drug
Water and its preparation method 0.0642±0.0038 >520 >8x10 3
Methanol 4.9546±0.4537 25.1218±0.4263 5.07
Ethanol 1.7970±0.1290 4.9125±0.4683 2.73
Acetone (acetone) 0.0829±0.0005 0.5004±0.0370 6.04
Acetic acid ethyl ester 0.0082±0.0018 0.0592±0.0042 7.22
The results in table 1 show that the solubility of breviscapine in each solvent is significantly improved in the co-amorphous material prepared in example 1, wherein the solubility improvement in water is extremely significant; from the above, the solubility of matrine in the co-amorphous system also reaches more than 279mg/mL in water, which is about 4.2 times that of matrine bulk drug (66.72 mg/mL). The erigeron breviscapus-matrine co-amorphous material is proved to have extremely remarkable improvement on the water solubility of the slightly soluble medicine erigeron breviscapus, and the water solubility of matrine in the co-formed material can be further improved.
Example 13: characterization of Breviscapine-matrine co-amorphous
The appropriate amount of the co-amorphous material obtained in example 1 was scanned by a powder X-ray diffractometer (PXRD) under the following measurement conditions: the scanning angle is 2 theta, the step length is 0.02 DEG, the scanning speed is 8 DEG/min, and the scanning range is 3-85 deg. The results are shown in FIG. 1A. FIG. 1A shows that the characteristic peak of the product formed in Experimental example 1 disappears, and is confirmed to be in an amorphous form, namely, a breviscapine-matrine co-amorphous substance; the erigeron breviscapus and matrine raw materials and the corresponding physical mixtures thereof all show characteristic diffraction peaks, which prove to be crystalline.
The appropriate amount of the co-amorphous material obtained in example 1 was taken and scanned by a Differential Scanning Calorimeter (DSC) under the following measurement conditions: taking a blank crucible as a reference, heating at a rate of 10 ℃/min, testing at a temperature ranging from 30 ℃ to 400 ℃ under the protection of nitrogen, and testing at a gas flow rate of 20mL/min. The results are shown in FIG. 1B. FIG. 1B shows that the product formed in Experimental example 1 has no significant endothermic or exothermic peak, and may be in an amorphous state, i.e., a breviscapine-matrine co-amorphous; while the erigeron breviscapus bulk drug has an endothermic peak at 139.3 ℃ and 197.4 ℃ and an exothermic peak at 212.8 ℃, and the methanol recrystallization DSC of the erigeron breviscapus has a little change, but still has obvious endothermic and exothermic peaks, which indicate that the erigeron breviscapus is in a crystalline state; the matrine bulk drug has an obvious endothermic peak at 85.9 ℃, and the methanol recrystallization is similar to the bulk drug, which shows that the matrine bulk drug is in a crystalline state; the physical mixture of breviscapine and matrine has unobvious endothermic and exothermic peaks, and is presumed to have a certain degree of interaction in the test heating process.
Taking a proper amount of the co-amorphous powder obtained in the example 1, adding a small amount of KBr, grinding and tabletting, and measuring a sample at 4000-400 cm by using a Fourier transform infrared spectrometer -1 The infrared absorption in the range is shown in FIG. 1C. FIG. 1C shows that the products formed in Experimental example 1 are shown at 3412, 2930, 1614, 1466, 1414, 1353, 1284, 1244, 1175, 1065 cm -1 Characteristic absorption exists at the same place, and the characteristic absorption is obviously different from the absorption spectrum of the crude drug or the physical mixture, thus proving the formation of a new phase.
The appropriate amount of the co-amorphous material obtained in example 1 was taken, observed under a polarizing microscope and photographed, and the result is shown in FIG. 1D. FIG. 1D shows that the product formed in Experimental example 1 is dark in field and amorphous; the matrine methanol recrystallized substance shows obvious birefringence, the breviscapine methanol recrystallized substance shows weak birefringence, and the physical mixture of the two raw materials has slight birefringence, and is in a crystalline state.
Example 14: evaluation of in vitro dissolution Performance of Breviscapine
In the embodiment of the invention, the dissolution rate of the breviscapine-matrine co-amorphous substance (molar ratio 1:1) is referred to the paddle method of the 2020 edition of Chinese pharmacopoeia: the release medium is water, the temperature is (37+/-0.5 ℃) and the rotating speed is 50rpm/min; accurately weighing a small amount of breviscapine, a proper amount of physical mixture and co-amorphous substance (example 1) in 900mL of medium, sampling 2mL at each preset time point, passing through a 0.22 μm microporous filter membrane, and supplementing isothermal and equal volume of dissolution medium; the absorption peak area was measured by HPLC, the cumulative dissolution rate was calculated for each period, and a dissolution curve was drawn, and the result was shown in fig. 2A (mean±sd, n=3).
FIG. 2A shows that the in vitro dissolution of the breviscapine bulk drug is slow, and the cumulative dissolution rate is less than 3.0% at 30 min; the dissolution of the breviscapine in the physical mixture of the breviscapine and the matrine is quickened, the dissolution is about 20% in 1min, and the cumulative dissolution is less than 40% in 30 min; the erigeron breviscapus-matrine co-amorphous substance has high leaching rate and extremely high leaching speed, and the leaching rate reaches equilibrium after 1min, and is more than 80%. The breviscapine-matrine co-amorphous substance has obvious effect of promoting in vitro dissolution of the insoluble drug breviscapine.
Example 15: evaluation of in vitro disintegration and dissolution Property of Breviscapine oral instant film
The disintegration time of the oral instant film of the erigeron breviscapus-matrine co-amorphous material (molar ratio 1:1) in example 5 of the present invention was tested by the following method: the film was taken and put into 300mL beakers containing 100mL of phosphate buffer dissolution medium (temperature: 37 ℃) at pH 6.8, magnetic stirring was started to slightly flow the medium, and when the film was contacted with the medium, the time required until the film was broken and dispersed was the disintegration time, and the result was shown in FIG. 3A (mean.+ -. SD, n=3).
Fig. 3A shows that the disintegration of different oral instant films is from fast to slow in turn: scutellarin-matrine co-amorphous oral instant membrane > matrine oral instant membrane > scutellarin-matrine physical mixture oral instant membrane > scutellarin bulk drug oral instant membrane; the prepared oral instant film can be disintegrated quickly, but the oral instant film prepared by taking the breviscapine-matrine co-amorphous substance as an intermediate is disintegrated most quickly.
The in vitro dissolution of the oral instant film of the breviscapine-matrine co-amorphous material (molar ratio 1:1) in example 5 of the present invention was tested by the following method: the film agent is fixed on the side wall of the middle part of a 100mL beaker by using double faced adhesive tape, 100mL simulated artificial saliva (2.38 g disodium hydrogen phosphate, 0.19g monopotassium phosphate, 0.8g sodium chloride, water to 1000mL, and hydrochloric acid to adjust pH=6.8) is added as a dissolution medium, and magnetic stirring is carried out, wherein the temperature is set to be (37+/-0.5); starting timing when the membrane agent contacts the medium, respectively sampling 2mL at a preset time point, passing through a microporous membrane with the thickness of 0.22 mu m, and simultaneously supplementing the isothermal and isovolumetric dissolution medium; the absorption peak area was measured by HPLC, the cumulative elution degree was calculated for each period, and the elution profile was plotted, and the result was shown in fig. 3B (mean±sd, n=3).
FIG. 3B shows that the oral instant membrane of the physical mixture of breviscapine and matrine is respectively 21%, 34% and 59% in vitro dissolution of the oral instant membrane of the total amorphous substance of breviscapine and matrine in 3min, and the total cumulative dissolution of the oral instant membrane of the physical mixture of breviscapine and matrine in 30min is more than 90%; the oral instant membrane can improve the dissolution performance of the poorly soluble drug breviscapine, and the oral instant membrane prepared by taking the breviscapine-matrine co-amorphous substance as an intermediate can be dissolved out most rapidly.
While the foregoing description illustrates and describes the preferred embodiments of the present invention, it is to be understood that the invention is not limited to the forms disclosed herein, but is not to be construed as limited to other embodiments, and is capable of numerous other combinations, modifications and environments and is capable of changes or modifications within the scope of the inventive concept as described herein, either as a result of the foregoing teachings or as a result of the knowledge or technology in the relevant art. And that modifications and variations which do not depart from the spirit and scope of the invention are intended to be within the scope of the appended claims.

Claims (10)

1. A breviscapine-matrine co-amorphous material, which is characterized in that: the amorphous substance consists of two components of breviscapine and matrine, wherein the molar ratio of the breviscapine to the matrine is 1:5-5:1.
2. The breviscapine-matrine co-amorphous material according to claim 1, wherein: the molar ratio of the breviscapine to the matrine is 1:1.
3. The breviscapine-matrine co-amorphous material according to claim 1 or 2, characterized in that: the co-amorphous material is in an amorphous form, and has no characteristic diffraction peak under the detection of a powder X-ray diffractometer.
4. The breviscapine-matrine co-amorphous material according to claim 1 or 2, characterized in that: the solubility of the breviscapine in water in the co-amorphous material reaches more than 1000 times of the solubility of a single breviscapine raw material medicine.
5. A process for preparing a breviscapine-matrine co-amorphous material as defined in claim 1, which is characterized in that: taking breviscapine and matrine raw materials according to a mole ratio, and preparing the co-amorphous substance by using one or more selected from a solvent evaporation method, a melting method and a grinding method.
6. The method for preparing the breviscapine-matrine co-amorphous material according to claim 5, wherein the method comprises the following steps: the co-amorphous material is prepared by solvent evaporation, wherein the solvent used in the preparation process is methanol, ethanol or a mixed solvent containing methanol and ethanol.
7. Use of a breviscapine-matrine co-amorphous material as claimed in claim 1 in preparing an oral immediate release formulation.
8. Use of a breviscapine-matrine co-amorphous material as claimed in claim 1 in the preparation of conventional formulations.
9. Use according to claim 7, characterized in that: the oral quick-release preparation is an oral quick-dissolving film, a dispersible tablet, an oral quick-disintegrating tablet or a dripping pill.
10. Use according to claim 8, characterized in that: the oral conventional preparation is tablets, capsules, granules, powder or pills.
CN202310216247.6A 2023-03-08 2023-03-08 Breviscapine-matrine dual drug-loaded co-amorphous substance and application thereof Pending CN116270690A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202310216247.6A CN116270690A (en) 2023-03-08 2023-03-08 Breviscapine-matrine dual drug-loaded co-amorphous substance and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310216247.6A CN116270690A (en) 2023-03-08 2023-03-08 Breviscapine-matrine dual drug-loaded co-amorphous substance and application thereof

Publications (1)

Publication Number Publication Date
CN116270690A true CN116270690A (en) 2023-06-23

Family

ID=86814468

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310216247.6A Pending CN116270690A (en) 2023-03-08 2023-03-08 Breviscapine-matrine dual drug-loaded co-amorphous substance and application thereof

Country Status (1)

Country Link
CN (1) CN116270690A (en)

Similar Documents

Publication Publication Date Title
AU2016400468B2 (en) Pharmaceutical preparation of palbociclib and preparation method thereof
AU2008327095B2 (en) Amorphous form of heterocyclic compound, solid dispersion and medicinal preparation each comprising the same, and process for production of the same
BG107958A (en) Steroid hormone products and methods for the preparation thereof
CN101869551A (en) Temozolomide freeze-dried preparation
EP3492466A1 (en) Oral solid preparation and use thereof
Ellenberger et al. Generation of a weakly acidic amorphous solid dispersion of the weak base ritonavir with equivalent in vitro and in vivo performance to Norvir tablet
TWI715291B (en) Pharmaceutical composition including parp inhibitor
IE58230B1 (en) Pharmaceutical composition comprising medroxyprogesterone acetate
US20200323838A1 (en) Lenalidomide immediate release formulations
CN107951841B (en) Nimodipine solid dispersion and preparation method of nimodipine solid dispersion tablet
CN111297823B (en) Preparation method of oseltamivir phosphate capsule
CN117547534A (en) Nicorandil sustained release preparation and preparation method thereof
KR101101962B1 (en) A method for preparing a new crystal form of adefovir dipivoxil
CN116270690A (en) Breviscapine-matrine dual drug-loaded co-amorphous substance and application thereof
CN106511291A (en) Acotiamide hydrochloride controlled release tablet and preparation method thereof
CN114191435B (en) Cabotinib, ai Leti and ceritinib pharmaceutical composition as well as preparation method and application thereof
CN106748996B (en) Sorafenib tosylate crystal compound and preparation method thereof
CN112022810B (en) Icaritin pharmaceutical composition and preparation method thereof
CN106749174A (en) A kind of sitafloxacin dihydrate crystal formation, preparation method and combinations thereof tablet
CN112315914A (en) Lenalidomide pharmaceutical composition and preparation method thereof
CN116440090B (en) Agomelatine-containing preparation and preparation method thereof
CN116421595B (en) Dapagliflozin pharmaceutical composition, and preparation method and application thereof
CN117257804A (en) Darafenib pharmaceutical composition as well as preparation method and application thereof
KR100222306B1 (en) A fast effective nilbadipine preparation and the preparation process thereof
RU2777433C2 (en) Method for obtaining anhydrous amorphous form of n-(2-chlorine-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolcarboxamide

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination