Nasal brain-entering drug delivery promoter and application thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a nasal brain-entering drug delivery accelerator and application thereof, and the accelerator is glycerin and chemical derivatives, chemical isotope markers, condensation compounds or salts thereof. The composition specifically comprises triglyceride, glyceryl ether, glycerophosphate, glyceryl amino acid salt, glyceryl alcohol, glyceric acid, glyceryl acyl, glyceryl glycolate, glyceryl stearate, glycerol or mannitol and the like. The accelerant can be used for preparing nasal drops, and the mass fraction of the accelerant in the nasal drops is 0.01-40%. Experiments prove that the accelerant can significantly improve the intranasal absorption (P < 0.001) of active ingredients, so that the nose-brain delivery efficiency of drugs is effectively improved, the accelerant is expected to be applied to enhancing the curative effect of intranasal administration on central nervous system diseases, brain tumors and other diseases, and a new thought and method are provided for diagnosis of the diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to a nasal brain drug delivery promoter and application. BACKGROUND

[0002] The treatment of central nervous system diseases has always been a major challenge in the medical field. This is because the central nervous system (including the brain and spinal cord) has a highly complex structure and function, and is protected by the blood-brain barrier (BBB), making it difficult for most drugs to effectively enter the brain. The blood-brain barrier is a barrier composed of brain vascular endothelial cells and tight junctions between cells, which limits the passage of substances from the blood into brain tissue. According to research, more than 98% of small molecule drugs and almost all large molecule drugs cannot cross the blood-brain barrier after systemic administration, resulting in very low bioavailability of drugs in the brain and potentially serious side effects on the body.

[0003] To solve this problem, scientists have been looking for ways to bypass the blood-brain barrier and directly deliver drugs to the brain. Among them, intranasal administration is a widely studied and applied method. Through intranasal administration, drugs can directly enter the brain through the olfactory and trigeminal nerves, avoiding the limitations of the blood-brain barrier, and reducing the first-pass elimination of drugs in the liver or gastrointestinal tract and the side effects of systemic administration. Therefore, intranasal administration is considered a non-invasive and efficient central nervous system drug delivery method.

[0004] Currently, there are a variety of nasal drug delivery products for the treatment of central nervous system diseases, and have been approved. These products are mainly related to the treatment of common central nervous system diseases such as migraine and epilepsy. Although research on the use of nasal administration for the treatment of central nervous system diseases has made some progress, nasal brain drug delivery still faces the problem of low delivery efficiency, and most drugs still face many barriers in nasal delivery. Mucociliary clearance (MCC) is a factor that limits drug delivery through the nose, as mucociliary can move drugs from the nasal cavity to the oropharynx and clear them away. In addition, the barrier properties of the nasal epithelium also limit drug penetration and absorption. The nasal epithelium is composed of a layer of pseudostratified columnar cells connected by tight junctions. Hydrophobic small molecules can be absorbed by concentration gradient, while hydrophilic molecules need to rely on selective transport systems to cross the lipid bilayer, and large molecules and polar drugs need to further overcome the tight junction structure and be absorbed through the paracellular transport pathway. The nasal epithelial permeability barrier is also a major barrier that cannot be ignored in drug nasal delivery. It is of great significance to develop a promoter that can improve the efficiency of drug nasal brain delivery. SUMMARY

[0005] In view of the problems of low nasal absorption and low brain delivery efficiency of existing nasal drug delivery methods, the purpose of this invention is to provide a nasal brain drug delivery enhancer and its application.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A nasal-to-brain drug delivery enhancer is glycerol and its chemical derivatives, chemical isotope labels, condensates, or salts. Specifically, it includes triglycerides, glyceryl ethers, glycerophosphates, glyceryl amino acid salts, glycerols, glyceric acids, glyceryl acyl groups, glyceryl glycolic acid esters, glyceryl stearate, glycerol, mannitol, etc.

[0008] The promoter of the present invention can be used to prepare nasal drops that improve nasal-brain delivery efficiency, wherein the promoter accounts for 0.01-40% by mass of the nasal drops, preferably 2.5-10%.

[0009] The drug components in the nasal drops are any one or more of small molecule drugs, macromolecule drugs, nano- or micron-sized drugs.

[0010] When the drug component in the nasal drops is a small molecule drug, the mass fraction of the promoter is 5-10%, most preferably 7.5%. When the drug component in the nasal drops is a large molecule drug, the mass fraction of the promoter is 2.5-10%, most preferably 5%. When the drug component in the nasal drops is a nano or micron drug, the mass fraction of the promoter is 5-10%, most preferably 7.5%.

[0011] One or more of mannitol, ibuprofen, acetaminophen, flunarizine hydrochloride, rizatriptan benzoate, naproxen, caffeine, diclofenac sodium, tramadol hydrochloride, aspirin, codeine phosphate, methadone hydrochloride, dihydroergotamine mesylate, butorphanol tartrate, zolmitriptan, sumatriptan, levetiracetam, carbamazepine, phenytoin sodium, lamotrigine, sodium valproate, gabapentin, oxcarbazepine, phenobarbital, topiramate, clonazepam, midazolam, diazepam, lormetazepam, alprazolam, buspirone hydrochloride, oxazepam, midazolam, amobarbital, secobarbital, flupentixol melitracen, estazolam, clonazepam, tandospirone citrate, nitrazepam, triazolam, zolpidtarn tartrate, zopiclone, morphine, diphenidol hydrochloride, oryzanol, doxepin hydrochloride, ketamine, risperidone, olanzapine, fluoxetine, fluoxetine hydrochloride, tranexamic acid, phenolsulfonethale, hemostatic acid, desmopressin acetate, doxorubicin hydrochloride (doxorubicin hydrochloride), doxorubicin (epirubicin), pirarubicin, mitomycin, cyclophosphamide, ifosfamide, cisplatin, carboplatin, nedaplatin, thiotepa, capecitabine, fluorouracil, pemetrexed, tegafur, methotrexate, raltitrexed, dactinomycin, pirarubicin hydrochloride, vincristine sulfate, vindesine sulfate, vinorelbine tartrate, paclitaxel, goserelin acetate, temozolomide, ribavirin, acyclovir, ganciclovir, ceftriaxone sodium, cefotaxime, vancomycin, isoniazid, rifampicin, pyrazinamide, donepezil, donepezil hydrochloride, rivastigmine, galantamine hydrobromide, huperzine A, memantine, oxiracetam, carbidopa, levodopa, levodopa methyl ester, levodopa ethyl ester, entacapone, tolcapone, selegiline, selegiline hydrochloride, rasagiline, coenzyme Q10, pramipexole, pramipexole hydrochloride, ropinirole, piribedil, rotigotine, apomorphine, amantadine, and trihexphenidyl.

[0012] One or more of polypeptides, proteins (including antibodies), antibody conjugated drugs, polypeptide conjugated drugs, nucleic acid conjugated drugs, protein conjugated drugs, deoxyribonucleic acid, ribonucleic acid, micro ribonucleic acid, small interfering ribonucleic acid.

[0013] One or more of nanoliposomes, nanocapsules, nanospheres, polymer nanomicelles, microcapsules, microspheres, metal nanomedicines, non-metal nanomedicines, nanosuspensions, viruses, exosomes, cell membrane structure biomimetic nanosystems, bacterial membrane structure biomimetic nanosystems, and nanomedicine systems formed by loading the above nanoscale structures; wherein the cells and bacteria include stem cells, immune cells, blood cells, bacteria, fungi.

[0014] Further, the nasal drop medicine also includes an auxiliary material, and the auxiliary material includes but is not limited to one or more of pure water, amine (such as ethylenediamine, triethanolamine and the like), oil (such as oleic acid, corn oil and the like), ester (such as ethyl acetate, ethyl oleate and the like), salt (such as phosphate, sodium chloride and the like), essence.

[0015] Further, the dosage form of the nasal drop medicine includes but is not limited to solution (aromatic water, solution, glycerol, spirit, etc.), colloidal solution, emulsion (oil medicine and oil solution, etc.), semi-solid matrix (including nanogel, microgel, sol, etc.), suspension, etc.

[0016] Compared with the prior art, the beneficial effects of the present application are:

[0017] The present application provides a nasal brain drug delivery promoter, which can promote the penetration of drug ingredients through the nasal mucosa epithelium, thereby promoting the efficiency of brain delivery. The promoter has the characteristics of strong universality, significant effect, low cost, and convenient use. Experiments have proved that the promoter can significantly improve the intranasal absorption of active ingredients (P<0.001), thereby effectively improving the nasal-brain delivery efficiency of drugs, and is expected to be applied to enhance the curative effect of intranasal administration in the treatment of central nervous system diseases and brain tumors, and to provide new ideas and methods for the diagnosis of the above diseases.

[0018] Moreover, the promoter of the present application can be prepared into a nasal administration dosage form together with drug ingredients and other auxiliary materials, or directly prepared into a single preparation for use with other drugs. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 Fig. 2 is a fluorescence imaging diagram of the isolated brain of a mouse after intranasal administration of a doxorubicin hydrochloride (DOX·HCl) aqueous solution mixed with different mass fractions of glycerol for 2 hours.

[0020] Figure 2 Fig. 4 is a graph of the change of fluorescence intensity of the brain of a mouse with time before and after intranasal administration of an immunoglobulin G (IgG) aqueous solution mixed with different mass fractions of glycerol.

[0021] Figure 3 Fig. 6 is a graph of the change of fluorescence intensity of the brain of a mouse with time before and after intranasal administration of polyethylene glycol-poly(β-amino ester) loaded doxorubicin (DOX) nanomicelles (PEG-PAE@DOX, PPD) mixed with different mass fractions of glycerol.

[0022] Figure 4 Fig. 8 is a graph of the change of fluorescence intensity of the brain of a mouse with time before and after intranasal administration of polyethylene glycol-poly(lactic acid) (PEG-PLGA) microspheres mixed with different mass fractions of glycerol.

[0023] Figure 5Bioluminescence intensity in mouse brains 3 days after intranasal administration of Lent-EF1a-P2A-luciferase-CMV-coGFP-P2A-Puro lentivirus mixed with different mass fractions of glycerol.

[0024] Figure 6 The image shows the bioluminescence intensity in the mouse brain 4 hours after CTLL-2 cells mixed with different mass fractions of glycerol were administered intranasally.

[0025] Figure 7 The graph shows the change in fluorescence intensity in the mouse brain over time before and after intranasal administration of the antibody-drug conjugate Hercelium mixed with different mass fractions of glycerol. Detailed Implementation

[0026] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] Example 1: Glyceryl hydrochloride promotes the nasal entry of DOX·HCl into the brain.

[0028] DOX·HCl aqueous solutions were prepared using pure water and dispensed into 5 groups. Different masses of glycerol hydrochloride were added to each group to prepare mixed solutions with glycerol mass fractions of 0%, 2.5%, 5%, 7.5%, 10%, and 20% using pure water or buffer solution. SD rats were then administered the solutions intranasally. Two hours after administration, the rats were sacrificed and their brains were harvested. The fluorescence intensity of the isolated brain was detected using a fluorescence imaging system.

[0029] like Figure 1 As shown, compared with the control group (glycerol mass fraction 0%), all concentrations of glycerol significantly (P < 0.001) promoted intranasal absorption of DOX·HCl, improved the naso-brain delivery efficiency of small molecule drugs, and prolonged the duration of drug action.

[0030] The concentration of glycerol hydrochloride is preferably 2.5-10%, more preferably 5-10%, and most preferably 7.5%.

[0031] Example 2: Glycerol promotes IgG entry into the brain via the nose.

[0032] Cy5-labeled IgG was prepared and packaged into 5 groups. Different concentrations of glycerol aqueous solution were added to prepare IgG-Cy5 solutions with glycerol mass fractions of 0%, 2.5%, 5%, 7.5%, 10%, and 20%. The solutions were then administered intranasally to C57 mice, and the fluorescence intensity in the brain was detected at regular intervals using an in vivo fluorescence imaging system.

[0033] As shown in Figure 2 , compared with the control group (glycerol mass fraction 0%), all concentrations of glycerol can significantly (P<0.05) promote the intranasal absorption of IgG, improve the nasal-brain delivery efficiency of macromolecular drugs, and delay the action time of the drugs after 2h of administration.

[0034] Preferably, the concentration of glycerol is 2.5-10%, further preferably 2.5-5%, and most preferably 5%.

[0035] Example 3 Glycerol promotes PPD nanomicelles to enter the brain through the nose.

[0036] Cy5-labeled PPD (PPD-Cy5) nanomicelles were prepared and divided into 5 groups. Different amounts of glycerol and a certain volume of pure water or buffer were added to prepare PPD-Cy5 aqueous solutions with glycerol mass fractions of 0%, 2.5%, 5%, 7.5%, 10%, and 20%. C57 mice were then administered intranasally, and the brain fluorescence intensity was detected by a live fluorescence imaging system at certain time intervals.

[0037] As shown in Figure 3 , compared with the control group (glycerol mass fraction 0%), all concentrations of glycerol can significantly (P<0.05) promote the intranasal absorption of PPD, improve the nasal-brain delivery efficiency of nanomedicines, and delay the action time of the drugs after 1h of administration.

[0038] Preferably, the concentration of glycerol is 2.5-20%, further preferably 2.5-7.5%, and most preferably 5%.

[0039] Example 4 Glycerol hydrochloride promotes PEG-PLGA microspheres to enter the brain through the nose.

[0040] Cy5-labeled PPD (PPD-Cy5) nanomicelles were prepared and divided into 5 groups. Different amounts of glycerol and a certain volume of pure water or buffer were added to prepare PPD-Cy5 aqueous solutions with glycerol mass fractions of 0%, 2.5%, 5%, 7.5%, 10%, and 20%. C57 mice were then administered intranasally, and the brain fluorescence intensity was detected by a live fluorescence imaging system at certain time intervals.

[0041] As shown in Figure 4 , compared with the control group (glycerol mass fraction 0%), all concentrations of glycerol can significantly (P<0.05) promote the intranasal absorption of PPD, improve the nasal-brain delivery efficiency of nanomedicines, and delay the action time of the drugs after 1h of administration.

[0042] Preferably, the concentration of glycerol is 2.5-10%, further preferably 5-7.5%, and most preferably 7.5%.

[0043] Example 5 Glycerol promotes intranasal delivery of lentivirus into brain.

[0044] Lent-EF1a-P2A-luciferase-CMV-coGFP-P2A-Puro lentivirus was divided into 5 groups and added with different concentrations of glycerol phosphate buffer solution to prepare lentivirus suspensions with glycerol mass fractions of 0%, 2.5%, 5%, 7.5%, 10% and 20%, respectively, which were then intranasally administered to C57 mice. After 3 days, the bioluminescence intensity in the brain was detected by a live imaging system.

[0045] As shown in FIG. 2, compared with the control group (glycerol mass fraction 0%), glycerol of all concentrations significantly (P<0.05) promoted the intranasal delivery efficiency of lentivirus into the brain. Figure 5 Preferably, the glycerol concentration is 2.5-10%, further preferably 5-7.5%, and most preferably 7.5%.

[0046] Example 6 Glycerol promotes intranasal delivery of cells into brain.

[0047] Lent-EF1a-P2A-luciferase-CMV-coGFP-P2A-Puro lentivirus-transfected CTLL-2 cell suspension was prepared and glycerol solutions with mass fractions of 0%, 2.5%, 5%, 7.5%, 10% and 20% were prepared. Different concentrations of glycerol solution were intranasally administered to C57 mice, followed by immediate intranasal administration of T cell suspension. After 4 hours, the bioluminescence intensity in the brain was detected by a live fluorescence imaging system.

[0048] As shown in FIG. 4, compared with the control group (glycerol mass fraction 0%), glycerol of all concentrations extremely significantly (P<0.001) promoted the intranasal delivery efficiency of CTLL-2 cells into the brain.

[0049] Figure 6 Preferably, the glycerol concentration is 2.5-20%, further preferably 5-7.5%, and most preferably 7.5%.

[0050] Example 7 Glycerol promotes intranasal delivery of Herceptin into brain.

[0051] Cy5-labeled antibody-conjugated drug Herceptin was prepared and divided into 5 groups. Different amounts of glycerol were added to prepare drug solutions with glycerol mass fractions of 0%, 2.5%, 5%, 7.5%, 10% and 20%, respectively. Subsequently, C57 mice were intranasally administered with the drug solutions, and the fluorescence intensity in the brain was detected by a live fluorescence imaging system at certain time intervals.

[0052] As shown in FIG. 6, compared with the control group (glycerol mass fraction 0%), glycerol of all concentrations significantly (P<0.05) promoted the intranasal delivery efficiency of Herceptin into the brain.

[0053] Preferably, the glycerol concentration is 2.5-20%, further preferably 5-7.5%, and most preferably 7.5%. Figure 7 ​As shown, glycerol at all concentrations significantly (P<0.001) enhanced the nose-brain delivery efficiency of Herceptin compared to the control (glycerol mass fraction 0%) at 1 h and 2 h post-dose.

[0054] wherein the glycerol concentration is preferably 2.5-20%, further preferably 5-7.5%, most preferably 7.5%.

[0055] While embodiments of the application have been shown and described, it is to be understood that the application is not limited to these embodiments. Rather, it is the intention that modifications, changes, substitutions and variations be made to the embodiments without departing from the spirit and scope of the application, which is defined by the appended claims and their equivalents.

Claims

1. A nasal-to-brain drug delivery enhancer, characterized in that: It can be glycerol and its chemical derivatives, chemical isotope labels, condensates or salts.

2. The nasal-to-brain drug delivery enhancer according to claim 1, characterized in that: This includes triglycerides, glyceryl ethers, glyceryl phosphates, glyceryl amino acid salts, glycerols, glyceric acids, glyceryl acyl groups, glyceryl glycols, glyceryl stearates, glycerol, or mannitol.

3. The use of the promoter according to claim 1 or 2 in the preparation of nasal drops that improve nasal-brain delivery efficiency.

4. The use of the promoter according to claim 3 in the preparation of nasal drops with improved nasal-brain delivery efficiency, characterized in that: The promoter accounts for 0.01-40% of the mass fraction of the nasal drops.

5. The use of the promoter according to claim 4 in the preparation of nasal drops with improved nasal-brain delivery efficiency, characterized in that: The drug components in the nasal drops are any one or more of small molecule drugs, large molecule drugs, nano- or micron-sized drugs; When the drug component in the nasal drops is a small molecule drug, the mass fraction of the promoter is 5-10%; when the drug component in the nasal drops is a large molecule drug, the mass fraction of the promoter is 2.5-10%; when the drug component in the nasal drops is a nano or micron drug, the mass fraction of the promoter is 5-10%.

6. The use of the promoter according to claim 5 in the preparation of nasal drops with improved nasal-brain delivery efficiency, characterized in that: The small molecule drugs include mannitol, ibuprofen, acetaminophen, flunarizine hydrochloride, rizatriptan benzoate, naproxen, caffeine, diclofenac sodium, tramadol hydrochloride, aspirin, codeine phosphate, methadone hydrochloride, dihydroergotamine mesylate, butorphanol tartrate, zolmitriptan, sumatriptan, levetiracetam, carbamazepine, phenytoin sodium, lamotrigine, sodium valproate, gabapentin, oxcarbazepine, phenobarbital, topiramate, clonazepam, and midazolam. Diazepam, Lorazepam, Alprazolam, Buspirone Hydrochloride, Oxazepam, Midazolam, Amobarbital, Secobarbital, Flupentixol Melitracen, Estazolam, Clonazepam, Tandospirone Citrate, Nitrazepam, Triazolam, Zolpidem Tartrate, Zopiclone, Morphine, Difenidol Hydrochloride, Vitamin B1, Doxepin Hydrochloride, Ketamine, Risperidone, Olanzapine, Fluoxetine, Fluoxetine Hydrochloride, Tranexamic Acid, Ethamsylate, Tranexamic Acid, Desmopressin Acetate, Salt Doxorubicin, Pirarubicin, Mitomycin, Cyclophosphamide, Ifosfamide, Cisplatin, Carboplatin, Nedaplatin, Thiotepa, Capecitabine, Fluorouracil, Pemetrexed, Tegafur, Methotrexate, Raltitrexed, Actinomycin D, Pingyangmycin Hydrochloride, Vincristine Sulfate, Vincristine Sulfate, Vinorelbine Tartrate, Paclitaxel, Goserelin Acetate, Temozolomide, Ribavirin, Acyclovir, Ganciclovir, Ceftriaxone Sodium, Cefotaxime, Vancomycin, Isoniazid Rifampin, pyrazinamide, donepezil, donepezil hydrochloride, rivastigmine, galantamine hydrobromide, huperzine A, memantine, piracetam, dopacarzine, carbidopa, levodopa, levodopa methyl ester, levodopa ethyl ester, entacapone, tocapone, selegiline, selegiline hydrochloride, rasagiline, coenzyme Q10, pramipexole, pramipexole hydrochloride, ropinirole, pibediil, rotigotine, apomorphine, amantadine, and trihexyphenidyl.

7. The use of the promoter according to claim 5 in the preparation of nasal drops with improved nasal-brain delivery efficiency, characterized in that: The macromolecular drugs include one or more of the following: peptides, proteins, antibody-drug conjugates, peptide-drug conjugates, deoxyribonucleic acid, ribonucleic acid, microRNA, or small interfering RNA.

8. The use of the promoter according to claim 5 in the preparation of nasal drops with improved nasal-brain delivery efficiency, characterized in that: The nano and micro drugs include one or more of the following: liposomes, nanocapsules, nanospheres, microcapsules, microspheres, polymer nanomedicines, metal nanomedicines, non-metal nanomedicines, nanosuspensions, viruses, exosomes, biomimetic nanosystems with cell membrane structures, biomimetic nanosystems with bacterial membrane structures, and nanodrug delivery systems formed by using the above nanostructures; wherein, cells and bacteria include stem cells, immune cells, blood cells, bacteria, and fungi.

9. The use of the promoter according to claim 5 in the preparation of nasal drops with improved nasal-brain delivery efficiency, characterized in that: The nasal drops also include excipients, which include one or more of the following: purified water, amines, oils, esters, salts, and fragrances.

10. The use of the promoter according to claim 9 in the preparation of nasal drops with improved nasal-brain delivery efficiency, characterized in that: The dosage forms of the nasal drops include solutions, colloidal solutions, emulsions, semi-solid matrices, and suspensions.

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