CN115804754A - Morphine nasal spray and preparation method thereof - Google Patents
Morphine nasal spray and preparation method thereof Download PDFInfo
- Publication number
- CN115804754A CN115804754A CN202211637089.3A CN202211637089A CN115804754A CN 115804754 A CN115804754 A CN 115804754A CN 202211637089 A CN202211637089 A CN 202211637089A CN 115804754 A CN115804754 A CN 115804754A
- Authority
- CN
- China
- Prior art keywords
- morphine
- nasal spray
- gas
- concentration
- absorption enhancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 title claims abstract description 132
- 239000007922 nasal spray Substances 0.000 title claims abstract description 97
- 229940097496 nasal spray Drugs 0.000 title claims abstract description 96
- 229960005181 morphine Drugs 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 41
- 238000010521 absorption reaction Methods 0.000 claims abstract description 37
- 229940079593 drug Drugs 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000000022 bacteriostatic agent Substances 0.000 claims abstract description 26
- 239000003623 enhancer Substances 0.000 claims abstract description 26
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 21
- 239000002562 thickening agent Substances 0.000 claims abstract description 21
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 20
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 19
- 230000003204 osmotic effect Effects 0.000 claims abstract description 19
- 239000000463 material Substances 0.000 claims abstract description 6
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical group O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 229960004715 morphine sulfate Drugs 0.000 claims description 57
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 claims description 57
- 239000000243 solution Substances 0.000 claims description 43
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- 239000001116 FEMA 4028 Substances 0.000 claims description 15
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 15
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 15
- 229960004853 betadex Drugs 0.000 claims description 15
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 14
- 229920003082 Povidone K 90 Polymers 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000012047 saturated solution Substances 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 238000009210 therapy by ultrasound Methods 0.000 claims description 6
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 5
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 4
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 4
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 3
- 239000003002 pH adjusting agent Substances 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229920003081 Povidone K 30 Polymers 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229960004926 chlorobutanol Drugs 0.000 claims description 2
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- 229960005195 morphine hydrochloride Drugs 0.000 claims 1
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 claims 1
- 239000003895 organic fertilizer Substances 0.000 claims 1
- 238000002604 ultrasonography Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 16
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 4
- 230000002421 anti-septic effect Effects 0.000 abstract description 4
- 241000700159 Rattus Species 0.000 description 30
- 238000002474 experimental method Methods 0.000 description 28
- 230000000052 comparative effect Effects 0.000 description 20
- 238000012360 testing method Methods 0.000 description 15
- 239000008280 blood Substances 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 14
- 239000008213 purified water Substances 0.000 description 10
- 230000003385 bacteriostatic effect Effects 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000011521 glass Substances 0.000 description 6
- 208000024714 major depressive disease Diseases 0.000 description 6
- 210000002850 nasal mucosa Anatomy 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 206010012335 Dependence Diseases 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 description 3
- 230000000994 depressogenic effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000003928 nasal cavity Anatomy 0.000 description 2
- 235000010241 potassium sorbate Nutrition 0.000 description 2
- 239000004302 potassium sorbate Substances 0.000 description 2
- 229940069338 potassium sorbate Drugs 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 208000007415 Anhedonia Diseases 0.000 description 1
- 206010012374 Depressed mood Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010048010 Withdrawal syndrome Diseases 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229940067596 butylparaben Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000008642 heat stress Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000000110 microvilli Anatomy 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 238000012346 open field test Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a morphine nasal spray and a preparation method thereof. The morphine nasal spray is prepared from the following raw and auxiliary materials: main medicine, absorption enhancer, bacteriostatic agent, antioxidant, thickener, osmotic pressure regulator and water; the concentration of each component in the morphine nasal spray is as follows: 1mg/mL-10mg/mL of main drug, 0.01mg/mL-0.1mg/mL of absorption enhancer, 0.000005mg/mL-0.01mg/mL of bacteriostatic agent, 0.0001mg/mL-0.01mg/mL of antioxidant, 0.005mg/mL-0.1mg/mL of thickening agent and 0.2mg/mL-1.2mg/mL of osmotic pressure regulator; the main drug is morphine or salt thereof; the absorption enhancer is cyclodextrin. The nasal spray has good absorption effect, good stability, good antibacterial and antiseptic effects, and can effectively improve the effect of morphine on treating depression.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a morphine nasal spray and a preparation method thereof.
Background
The inventor finds that morphine has a good effect on common depression and even refractory depression through previous team research, and can change symptoms of depression, such as low mood, weight loss and the like of a sick rat.
Nasal Drug Delivery System (NDDS) refers to a formulation that is administered in the nasal cavity and absorbed through the nasal mucosa to exert a local or systemic therapeutic effect. The epithelial cells on the surface layer of the nasal mucosa are provided with a plurality of microvilli similar to the villi of the small intestine, so that the effective area of medicament absorption can be increased, and the epithelial lower layer of the nasal mucosa is provided with abundant capillaries and lymphatic capillaries, so that the medicament can be quickly absorbed and enter the circulation. The nasal cavity has an absorption channel through which water-soluble drugs can diffuse (one-way flow from the lumen into the blood). The nasal mucosa has water channels with smaller pore size and rich content, and the water channels are distributed 2 times of rectum and 3 times of jejunum, so that the water-soluble substance is very easy to be absorbed by the nasal mucosa.
Nasal administration is a very good way of delivering drugs directly to the blood circulation, avoiding intravenous cannulation, but enabling rapid and efficient drug delivery. For many drugs administered nasally, the rate of drug absorption, and blood drug levels are comparable to intravenous administration, and are generally superior to subcutaneous or intramuscular administration. In addition, nasal administration also has the advantages of being relatively simple, easy to use, safe and convenient, the mode of administration is substantially painless, and the administration can be realized without aseptic technique, intravenous catheters or other invasive devices. Because the nasal mucosa is close to the brain, after the nasal administration, the drug concentration of the drug in cerebrospinal fluid can exceed the drug concentration in plasma, and the nasal administration can quickly reach the drug concentration for treating the brain and spinal cord.
However, there is no report in the literature on the development of morphine as a nasally administrable formulation for the treatment of depression and even treatment-resistant depression.
Disclosure of Invention
Based on the above, the invention aims to provide a morphine nasal spray which has the advantages of good absorption effect, good stability and good bacteriostatic and antiseptic effects, and can effectively improve the effect of morphine on treating depression.
In order to achieve the purpose, the invention comprises the following technical scheme.
The morphine nasal spray is prepared from the following raw and auxiliary materials: main medicine, an absorption enhancer, a bacteriostatic agent, an antioxidant, a thickening agent, an osmotic pressure regulator and water;
the concentration of each component in the morphine nasal spray is as follows: 1mg/mL-10mg/mL of main drug, 0.01mg/mL-0.1mg/mL of absorption enhancer, 0.000005mg/mL-0.01mg/mL of bacteriostatic agent, 0.0001mg/mL-0.01mg/mL of antioxidant, 0.005mg/mL-0.1mg/mL of thickening agent and 0.2mg/mL-1.2mg/mL of osmotic pressure regulator;
the main drug is morphine or salt thereof; the absorption enhancer is cyclodextrin.
In some of these embodiments, the primary agent is selected from at least one of morphine sulfate, a hydrochloride salt of morphine, and a citrate salt of morphine.
In some of these embodiments, the absorption enhancer is dimethyl- β -cyclodextrin and/or hydroxypropyl- β -cyclodextrin.
In some of these embodiments, the absorption enhancer is dimethyl- β -cyclodextrin.
In some of these embodiments, the bacteriostatic agent is selected from at least one of benzalkonium chloride, ethylparaben, chlorobutanol, and butyl paraben.
In some of these embodiments, the antioxidant is selected from at least one of EDTA-2Na, sodium metabisulfite, and citric acid.
In some of these embodiments, the thickening agent is selected from at least one of povidone K90, povidone K30, methylcellulose, and polyethylene glycol 400.
In some of these embodiments, the osmolality adjusting agent is selected from at least one of sodium chloride, glycerol, and glucose.
In some of these embodiments, the concentration of the base drug in the morphine nasal spray is 2mg/mL to 6mg/mL.
In some of these embodiments, the concentration of the principal agent in the morphine nasal spray is 3mg/mL to 5mg/mL.
In some embodiments, the concentration of the principal agent in the morphine nasal spray is 3.5mg/mL to 4.5mg/mL.
In some of these embodiments, the concentration of the absorption enhancer in the morphine nasal spray is from 0.02mg/mL to 0.08mg/mL.
In some of these embodiments, the concentration of the absorption enhancer in the morphine nasal spray is from 0.04mg/mL to 0.06mg/mL.
In some embodiments, the bacteriostatic agent is present in the morphine nasal spray at a concentration of 0.00005mg/mL to 0.001mg/mL.
In some embodiments, the bacteriostatic agent is present in the morphine nasal spray at a concentration of 0.00008mg/mL to 0.001mg/mL.
In some embodiments, the concentration of the bacteriostatic agent in the morphine nasal spray is 0.00009mg/mL to 0.00012mg/mL.
In some of these embodiments, the concentration of the antioxidant in the morphine nasal spray is from 0.0008mg/mL to 0.0012mg/mL.
In some of these embodiments, the concentration of the thickener in the morphine nasal spray is from 0.01mg/mL to 0.03mg/mL.
In some of these embodiments, the concentration of the osmolality adjusting agent in the morphine nasal spray is from 0.7mg/mL to 0.9mg/mL.
In some of these embodiments, the concentration of each component in the morphine nasal spray is as follows: 3.5mg/mL-4.5mg/mL of main drug, 0.04mg/mL-0.06mg/mL of absorption enhancer, 0.00009mg/mL-0.00012mg/mL of bacteriostatic agent, 0.0009mg/mL-0.0011mg/mL of antioxidant, 0.015mg/mL-0.025mg/mL of thickening agent and 0.75mg/mL-0.85mg/mL of osmotic pressure regulator;
the main drug is morphine sulfate; the absorption enhancer is dimethyl-beta-cyclodextrin; the bacteriostatic agent is benzalkonium chloride; the antioxidant is EDTA-2Na; the thickening agent is povidone K90; the osmotic pressure regulator is sodium chloride.
In some embodiments, the morphine nasal spray further comprises a proper amount of pH regulator to regulate the pH of the morphine nasal spray to 5.5-6.5.
In some of these embodiments, the pH adjusting agent is a 1N sulfuric acid solution or a 1N sodium hydroxide solution.
The invention also provides a preparation method of the morphine nasal spray, which comprises the following technical scheme.
The preparation method of the morphine nasal spray comprises the following steps:
1) Adding the absorption enhancer into water, and stirring to prepare a saturated solution;
2) Adding the main medicine into the saturated solution obtained in the step 1), and performing ultrasonic treatment at normal temperature to obtain a solution 1;
3) Adding the bacteriostatic agent, the antioxidant, the thickening agent and the osmotic pressure regulator into a proper amount of water, and stirring until the bacteriostatic agent, the antioxidant, the thickening agent and the osmotic pressure regulator are completely dissolved to obtain a solution 2;
4) And (3) stirring and mixing the solution 1 and the solution 2 uniformly, and adding a pH regulator to regulate the pH value to obtain the product.
In some of these embodiments, the sonication time is between 0.5h and 2h.
Compared with the prior art, the invention has the following beneficial effects:
the morphine nasal spray is prepared by taking a certain amount of cyclodextrin (more preferably dimethyl-beta-cyclodextrin) as an absorption enhancer and matching with a certain amount of morphine or salt thereof, a bacteriostatic agent, an antioxidant, a thickening agent, an osmotic pressure regulator and water, and has good absorption effect, so that the treatment effect of morphine on depression, particularly on major depression and treatment-resistant depression, can be effectively improved. In addition, the morphine nasal spray has good stability, good bacteriostatic and preservative effects, no addiction, good safety and no toxic or side effect, and provides a therapeutic medicinal preparation with good curative effect and high safety for depression patients.
Furthermore, the stability and the bacteriostatic and antiseptic effects of the morphine nasal spray can be further improved by further optimizing auxiliary materials such as bacteriostatic agents and the like, so that the stability and the bacteriostatic and antiseptic effects of the morphine nasal spray prepared by the invention are more excellent, and the morphine nasal spray is favorable for long-time storage and use.
The preparation method of the morphine nasal spray provided by the invention has the advantages of simple process, easy control and contribution to industrial production.
Drawings
Fig. 1 is a graph comparing the blood concentration in example 2.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
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.
The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusions. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to only those steps or modules listed, but may alternatively include other steps not listed or inherent to such process, method, article, or device.
The "plurality" referred to in the present invention means two or more. "and/or" describes the association relationship of the associated objects, meaning that there may be three relationships, e.g., a and/or B, which may mean: a exists alone, A and B exist simultaneously, and B exists alone. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
The following are specific examples.
EXAMPLE 1 preparation of morphine sulfate nasal spray
The prescription of the morphine sulfate nasal spray of the embodiment is as follows:
TABLE 1
Name of raw and auxiliary materials | Effects in the prescription | Amount of the composition |
Morphine sulfate | Main drug | 400mg |
Dimethyl-beta-cyclodextrin | Promoting absorption | 4mg |
Benzalkonium chloride | Preservative/bacteriostatic agent | 0.01mg |
EDTA-2Na | Antioxidant agent | 0.1mg |
Povidone K90 | Thickening agent | 2mg |
Sodium chloride | Osmotic pressure regulator | 80mg |
Purified water | Solvent(s) | Adding to 100ml |
The preparation method comprises the following steps:
adding dimethyl-beta-cyclodextrin into purified water, stirring to prepare a saturated solution, adding morphine sulfate into the system, and performing ultrasonic treatment for 75min at normal temperature (25-30 ℃) to obtain a solution 1; adding benzalkonium chloride, EDTA-2Na, PVP K90 and sodium chloride into a proper amount of purified water, and stirring until the benzalkonium chloride, the EDTA-2Na, the PVP K90 and the sodium chloride are completely dissolved to obtain a solution 2; uniformly stirring and mixing the solution 1 and the solution 2, then adding a proper amount of 1N sulfuric acid solution or 1N sodium hydroxide solution, adjusting the pH value to 6, and filling the obtained solution into brown glass bottle containers; then a quantitative pump is installed to obtain the morphine sulfate nasal spray with the mass concentration of 4 mg/ml.
Comparative example 1 preparation of morphine sulfate nasal spray
The prescription of the morphine sulfate nasal spray of the comparative example is as follows:
TABLE 2
Name of raw and auxiliary materials | Effects in the prescription | Dosage of |
Morphine sulfate | Main medicine | 400mg |
Benzalkonium chloride | Preservative/bacteriostatic agent | 0.01mg |
EDTA-2Na | Antioxidant agent | 0.1mg |
Povidone K90 | Thickening agent | 2mg |
Sodium chloride | Osmotic pressure regulator | 80mg |
Purified water | Solvent(s) | Adding to 100ml |
The preparation method comprises the following steps:
morphine sulfate is added into purified water, and the mixture is subjected to ultrasonic treatment for 75min at the normal temperature (25-30 ℃) to obtain a solution 1; adding benzalkonium chloride, EDTA-2Na, PVP K90 and sodium chloride into a proper amount of purified water, and stirring until the benzalkonium chloride, the EDTA-2Na, the PVP K90 and the sodium chloride are completely dissolved to obtain a solution 2; uniformly stirring and mixing the solution 1 and the solution 2, then adding a proper amount of 1N sulfuric acid solution or 1N sodium hydroxide solution, adjusting the pH value to 6, and filling the obtained solution into brown glass bottle containers; then a quantitative pump is arranged to obtain the morphine sulfate nasal spray with the mass concentration of 4 mg/ml.
Comparative example 2 preparation of morphine sulfate nasal spray
The prescription of the morphine sulfate nasal spray of the comparative example is as follows:
TABLE 3
The preparation method comprises the following steps:
adding hydroxypropyl-beta-cyclodextrin into purified water, stirring to prepare a saturated solution, adding morphine sulfate into the system, and performing ultrasonic treatment at normal temperature (25-30 ℃) for 75min to obtain a solution 1; adding benzalkonium chloride, EDTA-2Na, PVP K90 and sodium chloride into a proper amount of purified water, and stirring until the benzalkonium chloride, the EDTA-2Na, the PVP K90 and the sodium chloride are completely dissolved to obtain a solution 2; uniformly stirring and mixing the solution 1 and the solution 2, then adding a proper amount of 1N sulfuric acid solution or 1N sodium hydroxide solution, adjusting the pH value to 6, and filling the obtained solution into brown glass bottle containers; then a quantitative pump is installed to obtain the morphine sulfate nasal spray with the mass concentration of 4 mg/ml.
Example 2 morphine sulfate nasal spray for treatment of major depressive disorder rat model experiment
2.1 experimental animals and test drugs:
50 healthy SD-cleaned rats of half male and female, 2-3 months old, and 250-300g in body weight. The test strains are randomly divided into 5 groups including a blank control group, a model group, an experiment group 1, a comparison experiment group 1 and a comparison experiment group 2, each group comprises 10 animals, and the animals are raised in a clean-grade laboratory. The test drug of experimental group 1 was morphine sulfate nasal spray prepared in example 1, the test drug of comparative experimental group 1 was morphine sulfate nasal spray prepared in comparative example 1, and the test drug of comparative experimental group 2 was morphine sulfate nasal spray prepared in comparative example 2.
2.2 rat major depressive disorder model construction:
the rat model of major depressive disorder is constructed by adopting a chronic unforeseen mild stimulation method (CUNS) for rats in a model group and an experimental group (rats are subjected to various stimulations which are 10 weeks after being bred adaptively for 2 weeks, wherein the stimulations comprise water cut-off, food cut-off, illumination for 12h at night, 100dB ring noise, braking, binding, suspension, tail clamping, electric shock on soles, ice water (4 ℃ and 5 min) swimming, cage closing, heat stress, day and night reversing, 3 times/day, use for 2 times, random arrangement and discontinuous appearance of the same kind of stimulations, and average 3 times of each stimulation.
2.3 Experimental procedures:
rats of experiment 1, comparative experiment 1 and comparative experiment 2 were treated by nasal administration on day 2 after successful modeling (rats were fixed in a glass container with an air outlet for 1 hour and then taken out, and 4mg/ml nebulized morphine sulfate solutions prepared according to example 1, comparative experiment 1 and comparative experiment 2 were contained in the glass container). The human and rat were dosed at 2mg/kg dose after conversion to body surface area, and the blank group and the model group were dosed with the same amount of physiological saline.
Blood was collected 3 times every 2 hours before administration, 2ml each time, and used as a blood concentration test. Blood was collected every 1 hour after administration, 2ml each time, and blood collected within 24 hours was used for blood concentration test.
2.4 statistical analysis:
statistical analysis of one-way variance was performed using SPSS 21 software, and the experimental data were all expressed in (x ± s), with a test level of α =0.05.
2.5 examination items:
2.5.1 open field test: records were made 1 day before molding and 1 day after 2 days of dosing. The recording was done in a quiet room, with an open wooden box of size 100cm 50cm, completely black on the inside wall and the bottom divided into 25 equal-area cells. Rats were placed in the center grid and observed to record their movements within 8 min. The number of horizontal crossing grids is the number of blocks of the rat crossing the bottom surface; the standing times are the standing times of two forelimbs off the ground. The open field experiment mainly reflects the behavior and emotion of animals to a new and different environment, wherein the vertical erection times mainly reflect the exploration capability and curiosity of rats to the instability of a strange environment, and the horizontal crossing number mainly reflects the excitability and autonomy of the rats to the new and different environment.
2.5.2 sugar Water preference experiments: records were made 1 day before molding and 1 day after 2 days of dosing. The adaptive training of 5% cane sugar water is carried out 48h before the experiment, then the water is cut off for 12h, the eating is not stopped, and the sugar water consumption within 1h in the afternoon (15-00-16 00). The sugar water experiment mainly reflects the loss degree of animal pleasure, and the anhedonia is the core symptom of major depression and is reflected by the intake of sugar water.
2.5.3 weight: body weight measurements were performed 1 day before molding and 1 day after 2 days of administration. The body weight reflects the overall condition of the animal, and studies show that major depressive disorder patients often have clinical weight loss.
2.5.4 blood concentration: the blood concentration of rats of the experimental group 1 and the comparative groups 1-2 was monitored at a specific time by high performance liquid chromatography.
3. Results of the experiment
3.1 behavioral observations and body weights:
TABLE 4 rat behavioural and body weight comparisons
3.2 blood concentration: the results are shown in FIG. 1.
3.3 analysis of results
Comparing the data of the blood concentration of rats in each group, it can be seen that when no absorption enhancer is added to the morphine sulfate nasal spray, the nasal spray of the prescription is not completely absorbed, the blood concentration level is not high, and the maximum concentration (Cmax) of the drug is only 140ng/ml (comparative experiment group 1). When dimethyl-beta-cyclodextrin is added into the prescription, the maximum concentration (Cmax) of the drug is increased from 140ng/ml of a comparative experiment group 1 without the addition of the absorption enhancer to 180ng/ml (experiment group 1), and the addition of the dimethyl-beta-cyclodextrin can greatly improve the drug absorption of the morphine sulfate nasal spray. In contrast, in the rats of the comparative experiment group 2 to which hydroxypropyl- β -cyclodextrin was added, the increase in Cmax of the dosing curve was less significant than that of the comparative experiment group 1, and therefore, the absorption promoting effect of dimethyl- β -cyclodextrin on morphine sulfate nasal spray was better.
As can be seen from the results in Table 4, the differences in the number of erection times, sugar water consumption, weight and horizontal crossing grid of rats in the blank group, the model group and the experimental group before the experiment have no statistical significance (P is more than 0.05), and no significant difference exists. After the experiment, the erection times, the sugar water consumption, the weight and the horizontal crossing grid number of the rats in the model group are obviously reduced compared with those in the blank group, the differences have statistical significance (P is less than 0.05), and the significant differences indicate that the model building is successful; after intervention treatment is carried out by morphine sulfate nasal spray, the erection times, sugar water consumption, body weight and horizontal crossing grid number of rats in each experimental group are obviously increased compared with those in a model group, and the difference has statistical significance (P <)
0.05 There was a significant difference indicating that the treatment was effective. However, the data after the test of the comparative experiment group and the blank group can be seen that the rats are not restored to the normal range after the comparative experiment group 1 is used; after the depressed rats of the experimental group 1 are subjected to nasal spray of morphine sulfate, all indexes and parameters of the depressed rats can reach the level of normal rats, namely the depressed symptoms of the rats of the experimental group 1 are effectively treated; after the comparative experiment group 2 is used, all indexes and parameters are worse than those of the experiment group 1. The combination of blood concentration data shows that the morphine sulfate nasal spray can effectively promote drug absorption by adding the absorption enhancer, thereby improving the treatment effect of morphine sulfate on depression, wherein, the absorption promotion effect of dimethyl-beta-cyclodextrin on the morphine sulfate nasal spray is better, and the treatment effect of the morphine sulfate nasal spray added with dimethyl-beta-cyclodextrin on depression is better.
EXAMPLE 3 preparation of morphine sulfate nasal spray
TABLE 5 morphine sulfate nasal spray formulation
The preparation method comprises the following steps:
according to the formulas in the table 5, adding dimethyl-beta-cyclodextrin into purified water, stirring to prepare a saturated solution, adding morphine sulfate into the system, and performing ultrasonic treatment at normal temperature (25-30 ℃) for 75min to obtain a solution 1; adding benzalkonium chloride, EDTA-2Na, PVP K90 and sodium chloride into a proper amount of purified water, and stirring until the benzalkonium chloride, the EDTA-2Na, the PVP K90 and the sodium chloride are completely dissolved to obtain a solution 2; uniformly stirring and mixing the solution 1 and the solution 2, then adding a proper amount of 1N sulfuric acid solution or 1N sodium hydroxide solution, adjusting the pH value to 6, and filling the obtained solution into brown glass bottle containers; then a quantitative pump is installed to obtain the morphine sulfate nasal spray with the mass concentration of 4 mg/ml.
Example 4 bacteriostatic efficacy testing experiment
1. The pharmacopoeial standards for bacterial and fungal requirements for nasal formulations are shown in table 6.
TABLE 6 bacterial and fungal requirements Standard for nasal formulations
* Note: NI: no. increase in number of viable micro-organisms compared to the previous reading, i.e.the number of viable micro-organisms is not increased.
2. The experimental process comprises the following steps:
morphine sulfate nasal spray (with the mass concentration of 4 mg/ml) prepared by the prescription 1-13 in the example 3 is inoculated by a specified microorganism inoculum, then the inoculated self-prepared morphine sulfate nasal spray is stored at the room temperature, samples are taken out according to specified time intervals, and the microorganisms in the samples are counted. The detection is carried out by referring to the non-sterile medicine microorganism limit standard and 1121 bacteriostasis efficacy test method of a general rule 1107 in the four parts of 2020 edition of Chinese pharmacopoeia.
3. The experimental results are as follows:
TABLE 7 results of the test of antibacterial effectiveness (cfu/ml) of morphine sulfate nasal sprays of different prescriptions
From the results in Table 7, it can be seen that: the formula 1 is not added with bacteriostatic agent, wherein each strain grows rapidly; the results of the prescription 2-7 show that the antibacterial effect of potassium sorbate with slightly high concentration and the antibacterial effect of potassium sorbate with lower concentration are good, but the ideal effect is still not achieved; from the results of the prescriptions 8-13, it is known that the addition of 0.01% benzalkonium chloride in the prescription can enable the obtained morphine sulfate nasal spray to achieve a very excellent bacteriostatic effect, and the addition amount of cyclodextrin does not affect the bacteriostatic effect.
Example 5 stability test
1. The experimental process comprises the following steps:
morphine sulfate nasal spray samples prepared by the prescriptions 1 to 13 of the example 3 are examined under the conditions that the temperature is 25 ℃, the temperature is 40 ℃, the relative humidity is 65% +/-5% and the illumination intensity is 4500 +/-500 LX, and the morphine sulfate content and related substance content of the samples are measured after 0 day, 10 days and 30 days. The determination method of morphine sulfate content and related substances is referred to high performance liquid chromatography 0512 in the fourth Provisions of Chinese pharmacopoeia 2020 edition.
2. The experimental results are as follows:
TABLE 8 stability test results
As can be seen from the data in the table 8, after the morphine sulfate nasal spray prepared by the formulas 1 to 13 is placed at 25 ℃ for 10 days, the change range of the content of morphine sulfate and the content of related substances is smaller than that of 0 day, and the preparation is more stable; after 30 days of standing, the content and related substances slightly change from 0 day, but are within an acceptable range; after the morphine sulfate nasal spray is placed at 40 ℃ for 10 days, the content and related substances of the morphine sulfate nasal spray obviously change compared with 25 ℃, the content of the morphine sulfate nasal spray is reduced and the related substances are increased after 30 days, but the morphine sulfate nasal spray still stays in an acceptable range, and in sum, the morphine sulfate nasal spray with the prescriptions 1-13 has good stability and meets the requirements of the preparation.
Example 6 addiction test
1. Pretreatment in a test: ordinary rats were randomly divided into 2 groups (blank control group and morphine sulfate nasal spray group) of 10 per group by body weight (about 200g, each half male and female).
2. The test method comprises the following steps: the morphine sulfate nasal spray group was nasally administered 2 times a day for 21 days (3 weeks total).
3. The administration mode is as follows:
(1) Morphine sulfate nasal spray group: 2 mg/kg/time in the first week, 2 mg/kg/time in the second week, and 4 mg/kg/time in the third week; the morphine sulfate nasal spray is the morphine sulfate nasal spray which is prepared in the example 1 and has the mass concentration of 4 mg/ml.
(2) Blank control group: the proper amount of normal saline solution is sprayed to the nose every time according to the weight.
Observing the withdrawal reaction condition of each group of rats within one week after withdrawal, performing statistical analysis by using SPSS 21 software, and analyzing the test data byAnd (4) showing.
4. Results of the experiment
From the results of table 9 above, it can be seen that after nasal spraying morphine to rats for 21 days, there was no significant difference in the number of times of erection, number of times of cleaning fur, number of times of stretching, wet dog-like shaking, number of times of licking vagina, and number of biting teeth array of rats in the morphine sulfate nasal spray group compared to rats in the blank control group, which indicates that the morphine sulfate nasal spray of the present invention does not cause withdrawal symptoms after administration, and has no addiction, good safety, and no toxic or side effects.
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 various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The morphine nasal spray is characterized by being prepared from the following raw and auxiliary materials: main medicine, an absorption enhancer, a bacteriostatic agent, an antioxidant, a thickening agent, an osmotic pressure regulator and water;
the concentration of each component in the morphine nasal spray is as follows: 1mg/mL-10mg/mL of main drug, 0.01mg/mL-0.1mg/mL of absorption enhancer, 0.000005mg/mL-0.01mg/mL of bacteriostatic agent, 0.0001mg/mL-0.01mg/mL of antioxidant, 0.005mg/mL-0.1mg/mL of thickening agent and 0.2mg/mL-1.2mg/mL of osmotic pressure regulator;
the main drug is morphine or salt thereof; the absorption enhancer is cyclodextrin.
2. The nasal spray of morphine, according to claim 1, wherein said absorption enhancer is dimethyl- β -cyclodextrin and/or hydroxypropyl- β -cyclodextrin, preferably dimethyl- β -cyclodextrin.
3. The morphine nasal spray according to claim 1, wherein the primary drug is selected from at least one of morphine sulfate, morphine hydrochloride and morphine citrate; and/or the presence of a gas in the gas,
the bacteriostatic agent is selected from at least one of benzalkonium chloride, ethylparaben, chlorobutanol and butyl p-hydroxybenzoate; and/or the presence of a gas in the atmosphere,
the antioxidant is at least one selected from EDTA-2Na, sodium metabisulfite and citric acid; and/or the presence of a gas in the atmosphere,
the thickening agent is selected from at least one of povidone K90, povidone K30, methylcellulose and polyethylene glycol 400; and/or the presence of a gas in the gas,
the osmotic pressure regulator is at least one selected from sodium chloride, glycerol and glucose.
4. The morphine nasal spray according to any one of claims 1 to 3, wherein the concentration of the main drug in the morphine nasal spray is 2mg/mL to 6mg/mL; and/or the presence of a gas in the gas,
the concentration of the absorption enhancer in the morphine nasal spray is 0.02mg/mL-0.08mg/mL; and/or the presence of a gas in the atmosphere,
the concentration of the bacteriostatic agent in the morphine nasal spray is 0.00005mg/mL-0.001mg/mL; and/or the presence of a gas in the gas,
the concentration of the antioxidant in the morphine nasal spray is 0.0008mg/mL-0.0012mg/mL; and/or the presence of a gas in the gas,
the concentration of the thickening agent in the morphine nasal spray is 0.01mg/mL-0.03mg/mL; and/or the presence of a gas in the atmosphere,
the concentration of the osmotic pressure regulator in the morphine nasal spray is 0.7mg/mL-0.9mg/mL.
5. The morphine nasal spray according to claim 4, wherein the concentration of the main drug in the morphine nasal spray is 3mg/mL-5mg/mL; and/or the presence of a gas in the gas,
the concentration of the absorption enhancer in the morphine nasal spray is 0.04mg/mL-0.06mg/mL; and/or the presence of a gas in the gas,
the concentration of the bacteriostatic agent in the morphine nasal spray is 0.00008mg/mL-0.001mg/mL.
6. The morphine nasal spray according to claim 1, wherein the concentration of each component in the morphine nasal spray is as follows: 3.5mg/mL-4.5mg/mL of main drug, 0.04mg/mL-0.06mg/mL of absorption enhancer, 0.00009mg/mL-0.00012mg/mL of bacteriostatic agent, 0.0009mg/mL-0.0011mg/mL of antioxidant, 0.015mg/mL-0.025mg/mL of thickening agent and 0.75mg/mL-0.85mg/mL of osmotic pressure regulator;
the main drug is morphine sulfate; the absorption enhancer is dimethyl-beta-cyclodextrin; the bacteriostatic agent is benzalkonium chloride; the antioxidant is EDTA-2Na; the thickening agent is povidone K90; the osmotic pressure regulator is sodium chloride.
7. The morphine nasal spray according to any one of claims 1 to 3, further comprising a suitable amount of pH adjusting agent to adjust the pH of the morphine nasal spray to 5.5 to 6.5.
8. The nasal spray of morphine, according to claim 7, wherein said pH adjusting agent is a 1N sulfuric acid solution or a 1N sodium hydroxide solution.
9. A method for preparing a nasal spray of morphine as claimed in any one of claims 1 to 8, comprising the steps of:
1) Adding the absorption enhancer into water, and stirring to prepare a saturated solution;
2) Adding the main drug into the saturated solution obtained in the step 1), and performing ultrasonic treatment at normal temperature to obtain a solution 1;
3) Adding the bacteriostatic agent, the antioxidant, the thickening agent and the osmotic pressure regulator into a proper amount of water, and stirring until the bacteriostatic agent, the antioxidant, the thickening agent and the osmotic pressure regulator are completely dissolved to obtain a solution 2;
4) And stirring and mixing the solution 1 and the solution 2 uniformly, and adding a pH regulator to regulate the pH value to obtain the water-soluble organic fertilizer.
10. The method for preparing a morphine nasal spray according to claim 9, wherein the ultrasound time is 0.5h-2h.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211637089.3A CN115804754A (en) | 2022-12-16 | 2022-12-16 | Morphine nasal spray and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211637089.3A CN115804754A (en) | 2022-12-16 | 2022-12-16 | Morphine nasal spray and preparation method thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115804754A true CN115804754A (en) | 2023-03-17 |
Family
ID=85486325
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211637089.3A Pending CN115804754A (en) | 2022-12-16 | 2022-12-16 | Morphine nasal spray and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115804754A (en) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5756483A (en) * | 1993-03-26 | 1998-05-26 | Merkus; Franciscus W. H. M. | Pharmaceutical compositions for intranasal administration of apomorphine |
US20020002175A1 (en) * | 2000-09-19 | 2002-01-03 | Charanjit Behl | Nasal delivery of apomorphine in combination with glycol derivatives |
CN1430960A (en) * | 2003-01-10 | 2003-07-23 | 复旦大学 | Central nerve antalgic preparation through nasal cavity administration |
US6677346B1 (en) * | 1999-06-16 | 2004-01-13 | Nastech Pharmaceutical Company Inc. | Methods comprising intranasal morphine |
CN1634062A (en) * | 2004-10-13 | 2005-07-06 | 北京国药龙立生物医药新技术有限公司 | Nose cavity administering formulation of nalmefene |
CN101883555A (en) * | 2007-11-09 | 2010-11-10 | 阿基米德开发有限公司 | Intranasal compositions |
CN102166219A (en) * | 2010-05-25 | 2011-08-31 | 杭州天龙药业有限公司 | Nasal administration preparation and application thereof |
-
2022
- 2022-12-16 CN CN202211637089.3A patent/CN115804754A/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5756483A (en) * | 1993-03-26 | 1998-05-26 | Merkus; Franciscus W. H. M. | Pharmaceutical compositions for intranasal administration of apomorphine |
US6677346B1 (en) * | 1999-06-16 | 2004-01-13 | Nastech Pharmaceutical Company Inc. | Methods comprising intranasal morphine |
US20020002175A1 (en) * | 2000-09-19 | 2002-01-03 | Charanjit Behl | Nasal delivery of apomorphine in combination with glycol derivatives |
CN1430960A (en) * | 2003-01-10 | 2003-07-23 | 复旦大学 | Central nerve antalgic preparation through nasal cavity administration |
CN1634062A (en) * | 2004-10-13 | 2005-07-06 | 北京国药龙立生物医药新技术有限公司 | Nose cavity administering formulation of nalmefene |
CN101883555A (en) * | 2007-11-09 | 2010-11-10 | 阿基米德开发有限公司 | Intranasal compositions |
CN102166219A (en) * | 2010-05-25 | 2011-08-31 | 杭州天龙药业有限公司 | Nasal administration preparation and application thereof |
Non-Patent Citations (1)
Title |
---|
周园等: ""环糊精在鼻腔给药系统中的应用"", 《中国医药工业杂志》, vol. 36, no. 8, 6 July 2005 (2005-07-06), pages 501 - 504 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2761342C2 (en) | Delivery of therapeutic agents to the central nervous system | |
AU2005257722B2 (en) | Composition comprising lactic acid and lactoferrin | |
RU2536264C2 (en) | Topical dermal composition containing salt and sugar as active ingredients for preventing and treating vaginosis, and using it | |
AU2019229354B2 (en) | Volatile organic compound formulations having antimicrobial activity | |
CN102397237B (en) | Tilmicosin micelle preparation and preparation method thereof | |
CN102363040B (en) | Antimicrobial peptide preparation for mucosal tissues | |
CN115804754A (en) | Morphine nasal spray and preparation method thereof | |
RU2604575C1 (en) | Pharmaceutical composition for treating infectious-inflammatory diseases of local application and method of its production and application | |
CN113813250B (en) | Pharmaceutical composition containing ketamine and preparation method and application thereof | |
RU2486896C1 (en) | Method of obtaining medication for activation of non-specific resistance, prevention and therapy of diseases in young agricultural animals | |
CN103948661A (en) | Medicine combination for treating gynecological diseases, prostatic diseases or anorectal diseases, and application for same | |
US11285122B2 (en) | Volatile organic compound formulations having antimicrobial activity | |
CN114699424A (en) | Novel application of bacteroides fragilis zwitterionic capsular polysaccharide or/and modified zwitterionic capsular polysaccharide | |
BR112021005603A2 (en) | formulation, and, methods for treating or preventing a pathogenic or wound infection, treating or preventing an oral infection, treating or preventing infection during or following a medical procedure, treating or preventing a fungal infection, administering the formulation, maintaining or improving health of an animal and disinfect a surface | |
CN103908479A (en) | Medical hydrogel for treating gynecological diseases or skin diseases and application of medical hydrogel | |
US9408868B2 (en) | Skin external composition comprising a combination of sodium chloride and glucose as active ingredients for treating vaginosis and the use thereof | |
CN105749261B (en) | Compound lysozyme hydrochloride vaginal tablet and preparation method thereof | |
RU2802308C2 (en) | Compositions of volatile organic substances with antimicrobial activity | |
CN116159018A (en) | Novel external brimonidine gel | |
CN117338766A (en) | Application of mejunin C in dihydro | |
CN114903973A (en) | Respiratory tract mucosa immunity enhancing pharmaceutical composition | |
CN108309967A (en) | For the traditional Chinese medicine monomer composition of antagonism injury of lungs and its application | |
CN111658763A (en) | Gynecological antibacterial gel and preparation method thereof | |
CN106389433A (en) | Application of hetrazan in preparing drug for treating psoriasis | |
CN1395963A (en) | Composite medicine for disinfecting and relieving inflammation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |