阅读说明：本技术 药物组合物及其制备方法和应用 (Pharmaceutical composition, preparation method and application thereof ) 是由 王化录 王鹿荧 于 2021-10-29 设计创作，主要内容包括：本发明涉及药物制剂技术领域,具体而言,涉及一种药物组合物及其制备方法和应用。所述药物组合物包括纳米黄酮苷和药物活性小分子,所述纳米黄酮苷具有式(I)所示的结构通式,其中,R-(1)～R-(9)各自独立地选自-H、-OH、C-(1)～C-(6)烷基、烷氧基或取代烷基,且R-(1)和R-(2)中至少有一个为-OH。本发明提供的纳米黄酮苷和药物活性小分子组合物具有更高的生物活性和生物利用度。而且将该药物组合物作为药物制剂后,药物溶出度更好,可以被人体更多吸收并发挥药效作用,为满足临床需求提供了保障。(The invention relates to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition, and a preparation method and application thereof. The pharmaceutical composition comprises nanometer flavonoid glycoside and pharmaceutically active small molecules, wherein the nanometer flavonoid glycoside has a structural general formula shown in formula (I), wherein，R 1 ～R 9 Each independently selected from-H, -OH, C 1 ～C 6 Alkyl, alkoxy or substituted alkyl, and R 1 And R 2 At least one of them is-OH. The nanometer flavonoid glycoside and medicinal active small molecule composition provided by the invention has higher biological activity and bioavailability. And after the pharmaceutical composition is used as a pharmaceutical preparation, the pharmaceutical dissolution is better, the pharmaceutical composition can be absorbed by human bodies more and can play the pharmacodynamic action, and the guarantee is provided for meeting clinical requirements.)

1. A pharmaceutical composition is characterized by comprising nanometer flavonoid glycoside and pharmaceutically active small molecules,

the nanometer flavonoid glycoside has a structural general formula shown in a formula (I):

wherein R is₁～R₉Each independently selected from-H, -OH, C₁～C₆Alkyl, alkoxy or substituted alkyl, and R₁And R₂At least one of them is-OH;

the pharmaceutically active small molecule is imatinib, ibrutinib, gefitinib, erlotinib, nilotinib, dasatinib, lapatinib, prazolamide, oxicetib, paleacinib, galantamine, lifloximate, memantine, fingolimod, sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, dagliptin, engeletzin, canagliflozin, oseltamivir, amantamide, hydroxychloroquine, roxithromycin, azithromycin, amoxicillin, cefaclor, cefixime, cefbuperamide, cefetamet, cefuroxime, meropenem, tebipenem, ofloxacin, levofloxacin, moxifloxacin, lamivudine, telbivudine, tenofovir, entecavir, adefovir, alfuzin, temifvirin, ritavivir, sulpiride, ritivir, ritavivir, amivudine, trevudine, sethoxydim, tamiflu, Any one of nevirapine, indinavir, ritonavir, darunavir, latiravir and doritaravir.

2. The pharmaceutical composition of claim 1, wherein R is₁And R₂Are all selected from-OH.

3. The pharmaceutical composition of claim 1, wherein the nanometer flavonoid glycoside is nanometer baicalin or nanometer scutellarin.

4. The pharmaceutical composition of claim 1, wherein the particle size of the nanometer flavonoid glycoside is 50nm to 500 nm.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the mass ratio of the nano flavonoid glycoside to the pharmaceutically active small molecule is 1:100 to 100: 1.

6. The pharmaceutical composition of claim 5, wherein the mass ratio of the nano flavonoid glycoside to the pharmaceutically active small molecule is 1:10 to 10: 1.

7. The pharmaceutical composition of claim 1, comprising therapeutically effective amounts of said nanosized flavonoid glycosides and said pharmaceutically active small molecules, and a pharmaceutically acceptable carrier, excipient or diluent.

8. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 7, comprising the steps of:

grinding flavonoid glycoside into nanometer flavonoid glycoside, and mixing nanometer flavonoid glycoside and pharmaceutically active small molecule.

9. The method for preparing a pharmaceutical composition according to claim 7, wherein in the step of grinding flavonoid glycoside into nanometer flavonoid glycoside, the rotation speed of grinding is 1000rpm to 3000rpm, and the grinding time is 10min to 40 min.

10. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 6, comprising the steps of:

mixing flavonoid glycoside and pharmaceutically active small molecule, and grinding the mixture to obtain the composition.

11. The method for preparing a pharmaceutical composition according to claim 9, wherein the step of grinding the mixture to obtain the composition comprises a grinding rotation speed of 2000rpm to 3000rpm for 20min to 60 min.

12. The use of the pharmaceutical composition of any one of claims 1 to 7 for the preparation of an anti-inflammatory drug, wherein said nanosized flavonoid glycoside is nanosized baicalin or nanosized scutellarin, and said pharmaceutically active small molecule is hydroxychloroquine.

13. The use according to claim 12, wherein the anti-inflammatory agent is used for the treatment of inflammatory diseases, such as malaria, rheumatoid arthritis, systemic lupus erythematosus, macular arthritis, plaque-like stomatitis, or Q-fever, and other rheumatic diseases.

Technical Field

The invention relates to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition, and a preparation method and application thereof.

Background

Baicalin and scutellarin are flavonoid glycosides (flavonoid glycosides for short), and have rich pharmacological activities, such as improving oxidation resistance by resisting lipid peroxidation, scavenging free radicals and superoxide anions, improving blood circulation, increasing blood flow, resisting platelet aggregation, inhibiting virus infection, enhancing immunity, resisting cell anoxia, protecting nerve, inhibiting tumor cell growth, etc.

Clinical application proves that the flavonoid glycoside natural product has exact antibacterial and anti-inflammatory effects and has the effects of resisting inflammation, inhibiting bacteria, relieving spasm and the like in the treatment of gastrointestinal diseases. However, because of low water solubility of baicalin, after most of common baicalin preparations circulated in the market are orally taken, because the solubility of baicalin in gastrointestinal fluids is low, the amount of baicalin entering blood circulation through a biological membrane is small, the oral bioavailability is very low, a certain treatment effect can be achieved only by increasing the administration dosage in clinic, but the increase of the administration dosage brings inconvenience to the administration and preparation process of patients.

Therefore, how to improve the bioavailability and bioactivity of flavonoid glycoside natural medicines is a technical problem to be solved urgently.

Disclosure of Invention

Based on the above, there is a need for a pharmaceutical composition with higher bioavailability and better bioactivity, and a preparation method and application thereof.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

the invention provides a pharmaceutical composition, which comprises nanometer flavonoid glycoside and drug active small molecules,

the nanometer flavonoid glycoside has a structural general formula shown in a formula (I):

wherein R is₁～R₉Each independently selected from-H, -OH, C₁～C₆Alkyl, alkoxy or substituted alkyl, and R₁And R₂At least one of them is-OH;

the pharmaceutically active small molecule is imatinib, ibrutinib, gefitinib, erlotinib, nilotinib, dasatinib, lapatinib, prazolamide, oxicetib, paleacinib, galantamine, lifloximate, memantine, fingolimod, sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, dagliptin, engeletzin, canagliflozin, oseltamivir, amantamide, hydroxychloroquine, roxithromycin, azithromycin, amoxicillin, cefaclor, cefixime, cefbuperamide, cefetamet, cefuroxime, meropenem, tebipenem, ofloxacin, levofloxacin, moxifloxacin, lamivudine, telbivudine, tenofovir, entecavir, adefovir, alfuzin, temifvirin, ritavivir, sulpiride, ritivir, ritavivir, amivudine, trevudine, sethoxydim, tamiflu, Any one of nevirapine, indinavir, ritonavir, darunavir, latiravir and doritaravir. .

In some embodiments, R₁And R₂Are all selected from-OH.

In some embodiments, the nano-flavonoid glycoside is nano-baicalin or nano-scutellarin.

In some embodiments, the mass ratio of the nanosized flavonoid glycoside to the pharmaceutically active small molecule is 1:100 to 100: 1.

In some embodiments, the mass ratio of the nanosized flavonoid glycoside to the pharmaceutically active small molecule is from 1:10 to 10: 1.

In another aspect of the present invention, a preparation method of the pharmaceutical composition is also provided, which comprises the following steps:

grinding flavonoid glycoside into nanometer flavonoid glycoside, and mixing nanometer flavonoid glycoside with medicinal active small molecule.

In some embodiments, in the step of grinding the flavonoid glycoside into the nanometer flavonoid glycoside, the rotation speed of grinding is 1000rpm to 3000rpm, and the grinding time is 10min to 40 min.

In some embodiments, the pharmaceutical composition contains therapeutically effective amounts of the nano-flavonoid glycoside and the pharmaceutically active small molecule, and a pharmaceutically acceptable carrier, excipient or diluent.

Further, the invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:

mixing flavonoid glycoside and pharmaceutically active small molecule, and grinding the mixture to obtain the composition.

In some embodiments, the step of grinding the mixture to obtain the composition comprises grinding at a rotation speed of 2000rpm to 3000rpm for 20min to 60 min.

In another aspect of the present invention, an application of the pharmaceutical composition in the preparation of anti-inflammatory drugs is provided, wherein the nanometer flavonoid glycoside is nanometer baicalin or nanometer scutellarin, and the pharmaceutically active small molecule is hydroxychloroquine.

In some embodiments, the anti-inflammatory drug is used for the treatment of inflammatory diseases, such as malaria, rheumatoid arthritis, systemic lupus erythematosus, macular arthritis, plaque-like stomatitis, or Q-heat, and other rheumatic diseases.

Compared with the prior art, the invention has the beneficial effects that:

compared with the flavonoid glycoside with large particle size, the solubility of the nanometer flavonoid glycoside and the pharmaceutical active micromolecule composition provided by the invention is increased, the dissolving speed is accelerated, the nanometer flavonoid glycoside and the pharmaceutical active micromolecule composition can be combined for use, the nanometer flavonoid glycoside and the pharmaceutical active micromolecule can generate synergistic effect, and compared with the single use of the nanometer flavonoid glycoside and the pharmaceutical active micromolecule composition, the combination of the nanometer flavonoid glycoside and the pharmaceutical active micromolecule composition has higher biological activity and bioavailability. And after the composition is used as a medicinal preparation, the medicine dissolution rate is better, the composition can be absorbed by human bodies more and can play the effect of the medicine, and the guarantee is provided for meeting the clinical requirement.

Detailed Description

The present invention will be described in further detail with reference to specific examples. The 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 in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

Terms and definitions

Unless otherwise stated or contradicted, terms or phrases used herein have the following meanings:

the term "alkyl" refers to a saturated hydrocarbon containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing the term, e.g., "C₁～C₆Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms, which may be independently at each occurrence C₁Alkyl radical, C₂Alkyl radical, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl or C₆An alkyl group. Suitable examples include, but are not limited to: methyl (Me, -CH)₃) Ethyl (Et-CH)₂CH₃) 1-propyl (n-Pr, n-propyl, -CH)₂CH₂CH₃) 2-propyl (i-Pr, i-propyl, -CH (CH)₃)₂) 1-butyl (n-Bu, n-butyl, -CH)₂CH₂CH₂CH₃) 2-methyl-1-propyl (i-Bu, i-butyl, -CH)₂CH(CH₃)₂) 2-butyl (s-Bu, s-butyl, -CH (CH)₃)CH₂CH₃) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH)₃)₃) 1-pentyl (n-pentyl, -CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) 1-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) And 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)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 the term, e.g., "C₁～C₆Alkoxy "means that the alkyl moiety contains 1 to 6 carbon atoms and, at each occurrence, may be independently C₁Alkoxy radical, C₂Alkoxy radical, C₃Alkoxy radical, C₄Alkoxy radical, C₅Alkoxy or C₆An alkoxy group. Suitable examples include, but are not limited to: methoxy (-O-CH)₃or-OMe), ethoxy (-O-CH)₂CH₃or-OEt) and tert-butoxy (-O-C (CH)₃)₃or-OtBu).

"pharmaceutically acceptable" refers to those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to a patient 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, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Each carrier, excipient or diluent must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious 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 gum 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.

Reference to "substituted" of a group means that one or more hydrogen atoms attached to the member atoms within the group is replaced by a substituent selected from the group of defined or suitable substituents. It is 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 it is stated that a group may contain one or more substituents, one or more member atoms within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent, so long as such substitution is in accordance with the allowed valency of the atom. "Member atom" means an atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bonded 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.

Composition comprising a metal oxide and a metal oxide

The invention provides a pharmaceutical composition, which comprises nanometer flavonoid glycoside and pharmaceutically active small molecules.

The nanometer flavonoid glycoside has a structural general formula shown in a formula (I):

wherein R is₁～R₉Each independently selected from-H, -OH, C₁～C₆Alkyl, alkoxy or substituted alkyl, and R₁And R₂At least one of them is-OH.

In some embodiments, R₁And R₂Are all selected from-OH.

In some embodiments, R₃Is selected from-H or-OCH₃。

In some embodiments, R₅、R₆、R₉Are all selected from-H.

In some embodiments, R₇、R₈Each independently selected from-H or-OH.

In some embodiments, R₈Is selected from-H.

In some embodiments, R₇Is selected from-OH.

In other embodiments, R₇Is selected from-H.

In some embodiments, the nano-flavonoid glycoside is nano-apigenin flavonoid glycoside, nano-baicalin, nano-scutellarin, nano-chrysin flavonoid glycoside or nano-wogonoside.

Preferably, the nanometer flavonoid glycoside is nanometer baicalin or nanometer scutellarin.

The molecular structure of the nanometer baicalin is shown as the formula (I-I):

the molecular structure of the scutellarin is shown as the formula (I-II):

in some embodiments, the particle size distribution of the nano flavonoid glycoside ranges from 50nm to 500 nm. The nanometer flavonoid glycoside in the particle size distribution range has better solubility and dissolution speed.

Specific examples of pharmaceutically active small molecules may include, but are not limited to, imatinib, ibrutinib, gefitinib, erlotinib, nilotinib, dasatinib, lapatinib, pezopanib, oxitinib, papocetine, galantamine, lifastimin, memantine, fingolimod, sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, dagliptin, engagliflozin, canagliflozin, oseltamivir, amantadine, hydroxychloroquine, roxithromycin, azithromycin, amoxicillin, cefaclor, cefixime, cefbupirisone, cefetamet, cefuroxime, meropenem, tebipenem, oxacine, levofloxacin, ciprofloxacin, moxifloxacin, lamivudine, telbivudine, tenofovir, entecavir, adefovir, lasofovir, sulosin, sulivir, alfuzosin, tavir, tazivir, mazivudine, and tamiflu, Emtricitabine, stavudine, nevirapine, indinavir, ritonavir, darunavir, latiravir, and doritaravir.

In some embodiments, the mass ratio of the nanometer flavonoid glycoside to the pharmaceutically active small molecule is any value between 1:100 and 100:1, and may be, for example, 1:50, 1:25, 1:20, 1:15, 1:10, 1:5, 1:1, 5:1, 10:1, 15:1, 20:1, 25:1, 50:1, or the like.

In some preferred embodiments, the mass ratio of the nanosized flavonoid glycoside to the pharmaceutically active small molecule is any value between 1:10 and 10: 1.

In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the nano-flavonoid glycoside of any of the above embodiments and a pharmaceutically active small molecule, and a pharmaceutically acceptable carrier, excipient or diluent.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:

s10, grinding the flavonoid glycoside into nanometer flavonoid glycoside, and mixing the nanometer flavonoid glycoside with the medicinal active small molecules.

In step S10, the flavonoid glycoside prior to unmilling is typically a commercially available unmilled flavonoid glycoside having a particle size greater than 1 micron.

In some embodiments, in step S10, the rotation speed of milling is independently selected from any value between 1000rpm and 3000rpm, and the time of milling is independently selected from any value between 10min and 40 min.

Step S10 may include adding a suspending agent to the flavonoid glycoside and grinding with water to form a flavonoid glycoside nanosuspension, adding the pharmaceutically active small molecule to the flavonoid glycoside nanosuspension, and mixing the nanosized flavonoid glycoside and the pharmaceutically active small molecule. The suspending agent is added for further dispersing the nanometer flavonoid glycoside and preventing the nanometer flavonoid glycoside from agglomerating.

Examples of the suspending agent may include, but are not limited to, polyethylene glycol, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, fatty acid glyceride, polyhydric alcohol type nonionic surfactant, polyoxyethylene type nonionic surfactant, poloxamer, tween, vitamin E polyethylene glycol succinic acid vinegar, phospholipid, gelatin, xanthan gum, sodium lauryl sulfate, sodium deoxycholate, and a combination thereof.

The invention further provides another preparation method of the pharmaceutical composition, which comprises the following steps:

s30, mixing flavonoid glycoside and pharmaceutically active small molecules, and grinding the mixture to obtain the composition.

In step S30, the flavonoid glycoside prior to unmilling is typically a commercially available unmilled flavonoid glycoside having a particle size greater than 1 micron.

In some embodiments, in step S40, the rotation speed of the milling is independently selected from any value between 2000rpm and 3000rpm, and the time of the milling is independently selected from any value between 20min and 60 min. The diameter of a working cavity of the nano grinder used for grinding is 85 mm. If the diameter of the working cavity of the nano grinder is changed, the rotating speed is adjusted correspondingly.

Step S30 may include grinding the large particle size flavonoid glycoside, the pharmaceutically active small molecule, the suspending agent, and water together to form a nanosuspension, and drying the nanosuspension to obtain the nano-mixture particles. Step S20 is mixing the nanoparticles and the pharmaceutically active small molecules. The purpose of the suspending agent is to further disperse the flavonoid glycosides and prevent them from agglomerating.

The suspending agent in this step may be the same as the above-mentioned suspending agent, and will not be described herein again.

In some embodiments, the nano-flavonoid glycoside is selected from nano-baicalin or nano-scutellarin, and the pharmaceutically active small molecule is selected from hydroxychloroquine.

Furthermore, the invention also relates to the application of the pharmaceutical composition in preparing anti-inflammatory drugs, wherein the nanometer flavonoid glycoside in the composition is selected from nanometer baicalin or nanometer scutellarin, and the pharmaceutically active small molecule is selected from hydroxychloroquine.

In some embodiments, the inflammatory disease is a rheumatic disease such as malaria, rheumatoid arthritis, systemic lupus erythematosus, macular arthritis, plaque-like stomatitis, or Q-fever.

Administration and formulation

The production of the medicament comprising the pharmaceutical composition of the present invention and its use may be carried out according to well-known pharmaceutical methods.

Although the compositions of the invention useful in the treatment according to the invention may be administered as the original chemical compound, it is preferred to incorporate the active ingredient in the pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical adjuvants. The compositions of the present invention may be anhydrous or solvated.

In a preferred embodiment, the present invention provides a medicament comprising a composition useful according to the present invention 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 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 by sustained release systems. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compositions of the invention, which matrices may be in the form of shaped articles, e.g. films, or microcapsules.

The compositions useful according to the invention, together with conventional adjuvants, carriers or diluents, may thus be placed in the form of medicaments and unit doses thereof. Such forms include: solids, in particular in the form of tablets, filled capsules, powders and pills (pellets); and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, universal drugs (elixir) and capsules filled therewith, all forms for oral administration, suppositories for rectal administration and sterile injection solutions for parenteral use. These medicaments and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without other active compounds or ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

The compositions useful according to the present invention can 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 comprise one or more of the compositions useful according to the present invention as active ingredients.

For the preparation of a medicament from a composition 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. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or a coating material.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient is mixed with the 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 a coating material as a carrier, providing a capsule in which the active component is surrounded by, and thus associated with, a carrier, with or without a carrier. Similarly, cachets and lozenges (lozenge) 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 ingredient is dispersed homogeneously therein, such as by stirring. The molten homogeneous mixture is then poured into a suitably sized mould, allowed to cool and thereby solidify. Compositions suitable for vaginal administration may be presented as pessaries (pessary), tampons (tampons), creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Liquid preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as aqueous polyethylene glycol solutions.

Thus, the compositions 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 ampoules with added preservatives, pre-filled syringes, small volume infusion or in multi-dose containers. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles (vehicles), and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, for constitution before use, by sterile isolation of a sterile solid or by lyophilization from solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the comminuted active ingredient in water with a viscous material such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient, these preparations may contain coloring agents, flavoring agents, 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 compositions of the present invention may be administered in a formulation containing from 0.001% to 70% by weight of the composition, preferably from 0.01% to 70% by weight of the composition, even more preferably from 0.1% to 70% by weight of the composition. In one embodiment, a suitable amount of the composition 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 (usually sucrose and acacia or tragacanth), pastilles comprising the active ingredient in an inert base (such as gelatin and glycerin or sucrose and acacia) (pastilles) and mouthwashes comprising the active ingredient in a suitable liquid carrier (mouthwash).

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 multi-dose form. 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 metered atomizing spray pump.

Administration to the respiratory tract may also be accomplished by way of an aerosol formulation in which the active ingredient is provided in pressurized packs 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 providing a metering valve.

Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the composition in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel within the nasal cavity. The powder compositions may be presented in unit dosage form, for example, as capsules or cartridges of gelatin (cartridges), or as blister packs (blister packs) from which the powder may be administered by means of an inhaler.

If desired, pharmaceutical compositions suitable for the sustained release of the active ingredient may be used.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Moreover, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the packaged form of a suitable number of any of these dosage forms. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

Additional details regarding The art of formulation and administration can be found in The latest edition of "Remington's Pharmaceutical Sciences (Maack Publishing Co. Easton, Pa.) and Remington: The science and practice of medicine", Lippincott Williams and Wilkins.

Suitable formulations and ways of producing them are also disclosed, for example, in "Arzneiformenlehre, Paul Heinz List, Ein Lehrbuchfurf pharmacy, Wissenschaftliche Verlagsgesellschaft Stuttgart,4. Aufiage, 1985" or "The same and practice of industrial pharmacy", Varghese Publishing House,1987 "or" model pharmaceuticals ", edited by James Swarbrickick, 2 nd edition" written 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 and not limit the scope of the invention. Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods. The experimental procedures, in which specific conditions are not indicated in the examples, were carried out according to conventional conditions, such as those described in the literature, in books, or as recommended by the manufacturer.

Example 1 preparation of nanometer baicalin

1) Adding 50 g of baicalin, 500 ml of water, tween-2050 mg of a suspending agent, 50mg of hydroxypropyl methylcellulose and 600050 mg of polyethylene glycol into a nano-grinder, and grinding at 2000rpm for 20 minutes to obtain baicalin nano-suspension, wherein the particle size of the baicalin is distributed in the range of 50-500 nm.

2) And drying the obtained baicalin nanometer suspension in fluidized bed drying equipment at 65 deg.C until the water content is about 3%, and making into baicalin nanometer granule.

The prepared baicalin nanoparticles have a 3-fold increase in solubility at 20 ℃ in 10 minutes compared to baicalin that was not nanomilled.

EXAMPLE 2 preparation of Nano scutellarin

Substantially the same as in example 1 except that baicalin was replaced with scutellarin. The scutellarin particle size distribution is within 50 nm-500 nm.

The solubility of the obtained scutellarin nanoparticles is increased by 3 times at 10min and 20 deg.C compared with scutellarin not subjected to nanometer grinding

Example 3: 1g of baicalin nano-particles (calculated by the content of baicalin) obtained in example 1 and 10 g of hydroxychloroquine are uniformly mixed to obtain the baicalin nano-particle hydroxychloroquine composition, wherein the ratio of the baicalin to the hydroxychloroquine is 1: 10.

Example 4: 10 g of baicalin nano-particles (calculated by the content of baicalin) obtained in example 1 and 1g of hydroxychloroquine are uniformly mixed to obtain the baicalin nano-particle hydroxychloroquine composition, wherein the ratio of the baicalin to the hydroxychloroquine is 10: 1.

Example 5: 1g of scutellarin nanoparticles (based on the content of scutellarin) and 10 g of hydroxychloroquine obtained in example 2 were mixed uniformly to obtain scutellarin nanoparticle hydroxychloroquine composition, wherein the ratio of scutellarin to hydroxychloroquine was 1: 10.

Example 6: 10 g of scutellarin nanoparticles (based on the content of scutellarin) and 1g of hydroxychloroquine obtained in example 2 were mixed uniformly to obtain scutellarin nanoparticle hydroxychloroquine composition, wherein the ratio of scutellarin to hydroxychloroquine was 10: 1.

Example 7: 29 g of baicalin nano-particles (calculated by the content of baicalin) obtained in example 1 and 21 g of hydroxychloroquine are uniformly mixed to obtain the baicalin nano-particle hydroxychloroquine composition, wherein the ratio of the baicalin to the hydroxychloroquine is 29: 21.

Example 8: 29 g of scutellarin nanoparticles (based on the content of scutellarin) and 21 g of hydroxychloroquine obtained in example 2 were mixed uniformly to obtain scutellarin nanoparticle hydroxychloroquine composition, wherein the ratio of scutellarin to hydroxychloroquine was 29: 21.

Example 9 animal in vivo anti-inflammatory Activity assay

A blank administration group, a negative control group and different active ingredient administration groups are respectively arranged.

1. Test animal

Mice: c57BL/6J mice, male, weighing 20g,6-8 weeks old. All mice were fed food and water ad libitum and were kept at room temperature (23 + -2) ° c.

2. Test method

Negative control group: 10 mice without any treatment were given physiological saline

Mice with inflammation were established and randomly grouped into groups of 10 mice each, and the dosing schedule was as follows:

blank dosing group: administration of physiological saline

Baicalin group: the unground baicalin was administered once daily by intragastric administration at a dose of 29mg/kg for 3 consecutive days.

Scutellarin group: administering unground scutellarin once daily for 3 days continuously by intragastric administration at a dosage of 29 mg/kg.

Hydroxychloroquine group: hydroxychloroquine is administrated once daily for 3 days continuously by intragastric administration at a dosage of 21 mg/kg.

Group 1: mixing unground baicalin and hydroxychloroquine at a ratio of 10:1, and administering by intragastric administration at a dose of 310mg/kg once a day for 3 days.

Group 2: the mixture of unground scutellarin and hydroxychloroquine at a ratio of 10:1 is administered by intragastric administration at a dose of 310mg/kg once a day for 3 consecutive days.

Group 3: the baicalin nanoparticle hydroxychloroquine composition obtained in example 3 (baicalin to hydroxychloroquine ratio of 1:10) was administered once daily for 3 consecutive days by intragastric administration at a dose of 24 mg/kg.

Group 4: the baicalin nanoparticle hydroxychloroquine composition obtained in example 4 (baicalin to hydroxychloroquine ratio of 10:1) was administered once daily for 3 consecutive days by gavage at a dose of 310 mg/kg.

Group 5: the scutellarin nanoparticle hydroxychloroquine composition obtained in example 5 (scutellarin to hydroxychloroquine ratio is 1:10) was administered once daily for 3 consecutive days by gavage administration at a dose of 24 mg/kg.

Group 6: the scutellarin nanoparticle hydroxychloroquine composition obtained in example 6 (scutellarin to hydroxychloroquine ratio is 10:1) was administered at a dose of 310mg/kg by gavage once a day for 3 consecutive days.

Group 7: the baicalin nanoparticle hydroxychloroquine composition obtained in example 7 (baicalin to hydroxychloroquine ratio of 29:21) was administered once daily for 3 consecutive days by gavage at a dose of 50 mg/kg.

Group 8: the scutellarin nanoparticle hydroxychloroquine composition obtained in example 8 (scutellarin to hydroxychloroquine ratio is 29:21) was administered once daily for 3 consecutive days by gavage administration at a dose of 50 mg/kg.

After the administration, blood was taken to measure inflammatory cytokines, and the inflammatory cytokines measured in the blank administration group were about 3 times as much as those in the negative control group, and the relative mean value of inflammatory cytokines in mice in each group (i.e., the inflammatory cytokine value in mice in each group divided by the inflammatory cytokine value in the blank administration group) was calculated with the mean value of inflammatory cytokines in the blank administration group as 100%, and the results were as follows:

the mean value of inflammatory cytokines in the blank group was 100%, the relative mean value of inflammatory cytokines in the unground baicalin group (dose of 29mg/kg) was 92%, the relative mean value of inflammatory cytokines in the unground scutellarin group (dose of 29mg/kg) was 90%, the relative mean value of inflammatory cytokines in the hydroxychloroquine group (dose of 21mg/kg) was 54%, the relative mean value of inflammatory cytokines in the group 1 (dose of 310mg/kg) was 55%, the relative mean value of inflammatory cytokines in the group 2 (dose of 310mg/kg) was 53%, the relative mean value of inflammatory cytokines in the group 3 (dose of 24mg/kg) was 46%, the relative mean value of inflammatory cytokines in the group 4 (dose of 310mg/kg) was 47%, the relative mean value of inflammatory cytokines in the group 5 (dose of 24mg/kg) was 47.5%, the relative mean value of inflammatory cytokines in the group 6 (dose of 310mg/kg) was 49.2%, the relative mean value of inflammatory cytokines in the group 7 (dose of 50mg/kg) was 45.8%, the relative average value of inflammatory cytokines in the group 8 (dose of 50mg/kg) is 47.5%, and compared with the blank administration group, the unground baicalin group and the unground scutellarin group have only slight effect of reducing the inflammatory cytokines; the hydroxychloroquine group, the unground baicalin and hydroxychloroquine group and the unground scutellarin and hydroxychloroquine group have medium-intensity inflammatory factor reduction effects, the levels of the three groups are basically consistent, and the unground scutelloside or scutellarin have no obvious enhancement effect on the inflammatory factor reduction effect of hydroxychloroquine; the baicalin nanoparticles or scutellarin nanoparticles and hydroxychloroquine group with three proportions have stronger effect of reducing inflammatory factors, and the effect is more than 50%. Therefore, the nano-ground baicalin or scutellarin has obvious promotion effect on the inflammatory factor reduction effect of hydroxychloroquine, while the unground baicalin or scutellarin has no promotion effect.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.