Nerve disease medicine composition as well as preparation method and application thereof

Abstract

The invention discloses a pharmaceutical composition of edaravone, borneol and blumea balsamifera or active ingredients thereof, and a preparation, a preparation method and application of the pharmaceutical composition, in free radical scavenging and ALS pharmacodynamic tests, when the weight ratio of the borneol and the blumea balsamifera in the three active ingredients is 10%-35%, and the weight ratio of the blumea balsamifera in the borneol is 0.05%-1.5%, the pharmaceutical effect is optimal; the blumea balsamifera can offset the anti-inflammatory effect of the dextroborneol when the concentration of the blumea balsamifera is higher than or lower than the concentration range, and the effectiveness is better when the concentration of the blumea balsamifera is within the range of the patent; the L-borneol has low dose dependence on the enhancement effect of the permeability of the blood brain barrier, and the transmembrane transport of the medicine can be obviously promoted within the concentration range of 0.05-1.5%. In addition, volatilization of borneol and borneol tablets or active ingredients thereof in the prescription can be effectively inhibited, the problems that the feeding amount is difficult to control in the production process of the products, the content is unstable during storage and the like, which puzzle the industry all the time, are well solved, and the process is simple and controllable.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical compositions for neurological diseases, and more particularly, to a composition of edaravone, borneol, blumea balsamifera or its active ingredients, and a preparation method and use thereof. Background Art

[0002] Edaravone, namely 3-methyl-1-phenyl-2-pyrazolin-5-one, is a brain protectant with the chemical formula C 10 H 10 N2O, mainly used as a free radical scavenger. It has the advantages of wide distribution, short half-life, safety, low toxicity, etc., and is an effective first-line therapeutic drug for clinical ischemic stroke. It is reported that edaravone can also slow down the progression of ALS symptoms and neuronal degeneration in mutant SOD1G93A mice (Exp Neurol. 2008, 213(2):448-55). Patent WO2005 / 075434 discloses the application of 3-methyl-1-phenyl-2-pyrazolin-5-one in the treatment of amyotrophic lateral sclerosis.

[0003] Borneol, also known as 2-camphanol and borneol, is a terpene. It is a white translucent hexagonal crystal with an odor like camphor. Dextro-2-camphanol is a leafy or hexagonal plate crystal, which forms camphor when oxidized. It can be prepared by reducing camphor with metallic sodium in an ethanol solution or by esterifying pinene with oxalic acid in the presence of a catalyst and then hydrolyzing. It is widely used in the preparation of rosemary and lavender type fragrances and in traditional Chinese medicine, and among them, (+)-2-camphanol is also known as dextrorotatory borneol. Dextrorotatory borneol, namely (+)-2-camphanol, is the main component of the commonly used traditional Chinese medicine natural borneol. Research shows that natural borneol has a strong anti-inflammatory effect, probably by inhibiting the activation of the transcription factor NF-κB, inhibiting the expression of inflammatory proteins (iNOS and COX-2) and the release of inflammatory cytokines (TNF-α, IL-1β, IL-6, etc.), thereby playing a role in cell protection.

[0004] Patent 201680029994.7 discloses that a composition of 3-methyl-1-phenyl-2-pyrazolin-5-one and borneol with a mass ratio of 4:1 has a synergistic effect in the treatment of amyotrophic lateral sclerosis and related disorders. There is no report on the synergistic efficacy of blumea balsamifera combined with the above components.

[0005] Blumea balsamifera, also known as levoborneol, is derived from the plant Blumea balsamifera DC. Its effects on the central nervous system have the characteristics of multiple targets and multiple mechanisms. It has both therapeutic potential such as neuroprotection, anti-inflammatory and antioxidant effects, and also has a dose-dependent dual regulatory effect. Its effects on the central nervous system are mainly reflected in the following aspects, which can be summarized in combination with research progress and clinical applications as follows: 1. Neuroprotection and antioxidant effects (-)-borneol can protect the central nervous system by inhibiting neuronal apoptosis and scavenging free radicals. Research has shown that it exhibits anti-apoptotic and antioxidant effects in human neuroblastoma cells (SH-SY5Y), possibly by regulating apoptosis-related proteins (such as Bax / Bcl-2) and antioxidant enzyme activities.

[0006] 2. Regulating the activity of GABA receptors (-)-borneol has a highly positive regulatory effect on γ-aminobutyric acid (GABA) receptors (EC50 = 237 μM), and can enhance the opening of GABA-mediated chloride channels, thereby inhibiting the overexcitation of the central nervous system. This mechanism makes it potentially have the potential for sedation, anti-convulsion and anti-anxiety.

[0007] 3. Bidirectional regulation of central nervous function (-)-borneol can have a bidirectional regulatory effect on the central nervous system through the olfactory pathway: Wakefulness-promoting effect: At low concentrations, it stimulates olfactory receptors and refreshes the mind and improves cognitive functions (such as memory and attention) through the olfactory-limbic system pathway.

[0008] Sedative effect: At high concentrations, it inhibits the excessive release of neurotransmitters, reduces central excitability, and relieves anxiety and insomnia.

[0009] 4. Improving the permeability of the blood-brain barrier The small molecular characteristics of (-)-borneol make it easy to penetrate the blood-brain barrier, and it can promote other drug components to enter the central nervous system, improving the efficacy of combined medications. For example, when combined with moschus, it can enhance the effect of resuscitating the patient from unconsciousness.

[0010] 5. Anti-inflammatory and antiviral effects (-)-borneol relieves neuroinflammation in cerebral ischemia and neurodegenerative diseases (such as Alzheimer's disease) by inhibiting inflammatory signaling pathways such as NF-κB and reducing the release of inflammatory factors (such as interleukin) in the central nervous system. In addition, its antiviral activity may indirectly protect the central nervous system from virus invasion.

[0011] Patent CN200980100527.9 discloses the application of a specific proportion composition of edaravone and (+)-2-borneol injection in the preparation of drugs for treating cerebrovascular diseases, especially ischemic cerebrovascular diseases. This composition shows better pharmacodynamic results compared with edaravone injection. The currently marketed products of edaravone and (+)-2-borneol are only injections, and there is still a lack of oral preparations suitable for patients with dysphagia.

[0012] Patent CN201780048512.7 discloses an edaravone and (+)-2-bornanol compound sublingual tablet. This sublingual tablet has good effects and can solve the volatilization of 2-bornanol. However, during the preparation process of this sublingual tablet, after mixing 2-bornanol with fillers and binders, it is freeze-dried and then pressed into tablets. The process steps are complex. Additionally, during the freeze-drying process, it is difficult to avoid the volatilization of 2-bornanol, resulting in a decrease in the content of intermediates, affecting the accurate feeding during production and the drug content during product storage.

[0013] The present invention provides a pharmaceutical composition containing three active ingredients, edaravone, borneol, and moxa leaf, and its preparation method, preparation, and clinical use, which have not been reported before. Summary of the Invention

[0014] The present invention provides a borneol-based pharmaceutical composition for treating stroke and its sequelae, neurodegeneration, and cardiovascular and cerebrovascular diseases, and its preparation method and uses, in particular, a pharmaceutical composition containing edaravone, borneol, and moxa leaf or their active ingredients for treating stroke and amyotrophic lateral sclerosis, and its preparation and preparation method.

[0015] In the free radical scavenging and ALS pharmacodynamic experiments of the present invention, when this composition is administered orally, sublingually, orally, or by injection, in the free radical scavenging and ALS pharmacodynamic experiments, when the weight ratios of borneol and moxa leaf among the three active ingredients are 10%-35% and the weight ratio of moxa leaf to borneol is 0.05-1.5%, the pharmacodynamic effects are all optimal; and it has a very good effect in terms of anti-inflammatory effect. When moxa leaf is higher or lower than this concentration range, it will offset the anti-inflammatory effect of camphene. The effectiveness is better within the scope of this patent; the enhancing effect of l-borneol on the blood-brain barrier permeability shows low-dose dependence, and the drug transmembrane transport can be significantly promoted within the concentration range of 0.05%-1.5%; animal experiments show that 0.5% l-borneol can increase the brain concentration of edaravone by about 1.8 times, which matches the range of the increase in blood drug concentration required clinically. The above conclusions of the present invention exceed the current existing cognition, indicating that the three active ingredients of the present invention form a triple mechanism synergism in antioxidant, anti-inflammatory, and increasing blood-brain barrier permeability within the scope of this patent, greatly ensuring the good curative effect of the products of the present invention in the treatment of stroke.

[0016] In addition, borneol substances are prone to volatilization, which is a difficult problem that is not easily solved during the preparation process or storage process. During the process of screening the prescription by the inventor of the present invention, numerous excipients were screened. It was unexpectedly found that glyceryl behenate or / and stearic acid, which is usually used as a lubricant, flavoring agent, or sustained-release matrix, can effectively inhibit the volatilization of borneol in the prescription, and well solve the problems that have always troubled the industry, such as the control of the feeding amount during the production of borneol-containing products and the content stability during product storage.

[0017] Particularly importantly, in the research of the present invention, it was also unexpectedly found that the sublingual mucosal administration of this composition can achieve the same exposure as the injection solution. Combining the convenience of sublingual oral mucosal administration, it indicates that the sublingual mucosal administration route is superior. For the already marketed edaravone and dexborneol injection solution, it is not very convenient for patients to use, especially they cannot self-administer, which is even more inconvenient when an attack occurs or medication is needed at home or during a journey. The present invention provides strong support for the development of flexible and convenient non-injection dosage forms, especially sublingual preparations and orally disintegrating tablets.

[0018] In some embodiments, the present invention provides a pharmaceutical composition containing the active ingredients edaravone, borneol, and artemisia argyi leaf oil, characterized in that the proportion of borneol and artemisia argyi leaf oil in the active ingredients is 10% - 35%, preferably 15% - 25%; the proportion of artemisia argyi leaf oil in the weight of borneol is 0.02% - 2.0%, preferably 0.05% - 1.5%.

[0019] In some embodiments, the borneol is natural borneol, (+)-2-camphanol, or various isomers or their ester derivatives in pharmacy; preferably (+)-2-camphanol.

[0020] In some embodiments, the artemisia argyi leaf oil includes natural artemisia argyi leaf oil, (-)-borneol, or various isomers or their ester derivatives in pharmacy; preferably (-)-borneol.

[0021] In some embodiments, the composition further includes pharmaceutically acceptable related excipients.

[0022] In some embodiments, the composition preparations include pharmaceutical dosage forms such as tablets, capsules, oral solutions, membranes, granules, injections, orally disintegrating tablets, buccal tablets, sublingual membranes, buccal tablets, sublingual tablets, etc.

[0023] In some embodiments, the pharmaceutically acceptable excipients include one or a combination of stabilizers, fillers, disintegrants, binders, flavoring agents, and lubricants.

[0024] In some embodiments, the stabilizer is selected from the combination of one or two of glyceryl behenate or stearic acid.

[0025] In some embodiments, the weight ratio of borneol to the stabilizer is 10:1 to 1:10, preferably 5:1 to 1:5.

[0026] In some embodiments, when using glyceryl behenate and stearic acid as stabilizers simultaneously, the weight ratio of borneol:glyceryl behenate:stearic acid is 4:2:1 to 1:5:5.

[0027] In some embodiments, the filler is selected from one or more of mannitol, lactose, microcrystalline cellulose, corn starch, hydrolyzed oligostarch, polyvinyl acetate, and acrylic resin; optionally, the weight percentage of the filler is 10% to 70%, preferably 20% to 50%, and more preferably 30% to 40%.

[0028] In some embodiments, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, and sodium carboxymethyl starch, preferably one or a combination selected from cross-linked sodium carboxymethyl cellulose and cross-linked povidone; Optionally, the weight percentage of the disintegrant is 1% to 20%, preferably 5% to 15%.

[0029] In some embodiments, the flavoring agent includes a sweetening agent and a flavor. Among them, the sweetening agent is one or more of sucrose, glucose, sodium cyclamate, stevioside, dextrin, sodium saccharin, xylose, aspartame, sucralose, and acesulfame potassium, preferably one or more of sucralose, aspartame, and dextrin, and more preferably sucralose; Optionally, the weight percentage of the sweetening agent is 0.1% - 5%, preferably 1% - 3%.

[0030] In some embodiments, the lubricant is selected from one or more of magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate; Optionally, the weight percentage of the lubricant is 0.2% - 5%, preferably 0.5% - 3%.

[0031] In some embodiments, the pharmaceutically acceptable excipients of the injection preparation include at least one of a solubilizer, an antioxidant, an osmotic pressure regulator, and a pH regulator.

[0032] In some embodiments, the solubilizer is selected from at least one of ethanol, propylene glycol, isopropanol, or polyethylene glycol, preferably propylene glycol.

[0033] In some embodiments, from the stability data before and after sterilization, it shows that the antioxidant effects of sodium sulfite, sodium metabisulfite, and sodium bisulfite are better than those of other antioxidants such as vitamin C, etc., and sodium bisulfite is preferred.

[0034] In some embodiments, the osmotic pressure regulator is selected from at least one of sodium chloride and glucose.

[0035] In some embodiments, the pH regulator is selected from at least one of sulfuric acid, hydrochloric acid, sodium hydroxide, disodium hydrogen phosphate, or sodium bicarbonate.

[0036] In some embodiments, the process uses autoclaving, and the sterilization conditions are as follows: when the sterilization temperature is 115°C ± 3°C, the sterilization time is 30 - 48 minutes; or when the sterilization temperature is 121°C ± 3°C, the sterilization time is 8 - 16 minutes.

[0037] In some embodiments, nitrogen filling protection is required during the preparation process, the dissolved oxygen content is controlled at ≤4.0 mg / L, and the residual oxygen content in the headspace during filling is controlled at ≤3.0%.

[0038] The use of the pharmaceutical composition described in the present invention in the preparation of drugs for treating stroke and its sequelae, neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, as well as cardiovascular and cerebrovascular diseases, diabetic retinopathy, and diabetic peripheral neuropathy, especially in the preparation of drugs for treating stroke and / or amyotrophic lateral sclerosis.

[0039] For the convenience of accurately dosing the active ingredients and ensuring stable and balanced efficacy, the above weight ratios are calculated based on the main active ingredients (+)-2-borneol and l-borneol in borneol and Artemisia argyi leaf. If the starting materials are borneol and Artemisia argyi leaf herbs, they need to be converted according to the content of their main components (+)-2-borneol and l-borneol in the herbs; if the starting borneol and Artemisia argyi leaf are extracts or synthetic products of their main components (+)-2-borneol and l-borneol, they also need to be converted according to the measured data of their content.

[0040] Considering the characteristics of different dosage forms, the starting materials for the injectable dosage form should be extracts or synthetic products of the high-purity active ingredients (+)-2-borneol and l-borneol in borneol and Artemisia argyi leaf, and the purity should be above 98.0%. It can also be (+)-2-camphanol containing the corresponding content of l-borneol, and there is no need to separately add l-borneol; the starting materials for the non-injectable dosage form can either be extracts or synthetic products of the high-purity active ingredients (+)-2-borneol and l-borneol in borneol and Artemisia argyi leaf, or can be added in the form of borneol and Artemisia argyi leaf herbs. Similarly, it can also be (+)-2-camphanol containing the corresponding content of l-borneol, and there is no need to separately add l-borneol; to prevent the volatilization of (+)-2-borneol and l-borneol, esters of lower fatty acids such as formic acid, acetic acid, and ethyl propionate of the two can also be used as starting materials. Detailed implementation manners

[0041] The present invention will be further described below in conjunction with specific embodiments, and the advantages and characteristics of the present invention will become clearer as the description progresses. For those not specified in the embodiments, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. For reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0042] The embodiments of the present invention are merely exemplary and do not constitute any limitation to the scope of the present invention. Those skilled in the art should understand that details and forms of the technical solutions of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but such modifications and replacements all fall within the protection scope of the present invention.

Claims

1. A pharmaceutical composition containing the active ingredients edaravone, borneol and borneol syntheticum, characterized in that The weight proportion of borneol and borneol syntheticum in the three active ingredients is 10% - 35%, preferably 15% - 25%; borneol syntheticum accounts for 0.02% - 2.0% of the weight of borneol, preferably 0.05% - 1.5%.

2. The pharmaceutical composition according to claim 1, characterized in that The borneol includes natural borneol, (+)-2-camphanol or various pharmaceutically isomers thereof and their ester derivatives; preferably it is (+)-2-camphanol.

3. The pharmaceutical composition according to claim 1, characterized in that The borneol syntheticum includes natural borneol syntheticum, borneol or various pharmaceutically isomers thereof and their ester derivatives; preferably it is borneol.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The composition further includes pharmaceutically acceptable related excipients.

5. The pharmaceutical composition according to claims 1 to 3, characterized in that The composition preparations include pharmaceutical dosage forms such as tablets, capsules, oral solutions, films, granules, injections, orally disintegrating tablets, buccal tablets, sublingual films, buccal tablets, sublingual tablets, etc.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that, The pharmaceutically acceptable excipients of the solid preparations include one or several combinations of stabilizers, fillers, disintegrants, binders, flavoring agents and lubricants.

7. The pharmaceutical composition according to claim 6, wherein The stabilizer is selected from one or a combination of two of glyceryl behenate or stearic acid.

8. The pharmaceutical composition according to any one of claims 6 to 7, characterized in that, The weight ratio of the borneol to the stabilizer is 10:1 - 1:10, preferably 5:1 - 1:

5.

9. The pharmaceutical composition according to any one of claims 7 to 8, characterized in that, When using glyceryl behenate and stearic acid as stabilizers simultaneously, the weight ratio of borneol:glyceryl behenate:stearic acid is 4:2:1 - 1:5:

5.

10. The pharmaceutical composition according to claim 6, characterized in that, The filler is selected from one or several of mannitol, lactose, microcrystalline cellulose, corn starch, hydrolyzed oligosaccharides of starch, polyvinyl acetate, acrylic resin; optionally, the filler accounts for 10% - 70% of the total pharmaceutical composition by weight, preferably 20% - 50%, and further preferably 30% - 40%.

11. The pharmaceutical composition according to claim 6, wherein The disintegrant is selected from one or several of low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, preferably one or a combination selected from croscarmellose sodium and crospovidone; the disintegrant accounts for 1% - 20% of the total pharmaceutical composition by weight, preferably 5 - 15%.

12. The pharmaceutical composition according to claim 6, wherein The flavoring agent includes a sweetening agent and a fragrance. Among them, the sweetening agent is one or several of sucrose, glucose, sodium cyclamate, stevioside, dextrin, sodium saccharin, xylose, aspartame, sucralose, acesulfame potassium, preferably one or several of sucralose, aspartame, dextrin, and further preferably sucralose; the sweetening agent accounts for 0.1% - 5% of the total pharmaceutical composition by weight, preferably 1% - 3%.

13. The pharmaceutical composition according to claim 6, wherein The lubricant is selected from one or several of magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate; the lubricant accounts for 0.2% - 5% of the total pharmaceutical composition by weight, preferably 0.5% - 3%.

14. The preparation method of the pharmaceutical composition according to any one of claims 1 to 13, characterized in that, The preparation process steps include direct mixing, melt granulation or wet granulation, and tableting steps.

15. The pharmaceutical composition according to any one of claims 4-5, characterized in that, The pharmaceutically acceptable excipients of the injection administration preparation include at least one of solubilizers, antioxidants, osmotic pressure regulators, pH regulators.

16. The injection according to claim 15, characterized in that, The solubilizer is selected from at least one of ethanol, propylene glycol, isopropyl alcohol or polyethylene glycol, preferably propylene glycol.

17. The injection according to claim 15, characterized in that, The antioxidant is selected from one or two of sodium sulfite, sodium metabisulfite, sodium bisulfite, preferably sodium bisulfite.

18. The injection according to claim 15, wherein, The osmotic pressure regulator is selected from at least one of sodium chloride and glucose.

19. The injection according to claim 15, characterized in that, The pH regulator is selected from at least one of sulfuric acid, hydrochloric acid, sodium hydroxide, disodium hydrogen phosphate or sodium bicarbonate.

20. The preparation method of the injection according to claims 15 to 19, characterized in that, The process adopts a terminal sterilization process, and the sterilization conditions are: when the sterilization temperature is 115°C ± 3°C, the sterilization time is 30 - 48 minutes; or when the sterilization temperature is 121°C ± 3°C, the sterilization time is 8 - 16 minutes.

21. The preparation method according to claims 15 to 19, characterized in that, During the preparation process, nitrogen filling protection is required, the dissolved oxygen content is controlled at ≤ 4.0 mg / L, and the residual oxygen content in the headspace during filling is controlled at ≤ 3.0%.

22. The use of the pharmaceutical composition according to any one of claims 1 to 21 in the preparation of a medicament for treating stroke and its sequelae, neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, as well as cardiovascular and cerebrovascular diseases, diabetic retinopathy, diabetic peripheral neuropathy, preferably for the preparation of a medicament for treating stroke and / or amyotrophic lateral sclerosis.