CN113880900B - Flavonoid glycoside-organic amine DPP-4 inhibitor double salt compound as well as preparation method and application thereof - Google Patents

Flavonoid glycoside-organic amine DPP-4 inhibitor double salt compound as well as preparation method and application thereof Download PDF

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CN113880900B
CN113880900B CN202111280095.3A CN202111280095A CN113880900B CN 113880900 B CN113880900 B CN 113880900B CN 202111280095 A CN202111280095 A CN 202111280095A CN 113880900 B CN113880900 B CN 113880900B
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double salt
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baicalin
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CN113880900A (en
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王化录
王鹿荧
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Hangzhou Lalin Intelligent Technology Co ltd
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Abstract

The invention relates to a double salt of a flavonoid glycoside and an organic amine DPP-4 inhibitor, wherein the flavonoid glycoside has a structural general formula shown in the following formula (1), and R is 1 ～R 9 Each independently selected from-H, -OH, C 1 ～C 6 Alkyl, alkoxy or substituted alkyl, and R 1 And R is 2 At least one of them is selected from-OH. The invention also relates to a preparation method of the compound. The invention further relates to pharmaceutical compositions and uses comprising a therapeutically effective amount. The invention further relates to double salt nano particles obtained by double salt compound through nano grinding and application thereof.

Description

Flavonoid glycoside-organic amine DPP-4 inhibitor double salt compound as well as preparation method and application thereof
The present application claims priority from chinese patent office, application No. 2020111909899 entitled "flavonoid glycoside-organic amine DPP-4 inhibitor double salt, and preparation method and application thereof," filed on 30 months 10 in 2020, the entire contents of which are incorporated herein by reference.
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a flavonoid glycoside-organic amine DPP-4 inhibitor double salt compound and a preparation method and application thereof.
Background
Diabetes is a common metabolic disease characterized by hyperglycemia, which is caused by both genetic and environmental factors, and the fundamental pathological features are absolute insulin secretion (type 1 diabetes) or relatively insufficient insulin secretion (type 2 diabetes). Diabetes causes endocrine metabolic disorders such as glucose, protein, secondary water electrolyte metabolic disorders and acid-base balance disorders, and long-term complications such as blindness, renal failure, heart attack, stroke, vascular lesions, etc., and even foot neurodegeneration and central nervous system dysfunction. Among them, type2diabetes mellitus (T2 DM) is a major onset form of diabetes mellitus, accounting for 90% of the incidence of diabetes mellitus, and type2diabetes mellitus is ubiquitous in insulin resistance. Currently, western medicines for clinically treating diabetes are mainly classified into 6 types such as biguanides, sulfonylureas, alpha glucosidase inhibitors, insulin sensitizers, glinide insulin secretagogues, dipeptidyl peptidase 4 (DPP-4) inhibitors and the like. Dipeptidyl peptidase 4 (DPP-4) inhibitors have become important measures for the treatment of type2diabetes, such as sitagliptin, saxagliptin, alogliptin, which inhibit the inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), increase the levels of endogenous GLP-1 and GIP, promote insulin release from islet beta cells, and simultaneously inhibit glucagon secretion from islet alpha cells, thereby increasing insulin levels, lowering blood glucose, and being less likely to induce hypoglycemia and weight gain.
Baicalin and scutellarin are flavonoid glycosides (simply referred to as flavonoid glycoside) and have abundant pharmacological activities, such as improving antioxidant capacity through lipid peroxidation, scavenging free radicals and superoxide anions, improving blood circulation, increasing blood flow, resisting platelet aggregation, inhibiting virus infection, enhancing immunity, resisting cell hypoxia, neuroprotection, inhibiting tumor cell growth, etc.
In addition, how to improve the solubility, speed up the dissolution and increase the blood concentration of the poorly soluble drugs is also a problem to be solved urgently.
Disclosure of Invention
Based on the above, it is necessary to provide a flavonoid glycoside-organic amine DPP-4 inhibitor double salt compound, and a preparation method and application thereof. Compared with the organic amine DPP-4 inhibitor, the flavonoid glycoside-organic amine DPP-4 inhibitor double salt has higher inhibitory activity on DPP-4.
In one aspect of the invention, a double salt compound is provided, which is a double salt of flavonoid glycoside and an organic amine DPP-4 inhibitor, wherein the flavonoid glycoside has a structural general formula shown in the following formula (1):
Figure BDA0003329275370000021
wherein R is 1 ～R 9 Each independently selected from-H, -OH, C 1 ～C 6 Alkyl, alkoxy or substituted alkyl, and R 1 And R is 2 At least one of them is selected from-OH.
In one embodiment, R 1 And R is 2 Are all selected from-OH.
In one embodiment, the flavonoid glycoside is baicalin or scutellarin.
In one embodiment, the organic amine DPP-4 inhibitor contains at least one amino group, each of which is independently selected from the group consisting of-NH 2 -NR 'H or-NR' 2 And R' is an electron donor group.
In one embodiment, the organic amine DPP-4 inhibitor is selected from any one of sitagliptin, saxagliptin and alogliptin.
In one aspect of the present invention, there is also provided a method for preparing the double salt compound, comprising the steps of:
mixing and dissolving the flavonoid glycoside, the organic amine DPP-4 inhibitor and a polar aprotic organic solvent to obtain a mixed solution;
reacting the mixed solution to obtain a reaction solution; and
the solvent was removed from the reaction solution.
In one embodiment, the polar aprotic organic solvent is one or more of N, N-dimethylformamide, dimethylsulfoxide, or acetonitrile.
In another aspect of the present invention, there is further provided a pharmaceutical composition comprising a therapeutically effective amount of said double salt compound, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, in association with a pharmaceutically acceptable carrier, excipient or diluent.
In a further aspect of the invention, the use of said double salt compound or said pharmaceutical composition for the preparation of a DPP-4 inhibitor drug is provided.
In one embodiment, the DPP-4 inhibitor medicament is for the treatment of diabetes and complications. Preferably, the DPP-4 inhibitor is used for the treatment of type II diabetes and complications thereof.
In yet another aspect of the present invention, there is provided a double salt nanoparticle obtained from the double salt compound by nano-milling.
In a further aspect, the invention provides application of the double salt nano-particles in preparation of DPP-4 inhibitor drugs.
In one embodiment, the DPP-4 inhibitor medicament is for the treatment of diabetes and complications. Preferably, the DPP-4 inhibitor is used for the treatment of type II diabetes and complications thereof.
Compared with the prior art, the invention has the following beneficial effects:
the organic amine DPP-4 inhibitor is alkaline and can form salt with inorganic acid or small molecular organic acid to increase the stability and improve the physical properties, but the salt formed by the inorganic acid or the small molecular organic acid and the organic amine DPP-4 inhibitor which are generally used for forming salt of medicines in the prior art cannot improve the biological activity of the medicines. The double salt compound provided by the invention adopts flavonoid glycoside with a specific structure and an organic amine DPP-4 inhibitor to form double salt, the molecular structure of the flavonoid glycoside contains carboxyl and phenolic hydroxyl, and can be bonded with amino in the organic amine DPP-4 inhibitor, and the bonding effect between the flavonoid glycoside and the organic amine DPP-4 inhibitor is stronger than that of a common medicament to form salt. Compared with the organic amine DPP-4 inhibitor, the double salt has higher inhibitory activity on DPP-4.
The flavonoid glycoside is a natural compound with poor water solubility, but because of carboxyl and phenolic hydroxyl in the molecular structure, the flavonoid glycoside is easy to dissolve in alkali and forms salt with small molecular organic alkali, so that the water solubility of the flavonoid glycoside is enhanced. Further, the double salt compound provided by the invention is ground by a nano grinding technology, so that the particle size of the material is reduced, the particle size of the material reaches the nano level, and the double salt compound has better water solubility.
Drawings
FIGS. 1 to 4 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 1 of the present invention;
FIGS. 5 to 8 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 2 of the present invention;
FIGS. 9 to 12 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 3 of the present invention;
FIGS. 13 to 16 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 4 of the present invention;
FIGS. 17 to 20 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 5 of the present invention;
fig. 21 to 24 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 6 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
Abbreviations and symbols used herein are consistent with such abbreviations and symbols commonly used by those of skill in the chemical and biological arts. In particular, the following abbreviations may be used in the examples and throughout the specification.
DSC (differential scanning calorimetry) of DMF (N, N-dimethylformamide)
DPP-4 (dipeptidyl peptidase-4)
Terminology and definitions
Unless otherwise indicated or contradicted, terms or phrases used herein have the following meanings:
The term "alkyl" refers to a saturated hydrocarbon containing primary (positive) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, e.g., "C 1 ～C 6 Alkyl "means an alkyl group containing 1 to 6 carbon atoms, which at each occurrence may be, independently of one another, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl or C 6 An alkyl group. Suitable examples include, but are not limited to: methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ) 2-propyl (i-Pr, i-propyl, -CH (CH) 3 ) 2 ) 1-butyl (n-Bu, n-butyl, -CH) 2 CH 2 CH 2 CH 3 ) 2-methyl-1-propyl (i-Bu, i-butyl, -CH) 2 CH(CH 3 ) 2 ) 2-butyl (s-Bu, s-butyl, -CH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH) 3 ) 3 ) 1-pentyl (n-pentyl, -CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl group-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) 1-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) And 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 。
The term "alkoxy" refers to a group having an-O-alkyl group, i.e. an alkyl group as defined above, attached to the parent core structure via an oxygen atom. Phrases containing this term, e.g., "C 1 ～C 6 Alkoxy "means that the alkyl moiety contains from 1 to 6 carbon atoms and, at each occurrence, can be independently of one another C 1 Alkoxy, C 2 Alkoxy, C 3 Alkoxy, C 4 Alkoxy, C 5 Alkoxy or C 6 An alkoxy group. Suitable examples include, but are not limited to: methoxy (-O-CH) 3 or-OMe), ethoxy (-O-CH 2 CH 3 or-OEt) and t-butoxy (-O-C (CH) 3 ) 3 or-OtBu).
"amino" refers to derivatives of ammonia, non-limiting types of amino groups include-NH 2 -N (alkyl) 2 -NH (alkyl), -N (cycloalkyl) 2 -NH (cycloalkyl), -N (heterocyclyl) 2 -NH (heterocyclyl), -N (aryl) 2 -NH (aryl), -N(alkyl) (aryl), -N (alkyl) (heterocyclyl), -N (cycloalkyl) (heterocyclyl), -N (aryl) (heteroaryl), -N (alkyl) (heteroaryl), and the like.
By "pharmaceutically acceptable" is meant those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to patients and commensurate with a reasonable benefit/risk ratio.
"pharmaceutically acceptable carrier, excipient, or diluent" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier, excipient or diluent" includes buffers compatible with pharmaceutical administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Each carrier, excipient, or diluent must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) Starches, such as corn starch, potato starch, and substituted or unsubstituted beta-cyclodextrin; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
"substitution" in reference to a group means that one or more hydrogen atoms attached to a member atom within the group are replaced by substituents selected from the defined or suitable substituents. It is to be understood that the term "substituted" includes the following implicit conditions: such substitution should be consistent with the permissible valences of the substituted atoms and substituents and the substitution results in stable compounds. When the Chen Shuji group may contain one or more substituents, one or more member atoms within the group may be substituted. In addition, individual member atoms within the group may be substituted with more than one substituent, so long as such substitution is consistent with the permissible valence of the atom. "Member atom" refers to an atom or atoms that form a chain or ring. In the case where there is more than one member atom in the chain and within the ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. The atoms that make up the substituents on the chain or ring are not member atoms in the chain or ring.
The term "IC 50 "refers to the half maximal inhibitory concentration of a compound relative to the inhibition of a given activity, e.g., influenza a virus, DNA polymerase, RNA polymerase. IC (integrated circuit) 50 The smaller the value, the stronger the inhibitory activity of the compound for a given activity.
Compounds of formula (I)
In one aspect, the invention relates to a double salt compound which is a double salt of flavonoid glycoside and an organic amine DPP-4 inhibitor, wherein the flavonoid glycoside has a structural general formula shown in the following formula (1):
Figure BDA0003329275370000061
wherein R is 1 ～R 9 Each independently selected from-H, -OH, C 1 ～C 6 Alkyl, alkoxy or substituted alkyl, and R 1 And R is 2 At least one of them is selected from-OH.
The flavonoid glycoside has carboxyl hydrogen in gluconic acid unit and phenolic hydroxyl hydrogen (R) 1 Or R is 2 Hydrogen in (a), together forming a hydrogen ion rich region, which is a proton donor. The nitrogen atom of the organic amine in the organic amine DPP-4 inhibitor contains a lone pair electron and is a proton acceptor. The flavonoid glycoside-organic amine DPP-4 inhibitor double salt is formed by combining the flavonoid glycoside-organic amine DPP-4 inhibitor double salt. Due to steric hindrance, the yellowThe carboxyl hydrogen in the gluconic acid unit and the phenolic hydroxyl hydrogen in the flavone unit in the ketoside are respectively positioned at two sides of the sugar ring. When it is combined with an organic amine, the carboxyhydrogen and the phenolic hydroxyl hydrogen on both sides of the sugar ring are converted into the same side, as shown in formula (2), forming a microenvironment of proton nest (proton structure shown by a broken line frame of formula 2), carboxyl oxygen electron and nitrogen lone pair electron. From valence theory analysis, hydrogen protons and amines in proton pits can form very stable ammonium salts; from molecular orbit theoretical analysis, the empty orbit of hydrogen in a proton nest and the lone pair electron of amine can be perfectly combined; according to quantum chemistry and quantum entanglement theory analysis, the hydrogen electrons, carboxyl oxygen electrons and the lone electron pairs of nitrogen in organic amine are entangled in a salifying area, and because of the existence of quantum entanglement, after the organic acid and the organic base of the flavonoid glycoside-organic amine DPP-4 inhibitor double salt are dissociated from each other, the quantum entanglement formed during salifying is continued to exist, so that the biological activity of the flavonoid glycoside-organic amine DPP-4 inhibitor double salt is improved.
Figure BDA0003329275370000062
Preferably, said R 1 And R is 2 Are all selected from OH.
In some embodiments, R 3 Selected from-H or-OCH 3 。
In some embodiments, R 5 、R 6 、R 9 Are all selected from-H.
In some embodiments, R 7 、R 8 Each independently selected from-H or-OH.
In some embodiments, R 8 Selected from-H.
In some embodiments, R 7 Selected from-OH. In other embodiments, R 7 Selected from-H. In some embodiments, the flavonoid glycoside may be any one of apigenin flavonoid glycoside, baicalin, scutellarin, chrysin flavonoid glycoside or wogonin glycoside, and preferably, the flavonoid glycoside is baicalin or scutellarin.
The molecular structural formula of the baicalin is shown as the following formula (1-1):
Figure BDA0003329275370000071
the molecular structural formula of the scutellarin is shown as the following formula (1-2):
Figure BDA0003329275370000072
the organic amine DPP-4 inhibitor contains at least one amino group, and each amino group is independently selected from-NH 2 -NR 'H or-NR' 2 And R' is an electron donor group.
In some embodiments, R' alkyl or alkoxy.
In some embodiments, the organic amine DPP-4 inhibitor is selected from any one of sitagliptin, saxagliptin, and alogliptin.
Sitagliptin belongs to dipeptidyl peptidase-4 (DPP-4) inhibitors, and can be singly applied or combined with other oral hypoglycemic agents to form compound medicines for treating type 2 diabetes. The structural formula of sitagliptin is shown as follows:
Figure BDA0003329275370000081
Saxagliptin, a potent dipeptidyl peptidase-4 (Dipeptidyl Peptidase, DPP-4) inhibitor, can increase endogenous Glucagon-like Peptide-1 (glp-1) and Glucose-dependent insulinotropic polypeptide (GIP) levels by selectively inhibiting DPP-4, thereby regulating blood Glucose. The structural formula of saxagliptin is shown below:
Figure BDA0003329275370000082
alogliptin, a selective inhibitor of DPP-4, with chemical name of 2- [ [6- [ (3R) -3-aminopiperidin-1-yl ] -3-methyl-2, 4-dioxopyrimidin-1-yl ] methyl ] benzonitrile, has antidiabetic effect. The structural formula of alogliptin is shown as follows:
Figure BDA0003329275370000083
in one aspect, the invention also relates to a method for preparing the double salt compound, which comprises the following steps:
s10, mixing and dissolving the flavonoid glycoside, the organic amine DPP-4 inhibitor and a polar aprotic organic solvent to obtain a mixed solution;
s20, reacting the mixed solution to obtain a reaction solution; and
s30, removing the solvent from the reaction solution.
The molar ratio of the flavonoid glycoside to the organic amine DPP-4 inhibitor can be any ratio between 1:3 and 3:1, for example, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, preferably 1:1 can be further included.
The polar aprotic organic solvent may be one or more of N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile.
In step S10, the method for obtaining the mixed solution by mixing and dissolving the flavonoid glycoside, the organic amine DPP-4 inhibitor and the polar aprotic organic solvent may be various. Preferably, the method can comprise the following steps
S11, dissolving the flavonoid glycoside in the polar aprotic organic solvent to obtain a first solution;
s12, dissolving the organic amine DPP-4 inhibitor in the polar aprotic organic solvent to obtain a second solution;
and S13, mixing the first solution and the second solution to obtain the mixed solution.
The concentration of the flavonoid glycoside in the first solution is 0.1mol/L to 1.0mol/L, preferably 0.33mol/L.
The concentration of the organic amine DPP-4 inhibitor in the second solution is 0.1mol/L to 1.0mol/L, preferably 0.33mol/L.
In the step of carrying out the reaction of the mixed solution, the reaction temperature may be 30 to 100 ℃, preferably 50 to 70 ℃, more preferably 70 ℃.
The solvent removal method may be reduced pressure concentration, and the temperature of the reduced pressure concentration may be 40 to 70 ℃, preferably 60 ℃.
Step S30 further includes a step of purification. The purification method may be beating. The solvent used for beating can be ethyl acetate. The dosage of the ethyl acetate is preferably 1:1 to 1:5, and most preferably 1:3 according to mol/L of acid (baicalin or scutellarin); the beating temperature may be 5-50 deg.c, preferably 20-30 deg.c, for 20-40 min.
The purification also comprises the steps of filtering the solution after pulping, and further drying the filter cake after filtering. The drying method can be freeze drying or vacuum drying. The temperature of the vacuum drying may be 20 to 60 ℃, preferably 30 ℃, and the drying time may be 8 to 48 hours, preferably 24 hours. The freeze-drying temperature is less than 0 ℃, and the drying time can be 3 hours to 12 hours, preferably 6 hours.
In one aspect, the invention relates to a composition comprising a therapeutically effective amount of a double salt compound as described above, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
In one aspect, the invention relates to the use of said double salt compounds for the preparation of DPP-4 inhibitor drugs.
In some embodiments, DPP-4 inhibitor drugs prepared according to the double salt compounds of the present invention are used in the treatment of diabetes and complications thereof, preferably type two diabetes and complications thereof.
In one aspect, the invention further relates to a method of treating a neurodegenerative disease, preferably comprising administering to a patient suffering from a neurodegenerative disease in need thereof a suitable amount of a composition comprising a double salt compound according to the invention as defined above.
In one aspect, the invention further relates to a double salt nanoparticle obtained from the double salt compound of any of the above embodiments by nanomilling.
In some embodiments, the double salt nanoparticles have an average particle size of 50nm to 500nm.
In one aspect, the invention also relates to a method of preparing the double salt nanoparticle comprising:
mixing the double salt compound, the suspending agent and the solvent, and grinding the mixture by a nano grinder.
In some embodiments, the suspending agent is one or more of tween, hypromellose, polyethylene glycol, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, fatty acid glyceride, polyol-type nonionic surfactant, polyoxyethylene-type nonionic surfactant, poloxamer, vitamin E polyethylene glycol succinate, phospholipid, gelatin, xanthan gum, sodium lauryl sulfate, and deoxycholate.
In some preferred embodiments, the suspending agent is a combination of tween, hypromellose, and polyethylene glycol.
In some embodiments, the mass ratio of the double salt compound to the suspending agent is 1000: (0.5-3).
In some embodiments, the rotational speed of the grinding is 1000rpm to 3000rpm and the time of the grinding is 20 minutes to 60 minutes. The diameter of the working cavity of the nano grinder used for grinding is 85mm. If the diameter of the working cavity of the nano grinder is changed, the rotating speed should be correspondingly adjusted.
In one aspect, the invention further relates to the use of said double salt nanoparticles for the preparation of a DPP-4 inhibitor drug.
In some embodiments, the antimicrobial agent is used in the treatment of viral diseases and the DPP-4 inhibitor agent is used in the treatment of diabetes and complications thereof, preferably type 2 diabetes and complications thereof.
Administration and formulation
The production of medicaments containing the compounds according to the invention, their active metabolites or isomers and their use can be carried out according to well known pharmaceutical methods.
Although the compounds of the invention useful in therapy according to the invention may be administered in the form of the original chemical compound, it is preferred that the active ingredient is incorporated in the pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical excipients. Such salts of the compounds of the present invention may be anhydrous or solvated.
In a preferred embodiment, the present invention provides a medicament comprising a compound useful according to the invention or a pharmaceutically acceptable derivative thereof, together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic and/or prophylactic ingredients. The carrier or carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The medicaments of the present invention may be those suitable for oral, rectal, bronchial, nasal, topical, buccal, sublingual, transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or in a form suitable for administration by inhalation or insufflation (including powder and liquid aerosol administration) or administration by a slow release system. Suitable examples of slow release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in the form of shaped articles, e.g., films, or microcapsules.
The compounds useful according to the invention together with conventional adjuvants, carriers or diluents can therefore be placed into pharmaceutical and unit dosage forms thereof. Such forms include: solids, particularly in the form of tablets, filled capsules, powders and pills (pellets); and liquids, in particular aqueous or nonaqueous solutions, suspensions, emulsions, omnipotent drugs (elixir) and capsules filled therewith, all forms for oral administration, suppositories for rectal administration and sterile injectable solutions for parenteral use. These medicaments and unit dosage forms thereof may include conventional ingredients in conventional proportions, with or without other active compounds or components, and such unit dosage forms may contain any suitable effective amount of the active ingredient corresponding to the intended daily dosage range to be used.
The compounds useful according to the present invention may be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may include one or more compounds useful according to the present invention as active ingredients.
For the preparation of a medicament from a compound useful according to the invention, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets (cachets), suppositories, and dispersible granules. The solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilising agents, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or an encapsulating material (encapsulating material).
In powders, the carrier is a finely divided solid which is admixed with the finely divided active component. In tablets, the active ingredient is mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "formulation" is intended to include active compound formulations having an encapsulating material as a carrier, providing a capsule in which the active ingredient is surrounded by and thus bound to the carrier, with or without a carrier. Similarly, cachets and lozenges (lozenges) are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.
To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is uniformly dispersed therein, such as by stirring. The melted homogeneous mixture is then poured into a mold of moderate size, allowing it to cool and thereby solidify. Compositions suitable for vaginal administration may be presented as pessaries (pessaries), tampons (tampons), creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Liquid formulations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, parenteral injection liquid preparations may be formulated as aqueous polyethylene glycol solutions.
Thus, chemical compounds according to the invention may be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampules with added preservative, pre-filled syringes, small volume infusions or in multi-dose containers. The composition may take such forms as a suspension, solution or emulsion in an oily or aqueous vehicle (vehicle) and may contain a formulation (formulation agent), such as a suspending, stabilizing and/or dispersing agent. Alternatively, the active ingredient may be in the form of a powder obtained by sterile separation of sterile solids or by lyophilization of a solution for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
Aqueous solutions suitable for oral use may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the crushed active ingredient in water with a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
Also included are solid form formulations intended to be converted to liquid form formulations shortly before use for oral administration. Such liquid forms include solutions, suspensions and emulsions. These formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
In one embodiment of the invention, the drug is administered locally or systemically or by a combination of both routes.
For administration, in one embodiment, the compounds of the present invention may be administered in a formulation containing from 0.001% to 70% by weight of the compound, preferably from 0.01% to 70% by weight of the compound, even more preferably from 0.1% to 70% by weight of the compound. In one embodiment, a suitable amount of the compound administered is in the range of 0.01mg/kg body weight to 1g/kg body weight.
Compositions suitable for administration also include: lozenges comprising the active agent in a flavoured base (typically sucrose and acacia or tragacanth), pastilles comprising the active agent in an inert base (e.g. gelatin and glycerin or sucrose and acacia) and mouthwashes comprising the active agent in a suitable liquid carrier.
Solutions or suspensions are administered directly to the nasal cavity by conventional means, for example with a dropper, pipette or nebulizer. The compositions may be provided in single or multiple dosage forms. In the latter case of a dropper or pipette, this may be achieved by the patient administering a suitable predetermined volume of solution or suspension. In the case of a nebulizer, this can be achieved, for example, by a metering atomizing spray pump.
Administration to the respiratory tract may also be achieved by means of aerosols wherein the active ingredient is provided in a pressurized package with a suitable propellant such as a chlorofluorocarbon (CFC) (e.g. dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane), carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant, such as lecithin. The dosage of the medicament may be controlled by setting a metering valve.
Alternatively, the active ingredient may be provided in dry powder form, for example as a powder mixture of the compound in a suitable powder matrix such as lactose, starch derivatives such as hydroxypropyl methylcellulose, and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel within the nasal cavity. The powder composition may be presented in unit dosage form, for example, as a capsule or cartridge (cartridge) of gelatin, or as a blister pack (blister pack) from which the powder may be administered by an inhaler.
In compositions intended for administration to the respiratory tract, including intranasal compositions, the compounds typically have a small particle size, for example, about 5 microns or less. Such particle sizes may be obtained by means known in the art, for example by micronization.
Compositions suitable for sustained release of the active ingredient may be used, if desired.
The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged formulation containing discrete amounts of formulation, such as packaged tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be the packaging of any of a suitable number of these dosage forms. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
Additional details regarding techniques for formulation and administration can be found in the latest edition of "Remington's Pharmaceutical Sciences (Remington pharmaceutical science) (Maack Publishing co.easton, pa.) and remington: the science and practice of pharmacy", lippincott Williams and Wilkins.
Suitable formulations and ways of making them are also disclosed, for example, in "Arzneiformenlehre, paul Heinz List, einlehrbuchfurPharmazeuten, wissenschaftlicheVerlagsgesellschaft Stuttgart,4. Auflat, 1985" or "The theory and practice of industrial pharmacy", varghese Publishing House,1987 "or" Modern Pharmaceutics ", james Swarbrick editor, 2 nd edition," by Lachman et al.
The following are specific examples
The invention is further described below with reference to the following examples, which are intended to illustrate, but not limit the scope of the invention. Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods. The experimental methods without specific conditions noted in the examples were carried out according to conventional conditions, such as those described in the literature, books, or recommended by the manufacturer.
EXAMPLE 1 preparation of baicalin sitagliptin salt
Sitagliptin 4.07 g (0.01 mol) was suspended in 15ml of DMF, baicalin 4.46 g (0.01 mol) was added to 30ml of DMF, the above-mentioned sitagliptin DMF solution was added to the baicalin DMF solution, stirred at 70 ℃ for reaction for 15 hours, and the reaction solution was concentrated to dryness under reduced pressure at 60 ℃ to obtain a crude product.
The crude product was slurried with 30ml of ethyl acetate at room temperature for 20 minutes, filtered, the filter cake was divided equally into two equal parts, the first part was suspended in 15ml of water, and the solvent was removed by freeze-drying for 6 hours to give a pale yellow solid product. The second cake was dried in vacuo at 30℃for 24 hours to give the product as a pale yellow solid. The first part of the extract obtained 3.67 g of baicalin sitagliptin salt, and the yield was 85.92%. The second part of the extract obtained 3.65 g of baicalin sitagliptin salt, and the yield is 85.86%.
The product is subjected to structural characterization test by Nuclear Magnetic Resonance (NMR) hydrogen spectrum, infrared spectrum, DSC and XRD, and the results are shown in figures 1-4, and compared with the pure mixture of baicalin and sitagliptin, the product is more soluble, and the chemical shift of the NMR hydrogen spectrum shows that the carboxyl hydrogen of the baicalin and the sitagliptin-NH are more soluble 2 Salt formation and infrared spectroscopy also exhibit this feature, with thermal weight loss indicating that the product has a peak at 193 ℃, 336 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of baicalin and sitagliptin, which indicates that the product is salified.
EXAMPLE 2 preparation of scutellarin sitagliptin salt
Sitagliptin 4.07 g (0.01 mol) was suspended in 15ml of DMF, scutellarin 4.62 g (0.01 mol) was added to 30ml of DMF, the above-mentioned sitagliptin DMF solution was added to the scutellarin DMF solution, stirred at 70 ℃ for 15 hours, and the reaction solution was concentrated to dryness under reduced pressure at 60 ℃ to obtain a crude product.
The crude product was slurried with 30ml of ethyl acetate at room temperature for 20 minutes, filtered, the filter cake was divided equally into two equal parts, the first part was suspended in 15ml of water, and the solvent was removed by freeze-drying for 6 hours to give a pale yellow solid product. The second cake was dried in vacuo at 30℃for 24 hours to give the product as a pale yellow solid. The first part is 2.80 g of scutellarin sitagliptin salt with the yield of 64.47%, and the second part is 2.85 g of scutellarin sitagliptin salt with the yield of 65.45%.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the results are shown in figures 5-8, and compared with the pure mixture of scutellarin and sitagliptin, the product is more soluble, and the chemical shift of nuclear magnetic resonance hydrogen spectrum shows the carboxyl hydrogen of scutellarin and sitagliptin-NH 2 Salt formation and infrared spectra also show this characteristic, and thermal weight loss shows that the product has peaks at 198 ℃, 273 ℃, 312 ℃, 335 ℃ and 363 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of scutellarin and sitagliptin, which indicates that the product is salified.
EXAMPLE 3 preparation of baicalin saxagliptin salt
The preparation was substantially the same as in example 1 except that sitagliptin was replaced with 3.15 g (0.01 mol) of saxagliptin.
The first part is used for obtaining 3.60 g of baicalin saxagliptin salt with the yield of 96.49%, and the second part is used for obtaining 3.68 g of baicalin saxagliptin salt with the yield of 97.15%.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the results are shown in figures 9-12, and compared with the pure mixture of baicalin and saxagliptin, the product is more soluble, and the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that the carboxyl hydrogen of baicalin and the saxagliptin-NH are more soluble 2 Salification and infrared spectra also show this feature, and thermal weight loss shows that the product has a peak at 192℃and 349 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of baicalin and saxagliptin, which indicates that the product is salified.
EXAMPLE 4 preparation of scutellarin saxagliptin salt
The preparation was substantially the same as in example 2 except that sitagliptin was replaced with 3.15 g (0.01 mol) of saxagliptin.
The first part is 2.44 g of scutellarin saxagliptin salt with the yield of 62.68 percent, and the second part is 2.5 g of scutellarin saxagliptin salt with the yield of 63.45 percent.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the results are shown in figures 13-1316, compared with the pure mixture of the scutellarin and the saxagliptin, the product is more soluble, and the nuclear magnetic resonance hydrogen spectrum chemical shift shows that the carboxyl hydrogen of the scutellarin and the saxagliptin-NH 2 Salt formation and infrared spectrum also show this characteristic, and the thermal weight loss shows that the product has peaks at 117 ℃, 147 ℃, 195 ℃ and 356 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of scutellarin and saxagliptin, which indicates that the product is salified.
EXAMPLE 5 preparation of baicalin Alagliptin salt
The preparation was substantially the same as in example 1 except that sitagliptin was replaced with alogliptin 3.39 g (0.01 mol).
The first part is used for obtaining 3.44 g of baicalin alogliptin salt with the yield of 87.50%, and the second part is used for obtaining 3.50 g of baicalin alogliptin salt with the yield of 88.48%.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the results are shown in figures 17-20, and compared with the pure mixture of baicalin and alogliptin, the product is more soluble, and the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that the carboxyl hydrogen of baicalin and alogliptin-NH 2 Salt formation and infrared spectroscopy also showed this feature, and thermal weight loss showed that the product had a peak at 197 ℃, 220 ℃, 303 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of baicalin and alogliptin, which indicates that the product is salified.
EXAMPLE 6 preparation of scutellarin Alagliptin salt
The preparation was substantially the same as in example 2 except that sitagliptin was replaced with alogliptin 3.39 g (0.01 mol).
The first part is to obtain 3.33 g of scutellarin alogliptin salt with the yield of 83.19%, and the second part is to obtain 3.40 g of scutellarin alogliptin salt with the yield of 83.26%.
The product is subjected to structural characterization test by Nuclear Magnetic Resonance (NMR) hydrogen spectrum, infrared spectrum, DSC and XRD, and the results are shown in figures 21-24, and compared with the pure mixture of scutellarin and alogliptin, the product is more soluble and the chemical shift of the NMR hydrogen spectrum is obviousShowing the carboxyhydrogen of scutellarin and alogliptin-NH 2 Salt formation and infrared spectra also exhibit this feature, with thermal weight loss indicating that the product has a peak at 196℃and 365 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of scutellarin and alogliptin, which indicates that the product is salified.
Example 7 Activity test
Preparing test products with different concentrations from each double salt compound, measuring the activity of the compound by a chromogenic substrate method, taking glycylproline p-nitroaniline as a substrate, measuring the inhibition effect of the compound with different concentrations on DPP-4 under a slightly alkaline condition, and calculating the inhibition rate to obtain the IC50.
The pharmaceutical activity of each double salt compound is shown in table 2:
TABLE 2
Active ingredient name Target spot IC50(nM)
Sitagliptin DPP-4 20.8
Baicalin sitagliptin DPP-4 12.1
Scutellarin sitagliptin DPP-4 13.4
Sand gridRogliptin DPP-4 28.8
Baicalin saxagliptin DPP-4 15.2
Scutellarin saxagliptin DPP-4 16.3
Algliptin DPP-4 6.7
Baicalin alogliptin DPP-4 3.4
Scutellarin alogliptin DPP-4 2.9
Baicalin DPP-4 ＞100
Scutellarin (scutellarin) DPP-4 ＞100
As can be seen from table 2, the inhibition activity of baicalin sitagliptin double salt compound and scutellarin sitagliptin double salt compound on DPP-4 is stronger than that of sitagliptin on DPP-4;
the inhibition activity of the baicalin saxagliptin double salt compound and the scutellarin saxagliptin double salt compound on DPP-4 is stronger than that of oseltamivir on DPP-4;
the inhibition activity of the baicalin-alogliptin double salt compound and the scutellarin-alogliptin double salt compound on DPP-4 is stronger than that of lamivudine on DPP-4.
Example 8 preparation of baicalin and sitagliptin double salt nanoparticles
1. 50 g of baicalin sitagliptin double salt compound, 500 ml of water, 50 mg of suspending agent Tween-20 mg of hydroxypropyl methylcellulose, 50 mg of polyethylene glycol 6000 50 mg and grinding at 2000rpm for 40 minutes are added into a nano grinder to obtain a nano suspension of the baicalin sitagliptin double salt.
2. The obtained nano suspension of the baicalin sitagliptin double salt is dried in fluidized bed drying equipment, the drying inlet air temperature is 65 ℃, the drying is carried out until the water content is about 3%, and the baicalin sitagliptin double salt nano particles with the particle size distribution within the range of 50 nm-500 nm are prepared.
Compared with the baicalin sitagliptin double salt compound which is not subjected to nano grinding, the prepared baicalin sitagliptin double salt nano particles have the advantage that the solubility of the baicalin sitagliptin double salt compound is increased by 2.2 times at the temperature of 20 ℃ in 10 minutes.
Example 9 preparation of double salt nanoparticles of scutellarin and sitagliptin
The preparation method is basically the same as that of example 8, except that the baicalin sitagliptin double salt compound is replaced with the scutellarin sitagliptin double salt compound. The particle size distribution of the scutellarin and sitagliptin double salt nano-particles is in the range of 50 nm-500 nm.
Compared with the scutellarin and sitagliptin double salt compound which is not subjected to nano grinding, the solubility of the prepared scutellarin and sitagliptin double salt nano particles is increased by 2.0 times in 10 minutes at 20 ℃.
Example 10 preparation of baicalin saxagliptin double salt nanoparticles
The preparation method is basically the same as that of example 8, except that the baicalin sitagliptin double salt compound is replaced with a baicalin saxagliptin double salt compound. The particle size distribution of the baicalin saxagliptin double salt nano particles is within the range of 50 nm-500 nm.
Compared with the baicalin dasatinib double salt compound which is not subjected to nano grinding, the prepared baicalin dasatinib double salt nano particles have the advantage that the solubility of the baicalin dasatinib double salt compound is increased by 1.8 times at the temperature of 20 ℃ in 10 minutes.
Example 11 preparation of scutellarin-saxagliptin double salt nanoparticles
The preparation method is basically the same as that of example 10, except that the baicalin saxagliptin double salt compound is replaced with the scutellarin saxagliptin double salt compound. The particle size distribution of the scutellarin saxagliptin double salt nano particles is within the range of 50 nm-500 nm.
Compared with the scutellarin and saxagliptin double salt compound which is not subjected to nano grinding, the solubility of the prepared scutellarin and saxagliptin double salt nano particles is increased by 1.6 times in 10 minutes at 20 ℃.
Example 12 preparation of baicalin-alogliptin double salt nanoparticles
The preparation method is basically the same as that of example 8, except that the baicalin sitagliptin double salt compound is replaced with the baicalin alogliptin double salt compound. The particle size distribution of the baicalin-alogliptin double salt nano particles is within the range of 50 nm-500 nm.
Compared with the baicalin alogliptin double salt compound which is not subjected to nano grinding, the prepared baicalin alogliptin double salt nano particles have the advantage that the solubility of the baicalin alogliptin double salt compound is increased by 1.6 times at the temperature of 20 ℃ in 10 minutes.
Example 13 preparation of Diluface Alagliptin double salt nanoparticles
The preparation method is basically the same as that of example 12, except that the baicalin alogliptin double salt compound is replaced with the scutellarin alogliptin double salt compound. The particle size distribution of the scutellarin-alogliptin double salt nano particles is within the range of 50 nm-500 nm.
Compared with the scutellarin-alogliptin double salt compound without nano grinding, the solubility of the scutellarin-alogliptin double salt nano particles is increased by 1.8 times in 10 minutes at 20 ℃.
Example 14 animal in vivo Activity assay
A blank group, a baicalin group, a scutellarin group, a sitagliptin group, an alogliptin group, a dasatinib group, a baicalin sitagliptin double salt nanosuspension group (the preparation method of the baicalin sitagliptin double salt nanosuspension is referred to in example 8), a scutellarin sitagliptin double salt nanosuspension group (the preparation method of the scutellarin sitagliptin double salt nanosuspension is referred to in example 9), a baicalin alogliptin double salt nanosuspension group (the preparation method of the baicalin alogliptin nanosuspension is referred to in example 12), and a scutellarin alogliptin double salt nanosuspension group (the preparation method of the scutellarin alogliptin nanosuspension is referred to in example 13) are respectively arranged.
1. Test cells and animals
Primary diabetic mice: c57BL/6 nitric oxide synthase deficient mice, 6-8 weeks old. All mice were fed and drinking water freely and were kept at room temperature (23.+ -. 2 ℃ C.).
2. Test method
Diabetic nephropathy mice were established and eligible mice were randomly grouped into 10 groups each with the following dosing regimen:
blank control group: only physiological saline was administered.
Baicalin group: baicalin was prepared into a drug administration solution with sterile PBS, and the drug was administered once daily for 6 weeks in an amount of 8 mg/kg.
Scutellarin group: the scutellarin is prepared into a dosing solution by using sterile PBS, and the dosing amount is 8mg/kg, and the dosing is performed once daily for 6 weeks.
Sitagliptin group: sitagliptin was formulated into a dosing solution with sterile PBS and dosed at 7.2mg/kg, intragastric administration was performed once daily for 6 weeks.
Sitagliptin group: sitagliptin was formulated into a dosing solution with sterile PBS and dosed at 4.3mg/kg, intragastric administration was performed once daily for 6 weeks.
Baicalin sitagliptin double salt nano suspension group: the baicalin sitagliptin double salt nano suspension is taken as a dosing solution, and is subjected to gastric lavage once a day according to the dosage of 15mg/kg, and is continuously dosed for 6 weeks.
Scutellarin sitagliptin double salt nanosuspension group: the scutellarin and sitagliptin double salt nano suspension is taken as a dosing solution, and is subjected to gastric lavage once a day for 6 weeks according to the dosing amount of 15 mg/kg.
Baicalin alogliptin double salt nanosuspension group: the baicalin-alogliptin double salt nano suspension is taken as a dosing solution, and is subjected to gastric lavage once a day for 6 weeks according to the dosing amount of 10 mg/kg.
Scutellarin-alogliptin double salt nanosuspension group: the scutellarin and alogliptin double salt nano suspension is taken as a dosing solution, and is subjected to gastric lavage once a day for 6 weeks according to the dosing amount of 10 mg/kg.
After the end of the administration, the urine protein content was measured, and the proteinuria inhibition rate (proteinuria inhibition rate= (average proteinuria content of the blank group-average proteinuria content of each administration group)/average proteinuria content of the blank group 100%) was calculated as follows:
the inhibition rate of the proteinuria of the baicalin group (8 mg/kg) is 25.4%, the inhibition rate of the proteinuria of the scutellarin group (8 mg/kg) is 24.8%, the inhibition rate of the proteinuria of the sitagliptin group (7.2 mg/kg) is 32.6%, the inhibition rate of the proteinuria of the alogliptin group (4.3 mg/kg) is 34.8%, the inhibition rate of the proteinuria of the baicalin sitagliptin double salt (15 mg/kg) is 81.6%, the inhibition rate of the proteinuria of the scutellarin sitagliptin double salt (15 mg/kg) is 80.8%, the inhibition rate of the proteinuria of the baicalin alogliptin double salt (10 mg/kg) is 79.8%, the inhibition rate of the proteinuria of the scutellarin alogliptin double salt (10 mg/kg) is 79.6%, and the improvement effect of the urine of each double salt nanosuspension is obvious compared with the blank group, the natural product group and the small molecular group.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (11)

1. The double salt compound is characterized by being a double salt of flavonoid glycoside and an organic amine DPP-4 inhibitor, wherein the flavonoid glycoside is baicalin or scutellarin, and the organic amine DPP-4 inhibitor is selected from any one of sitagliptin, saxagliptin and alogliptin.
2. A process for the preparation of the double salt compound of claim 1, comprising the steps of:
Mixing and dissolving the flavonoid glycoside, the organic amine DPP-4 inhibitor and a polar aprotic organic solvent to obtain a mixed solution;
reacting the mixed solution to obtain a reaction solution; and
the solvent was removed from the reaction solution.
3. The method for producing a double salt compound according to claim 2, wherein the polar aprotic organic solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile.
4. A pharmaceutical composition comprising a therapeutically effective amount of the double salt compound of claim 1 in combination with a pharmaceutically acceptable carrier, excipient or diluent.
5. Use of a double salt compound according to claim 1 or a pharmaceutical composition according to claim 4 for the preparation of a DPP-4 inhibitor drug.
6. The use according to claim 5, wherein the DPP-4 inhibitor medicament is for the treatment of diabetes and complications.
7. The use according to claim 6, wherein the DPP-4 inhibitor medicament is for the treatment of type 2 diabetes and complications thereof.
8. A double salt nanoparticle obtained by nano-milling the double salt compound of claim 1.
9. Use of the double salt nanoparticle according to claim 8 for the preparation of a DPP-4 inhibitor drug.
10. The use according to claim 9, wherein the DPP-4 inhibitor medicament is for the treatment of diabetes and complications.
11. The use according to claim 10, wherein the DPP-4 inhibitor medicament is for the treatment of type 2 diabetes and complications thereof.
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