CN117860732A - Pharmaceutical composition containing nebivolol hydrochloride and preparation method thereof - Google Patents
Pharmaceutical composition containing nebivolol hydrochloride and preparation method thereof Download PDFInfo
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- CN117860732A CN117860732A CN202410045702.5A CN202410045702A CN117860732A CN 117860732 A CN117860732 A CN 117860732A CN 202410045702 A CN202410045702 A CN 202410045702A CN 117860732 A CN117860732 A CN 117860732A
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- pharmaceutical composition
- film
- prescription
- nebivolol hydrochloride
- medicine
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- 229940068174 nebivolol hydrochloride Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- JWEXHQAEWHKGCW-BIISKSHESA-N (R,S,S,S)-nebivolol hydrochloride Chemical compound Cl.C1CC2=CC(F)=CC=C2O[C@H]1[C@@H](O)CNC[C@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 JWEXHQAEWHKGCW-BIISKSHESA-N 0.000 title claims abstract 6
- 239000003814 drug Substances 0.000 claims abstract description 40
- 239000004014 plasticizer Substances 0.000 claims abstract description 17
- 239000000796 flavoring agent Substances 0.000 claims abstract description 16
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 16
- 238000001035 drying Methods 0.000 claims abstract description 14
- 239000000463 material Substances 0.000 claims abstract description 11
- 238000010521 absorption reaction Methods 0.000 claims abstract 3
- 239000003623 enhancer Substances 0.000 claims abstract 3
- 238000004090 dissolution Methods 0.000 claims description 48
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 14
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 13
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 13
- 239000003655 absorption accelerator Substances 0.000 claims description 11
- 235000011187 glycerol Nutrition 0.000 claims description 11
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 11
- 229960005150 glycerol Drugs 0.000 claims description 10
- 239000011248 coating agent Substances 0.000 claims description 9
- 238000000576 coating method Methods 0.000 claims description 9
- VYZKQGGPNIFCLD-UHFFFAOYSA-N 3,3-dimethylhexane-2,2-diol Chemical compound CCCC(C)(C)C(C)(O)O VYZKQGGPNIFCLD-UHFFFAOYSA-N 0.000 claims description 7
- 239000001361 adipic acid Substances 0.000 claims description 7
- 235000011037 adipic acid Nutrition 0.000 claims description 7
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- 229920006037 cross link polymer Polymers 0.000 claims description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000000758 substrate Substances 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 claims description 5
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 claims description 5
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 108010010803 Gelatin Proteins 0.000 claims description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- 239000004376 Sucralose Substances 0.000 claims description 4
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims description 4
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- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
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- 239000000126 substance Substances 0.000 claims description 4
- 235000019408 sucralose Nutrition 0.000 claims description 4
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 229920002125 Sokalan® Polymers 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000004584 polyacrylic acid Substances 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
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- OMPIYDSYGYKWSG-UHFFFAOYSA-N Citronensaeure-alpha-aethylester Natural products CCOC(=O)CC(O)(C(O)=O)CC(O)=O OMPIYDSYGYKWSG-UHFFFAOYSA-N 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- 229920001800 Shellac Polymers 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 2
- 229940045110 chitosan Drugs 0.000 claims description 2
- 229960001484 edetic acid Drugs 0.000 claims description 2
- 229940057975 ethyl citrate Drugs 0.000 claims description 2
- 239000010642 eucalyptus oil Substances 0.000 claims description 2
- 229940044949 eucalyptus oil Drugs 0.000 claims description 2
- 239000001087 glyceryl triacetate Substances 0.000 claims description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 2
- 229940041616 menthol Drugs 0.000 claims description 2
- 239000010502 orange oil Substances 0.000 claims description 2
- 229920000058 polyacrylate Polymers 0.000 claims description 2
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 2
- 239000011118 polyvinyl acetate Substances 0.000 claims description 2
- 229960004063 propylene glycol Drugs 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound 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 description 2
- 229940113147 shellac Drugs 0.000 claims description 2
- 239000004208 shellac Substances 0.000 claims description 2
- 235000013874 shellac Nutrition 0.000 claims description 2
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 229960002622 triacetin Drugs 0.000 claims description 2
- 235000013769 triethyl citrate Nutrition 0.000 claims description 2
- 235000019502 Orange oil Nutrition 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 16
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 abstract description 12
- 210000000214 mouth Anatomy 0.000 abstract description 4
- 239000000725 suspension Substances 0.000 abstract description 3
- 210000004877 mucosa Anatomy 0.000 abstract description 2
- 230000002829 reductive effect Effects 0.000 abstract description 2
- JWEXHQAEWHKGCW-VCVZPGOSSA-N (S,R,R,R)-nebivolol hydrochloride Chemical compound [Cl-].C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)C[NH2+]C[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 JWEXHQAEWHKGCW-VCVZPGOSSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 23
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- 239000000203 mixture Substances 0.000 description 20
- 229940079593 drug Drugs 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000009472 formulation Methods 0.000 description 9
- 229960000619 nebivolol Drugs 0.000 description 9
- 238000000227 grinding Methods 0.000 description 8
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229940124532 absorption promoter Drugs 0.000 description 3
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a pharmaceutical composition containing nebivolol hydrochloride and a preparation method thereof. The pharmaceutical composition comprises, by weight, 7% -14% of nebivolol hydrochloride, 50% -80% of a film forming material, no more than 20% of a plasticizer, no more than 10% of a flavoring agent and 2% -10% of an absorption enhancer. The specific surface area is large, the medicine can be rapidly dissolved in the oral cavity, the bioavailability and the compliance of patients are improved, and the medicine is easy to carry; has high mucosa adhesiveness, and can limit and prevent users from taking out the medicine, so as to avoid abuse of the medicine; the dosage of auxiliary materials is less, the compatibility change is less, and the stability is better compared with the stability of solution and suspension; the low-temperature drying process is adopted, so that the increase of nitrosamine impurities is reduced, and the stability of the nitrosamine is better than that of the original ground tablet.
Description
Technical Field
The invention relates to a medicine composition containing nebivolol hydrochloride and a preparation method thereof, in particular to a medicine composition containing nebivolol hydrochloride, which is applied by an oral film agent, and a preparation method thereof.
Background
Nebivolol hydrochloride (Nebivolol Hydrochloride), the chemical name of which is bis [2- (6-fluoro-chroman-2-yl) -2-hydroxyethyl ] amine hydrochloride, is a third-generation selective beta 1 receptor blocker with vasodilation function, can gently slow down heart rate and lower blood pressure, and is mainly used for treating primary hypertension and chronic heart failure.
The existing dosage form on the market is nebivolol hydrochloride tablets, and the oral solid preparation needs to achieve proper blood concentration in a patient within acceptable time after the medicine is orally taken, namely the medicine has to have good bioavailability in vivo, and the medicine needs to be dissolved in body fluid (gastric juice or intestinal juice) after the medicine is orally taken, so that the dissolution rate of the medicine in the body fluid is a very critical factor influencing the bioavailability of the oral medicine. Nebivolol hydrochloride is a crystalline drug, and therefore, how to increase the water solubility and dissolution rate, thereby improving the dissolution rate of nebivolol hydrochloride, becomes a key factor for preparing a solid preparation thereof.
In order to improve the dissolution rate of nebivolol hydrochloride and thus to improve the oral bioavailability, CN1140991 discloses a composition containing micronized nebivolol, which increases the dissolution rate of the main drug by increasing the specific surface area of the micronised substance through reducing the particle size of the drug particles by micronization process. CN101019858 is prepared by sieving main drug with common vibrating screen to obtain a certain particle size, and combining with a certain amount of solubilizer to obtain dissolution rate of more than 80% at 45 min. However, the micronization process is time-consuming, has a certain loss rate, and micronizes the main medicine to 20 μm, and even 8 μm has high requirements on method control, smashing equipment, operators and smashing environment.
Genotoxic impurities, also known as genotoxic impurities, refer to compounds that are capable of producing direct or indirect damage to DNA that may lead to cancer or genetic mutation. Even trace amounts of genotoxic impurities can seriously harm human health, causing irreversible damage. Therefore, strict control of genotoxic impurities in medicines has become important in order to ensure medication safety. In the processes of drug synthesis, production and storage, genotoxic impurities can be generated, and adverse effects can be caused to clinical application due to improper quality control.
Among the numerous genotoxic impurities, N-nitrosamines are the most common and the strongest carcinogen recognized worldwide. Nebivolol may generate nebivolol nitrosamine impurities during synthesis and preparation, and the higher temperature during preparation may promote the increase of nitrosamine impurities, the maximum daily dosage of nebivolol is 40mg, nebivolol nitrosamine impurities belong to class 4 according to EMA guidelines, AI value is 1500ng/day, therefore limit is 37.5ppm, and there is a quality safety hazard.
Disclosure of Invention
The invention aims to: the invention aims to provide a nebivolol hydrochloride oromembrane pharmaceutical composition for improving medication safety and compliance.
The technical scheme is as follows: the medicine composition containing nebivolol hydrochloride contains 7-14% of nebivolol hydrochloride, 50-80% of film forming material, not more than 20% of plasticizer, not more than 10% of flavoring agent and 2-10% of absorption accelerator by weight.
Wherein the film forming material is selected from at least one of polyvinyl alcohol (PVA), hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyacrylic acid and polyacrylate, polyvinyl acetate copolymer and polyacrylic acid, phthalic gelatin, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), sodium alginate, polyoxyethylene (PEO), vinyl acetate, trimethylpentanediol/adipic acid/glycerin crosslinked polymer, vinylpyrrolidone/vinyl acetate copolymer, carboxylated vinyl acetate copolymer; more preferred are Hypromellose (HPMC), trimethylpentanediol/adipic acid/glycerol cross-linked polymer, carboxylated vinyl acetate copolymer.
The plasticizer is at least one selected from glycerol, polyethylene glycol 200, polyethylene glycol 400, propylene glycol, butylene glycol, sorbitol, polysorbate, diethyl phthalate, ethyl citrate and triacetin; more preferred are glycerol, polyethylene glycol 400 and polyethylene glycol 200.
The flavoring agent is at least one selected from sucralose, ammonium monoglycyrrhetate, aspartame, eucalyptus oil, sweet orange oil, peppermint oil and menthol; more preferably sucralose, ammonium monoglycyrrhetate, peppermint oil.
The absorption promoter is at least one selected from polyethylene glycol 1000 vitamin E succinate, poloxamer, docusate sodium, benzalkonium chloride, cyclodextrin, polysorbate, chitosan and edetic acid; more preferably polysorbate 80, polyethylene glycol 1000 vitamin E succinate, poloxamer.
The pharmaceutical composition designed by the invention improves the dissolution rate of nebivolol hydrochloride in an oral mucosa administration mode, and improves the compliance of patients suffering from dysphagia.
Preferably, the preparation form of the pharmaceutical composition is an oral film, the thickness is 30-80 mu m, and the specification is 2X 10cm 2 。
Further preferably, the orosol film agent is completely dissolved in water at 25 ℃ within 60 seconds.
Further preferably, the stretch breaking force of the orolytic film agent is greater than 10N.
The preparation method of the pharmaceutical composition comprises the following steps:
(1) Dissolving a film forming agent in water;
(2) Adding a plasticizer into the solution prepared in the step (1) for dissolution; then adding nebivolol hydrochloride, a flavoring agent and an absorption accelerator, dissolving and defoaming;
(3) And (3) coating the liquid medicine prepared in the step (2) on a substrate, and drying the liquid medicine at the temperature of not more than 35 ℃ to form a film, thus obtaining the pharmaceutical composition.
The preparation method adopted by the invention adopts a low-temperature drying preparation process to strictly control the growth of nitrosamine impurities, and can conveniently and rapidly prepare the preparation product with complete and smooth appearance and satisfactory content dissolution.
Preferably, the temperature of the drying is no more than 30 ℃.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
1. the oral film has large specific surface area, can be rapidly dissolved in the oral cavity, is dispersed into a suspension of the medicine and auxiliary materials, is convenient to swallow, does not need to drink water, improves the bioavailability, improves the compliance of patients, and is easy to carry; has higher mucosa adhesiveness and is adhered to the inner side of the oral cavity or the palate, thereby limiting and preventing a user from taking out the oral cavity or the palate, avoiding the abuse of medicines and having obvious clinical advantages; the dosage of auxiliary materials is less, the compatibility change is less, and the stability is better compared with the stability of solution and suspension;
2. by adopting a low-temperature drying process, the increase of the nebivolol nitrosamine impurities can be reduced, and the stability of the nebivolol nitrosamine tablet is better than that of an original ground tablet adopting a granulating process.
Drawings
FIG. 1 is a graph showing the dissolution of a self-made film and a raw sheet in a hydrochloric acid medium having a pH of 2.0;
FIG. 2 is a graph showing the dissolution of a self-made film and a raw sheet in an acetic acid medium at pH 4.5;
FIG. 3 is a graph showing the dissolution of a self-made film and a raw sheet in a phosphate medium at pH 6.8.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Percentages and parts are by weight unless otherwise indicated.
The disintegration time limit measuring method comprises the following steps: the orosity film is clamped by clip, checked according to the four rules 0921 of Chinese pharmacopoeia 2020 edition (method under tablet item of disintegration time limit check method), the time that the orosity film is completely dissolved and passed through screen is recorded, the average value of disintegration time of 6 tablets of orosity film is recorded.
The tension measuring method comprises the following steps: and placing the prepared oral solution film finished product on a stretch breaking force tester, after a sample is pulled at a certain speed, reading the tensile strength, and recording the tensile strength of 6 oral solution films.
Dissolution rate measurement method: according to the second method (paddle method) of dissolution and release measurement of Chinese pharmacopoeia (2020 edition, four general rule 0931), the volume of dissolution medium is 900ml of 0.01N hydrochloric acid solution, the water is deaerated and purified water, the temperature is 37.0+/-0.5 ℃, the rotating speed is 50rpm, 6 samples are put into a dissolution cup for dissolution test, and the average value of dissolution amount of 6 oral films is calculated.
Example 1
1. Prescription of prescription
The hydroxypropyl methylcellulose is used as a film forming agent, nebivolol hydrochloride is prepared into the film forming agent, the drug loading rate is 7% -15%, and the specific prescription is shown in table 1.
TABLE 1 composition of prescriptions 1-2
2. Preparation method
Dispersing the prescription amount of hypromellose into hot water at 90 ℃, stirring to dissolve, cooling to room temperature, adding the prescription amount of plasticizer into the solution, stirring to dissolve, sequentially adding nebivolol hydrochloride, a flavoring agent and an absorption accelerator, stirring to dissolve, ultrasonically removing bubbles in the solution, uniformly coating the defoamed medicine-containing glue solution on a substrate by using a scraper, heating at 55+/-2 ℃ to dry to form a film, cutting into a proper shape and size, and packaging.
3. Quality evaluation
The nebivolol hydrochloride orosol film prepared in the prescription 1-2 has complete and smooth appearance, uniform color and no bubbles; the content dissolution meets the requirements, and the prepared oral soluble film can be completely dissolved in 60 seconds. The thickness, tension, disintegration time, dissolution and other parameters were measured as shown in Table 2.
TABLE 2 parameter determination results for formulations 1-2
| Prescription of prescription | Thickness (μm) | Tension (N) | Disintegration time (seconds) | Elution quantity (30 min) | Content (%) | Mouthfeel of the product |
| 1 | 65±3 | 11.6～14.9 | 22 | 98.8％ | 100.20％ | Preferably, it is |
| 2 | 65±3 | 12.5～18.8 | 38 | 97.2％ | 99.6％ | Preferably, it is |
Example 2
1. Prescription of prescription
The povidone/copovidone is used as a film forming agent, nebivolol hydrochloride is prepared into the film forming agent, the drug loading rate is about 7% -14%, and the specific prescription is shown in table 3.
TABLE 3 composition of prescriptions 3-4
2. Preparation method
Dispersing the film forming agent with the prescription amount into purified water, stirring to dissolve, respectively adding the plasticizer with the prescription amount into the solution, stirring to dissolve, sequentially adding nebivolol hydrochloride, the flavoring agent and the absorption accelerator, stirring to dissolve, ultrasonically removing bubbles in the solution, uniformly coating the defoamed medicine-containing glue solution on a base material by using a scraper, heating to dry at 55+/-2 ℃ to form a film, cutting into a proper shape and size, and packaging.
3. Quality evaluation
The nebivolol hydrochloride orosol film prepared in the prescription 3-4 has complete and smooth appearance, uniform color and no bubbles; the content dissolution meets the requirements, and the prepared oral soluble film can be completely dissolved in 60 seconds. The thickness, tension, disintegration time, dissolution rate and other parameters were measured as shown in Table 4.
TABLE 4 measurement results of recipe 3-4 parameters
| Prescription of prescription | Thickness (μm) | Tension (N) | Disintegration time (seconds) | Elution quantity (30 min) | Content (%) | Mouthfeel of the product |
| 3 | 60±3 | 7.4～9.8 | 10 | 99.2％ | 100.0％ | Preferably, it is |
| 4 | 60±3 | 8.6～10.9 | 15 | 98.6％ | 99.8％ | Preferably, it is |
Example 3
1. Prescription of prescription
The preparation method comprises the steps of adopting trimethylpentanediol/adipic acid/glycerin crosslinked polymer and carboxylated vinyl acetate copolymer as film forming agents, preparing nebivolol hydrochloride into the film forming agents, wherein the drug loading rate is about 7% -14%, and the specific prescription is shown in table 5.
TABLE 5 composition of prescriptions 5-6
2. Preparation method
Dispersing the film forming agent with the prescription amount into purified water, stirring to dissolve, respectively adding the plasticizer with the prescription amount into the solution, stirring to dissolve, sequentially adding nebivolol hydrochloride, the flavoring agent and the absorption accelerator, stirring to dissolve, ultrasonically removing bubbles in the solution, uniformly coating the defoamed medicine-containing glue solution on a base material by using a scraper, heating to dry at 55+/-2 ℃ to form a film, cutting into a proper shape and size, and packaging.
3. Quality evaluation
The nebivolol hydrochloride orosol film prepared by the prescription 5-6 has complete and smooth appearance, uniform color and no bubbles; the content dissolution meets the requirements, and the prepared oral soluble film can be completely dissolved in 60 seconds. The thickness, tension, disintegration time, dissolution rate and other parameters were measured as shown in Table 6 below.
TABLE 6 parameter determination results for prescription 5-6 films
| Prescription of prescription | Thickness (μm) | Tension (N) | Disintegration time (seconds) | Elution quantity (30 min) | Content (%) | Mouthfeel of the product |
| 5 | 60±3 | 12.6～14.8 | 32 | 97.6％ | 99.9％ | Preferably, it is |
| 6 | 60±3 | 13.8～14.9 | 26 | 98.2％ | 99.8％ | Preferably, it is |
In summary, the film formulations 1 to 6 meet the requirements of the detection indexes such as disintegration time limit, dissolution amount and the like, and the film formulations with the tension of more than 10N are preferred, so that hydroxypropyl methylcellulose HPMC E5, HPMC E15, trimethylpentanediol/adipic acid/glycerin crosslinked polymer and carboxylated vinyl acetate copolymer are preferred as the film formulations.
Example 4
1. Prescription of prescription
The nebivolol hydrochloride oral film is prepared by adopting HPMC E5 and HPMC E15 as film forming agents, and the tastes of different flavoring agents are examined, and the specific prescription is shown in the table 7 below.
TABLE 7 composition of prescriptions 7-10
2. Preparation method
Dispersing the film forming agent with the prescription amount into purified water, stirring to dissolve, respectively adding the plasticizer with the prescription amount into the solution, stirring to dissolve, sequentially adding nebivolol hydrochloride, the flavoring agent and the absorption accelerator, stirring to dissolve, ultrasonically removing bubbles in the solution, uniformly coating the defoamed medicine-containing glue solution on a base material by using a scraper, heating to dry at 55+/-2 ℃ to form a film, cutting into a proper shape and size, and packaging.
3. Quality evaluation
The nebivolol hydrochloride orosol film prepared by the prescription 7-10 has complete and smooth appearance, uniform color and no bubbles; the content dissolution meets the requirements, and the prepared oral soluble film can be completely dissolved in 60 seconds. The thickness, tension, disintegration time, dissolution rate and other parameters were measured as shown in Table 8 below.
TABLE 8 parameter determination results for formulations 7-10 film formulations
| Prescription of prescription | Thickness (μm) | Tension (N) | Disintegration time (seconds) | Elution quantity (30 min) | Content (%) | Mouthfeel of the product |
| 7 | 65±3 | 12.6～14.9 | 21 | 99.6％ | 100.4％ | Preferably, it is |
| 8 | 65±3 | 12.5～17.5 | 35 | 99.5％ | 100.0％ | Preferably, it is |
| 9 | 65±3 | 11.6～14.9 | 25 | 98.8％ | 99.6％ | Moderate to moderate |
| 10 | 65±3 | 12.8～18.0 | 33 | 99.4％ | 100.2％ | Preferably, it is |
In conclusion, the disintegration time limit, the dissolution amount and other detection indexes of the film preparation of the prescription 7-10 meet the requirements, and the taste is combined, and the flavoring agent is preferably sucralose, ammonium monoglycyrrhetate and peppermint oil.
Example 5
1. Prescription of prescription
Adopting HPMC E5 as a film forming agent to prepare nebivolol hydrochloride oral solution films, examining different plasticizers, and specifically preparing the following table 9.
TABLE 9 composition of prescriptions 11-14
2. Preparation method
Dispersing the film forming agent with the prescription amount into purified water, stirring to dissolve, respectively adding the plasticizer with the prescription amount into the solution, stirring to dissolve, sequentially adding nebivolol hydrochloride, the flavoring agent and the absorption accelerator, stirring to dissolve, uniformly coating the defoamed medicine-containing glue solution on a substrate by using a scraper, heating at 55+/-2 ℃ to dry to form a film, cutting into a proper shape and size, and packaging.
3. Quality evaluation
The nebivolol hydrochloride orosol film prepared by the prescription 11-14 has complete and smooth appearance, uniform color and no bubbles; the content dissolution meets the requirements, and the prepared oral soluble film can be completely dissolved in 60 seconds. The thickness, tension, disintegration time, dissolution rate and other parameters were measured as shown in Table 10 below.
TABLE 10 parameter determination results for prescriptions 11-14 film formulations
| Prescription of prescription | Thickness (μm) | Tension (N) | Disintegration time (seconds) | Elution quantity (30 min) | Content (%) | Mouthfeel of the product |
| 11 | 65±3 | 12.6～14.9 | 22 | 99.5％ | 100.0％ | Preferably, it is |
| 12 | 65±3 | 8.8～10.6 | 18 | 99.8％ | 98.7％ | Preferably, it is |
| 13 | 65±3 | 9.2～11.3 | 35 | 96.8％ | 98.6％ | Moderate to moderate |
| 14 | 65±3 | 7.2～9.9 | 21 | 100.2％ | 100.5％ | Preferably, it is |
In summary, the partial films of formulas 7-8 and 11-14 have poor stretch breaking, and glycerin, polyethylene glycol 400 and polyethylene glycol 200 are preferred as plasticizers.
Example 6
1. Prescription of prescription
The nebivolol hydrochloride orosol film is prepared by adopting trimethylpentanediol/adipic acid/glycerin crosslinked polymer as a film forming agent, and different absorption promoters are examined, and specific prescriptions are shown in the following table 11.
TABLE 11 composition of prescriptions 15-17
2. Preparation method
Dispersing the film forming agent with the prescription amount into purified water, stirring to dissolve, respectively adding the plasticizer with the prescription amount into the solution, stirring to dissolve, sequentially adding nebivolol hydrochloride, the flavoring agent and the absorption accelerator, stirring to dissolve, uniformly coating the defoamed medicine-containing glue solution on a substrate by using a scraper, heating at 55+/-2 ℃ to dry to form a film, cutting into a proper shape and size, and packaging.
3. Quality evaluation
The nebivolol hydrochloride orosol film prepared by the prescription 15-17 has complete and smooth appearance, uniform color and no bubbles; the content dissolution meets the requirements, and the prepared oral soluble film can be completely dissolved in 60 seconds. The thickness, tension, disintegration time, dissolution rate and other parameters were measured as shown in Table 12 below.
TABLE 12 parameter determination results for recipe 15-17 film formulations
| Prescription of prescription | Thickness (μm) | Tension (N) | Disintegration time (seconds) | Elution quantity (30 min) | Content (%) | Mouthfeel of the product |
| 15 | 65±3 | 11.6～13.8 | 25 | 98.7％ | 99.5％ | Preferably, it is |
| 16 | 65±3 | 12.0～13.6 | 30 | 99.6％ | 99.7％ | Preferably, it is |
| 17 | 65±3 | 10.9～14.7 | 36 | 98.2％ | 99.2％ | Preferably, it is |
In conclusion, the nebivolol hydrochloride oral film prepared in the prescription 15-17 has good parameters, and the absorption promoter is preferably polysorbate 80, polyethylene glycol 1000 vitamin E succinate or poloxamer.
Example 7
1. Prescription of prescription
Polyethylene glycol 400 is used as a plasticizer, trimethylpentanediol/adipic acid/glycerin crosslinked polymer is used as a film forming agent, ammonium monoglycyrrhetate is used as a corrigent, polyethylene glycol 1000 vitamin E succinate is used as an absorption accelerator, purified water is used as a solvent, and the drying temperature is examined, and the specific prescription is shown in the following table 13.
TABLE 13 composition of prescriptions 18-20
2. Preparation method
Dispersing the film forming agent with the prescription amount into purified water, stirring to dissolve, respectively adding the plasticizer with the prescription amount into the solution, stirring to dissolve, sequentially adding nebivolol hydrochloride, the flavoring agent and the absorption accelerator, stirring to dissolve, uniformly coating the defoamed medicine-containing glue solution on a substrate by using a scraper, heating, drying to form a film, cutting into a proper shape and size, and packaging. Wherein the drying parameters of the films of formulas 18-20 are shown in Table 14 below.
TABLE 14 drying parameters of the 18-20 formulation films
| Prescription of prescription | 18 | 19 | 20 |
| Setting temperature (DEG C) | 45.0 | 35.0 | 30.0 |
| Actual temperature (. Degree. C.) | 44.8～45.2 | 34.5～35.2 | 29.8～30.3 |
| Drying time (min) | 42 | 55 | 70 |
3. Quality evaluation
The nebivolol hydrochloride orosol film prepared by the prescription 18-20 has complete and smooth appearance, uniform color and no bubbles; the content dissolution meets the requirements, and the prepared oral soluble film can be completely dissolved in 60 seconds. The thickness, tension, disintegration time, dissolution rate and other parameters were measured as shown in Table 15 below.
TABLE 15 parameter determination results for prescription 18-20 films
| Prescription of prescription | Thickness (μm) | Tension (N) | Disintegration time (seconds) | Elution amount (30 m)in) | Content (%) | Mouthfeel of the product |
| 18 | 65±3 | 11.4～13.6 | 23 | 99.2％ | 99.6％ | Preferably, it is |
| 19 | 65±3 | 12.3～13.6 | 25 | 99.8％ | 100.0％ | Preferably, it is |
| 20 | 65±3 | 11.6～13.5 | 26 | 98.9％ | 99.5％ | Preferably, it is |
Example 8: comparative study of stability of self-made film and original ground tablet and dissolution in different dissolution media
1. Stability of
TABLE 16 nebivolol hydrochloride tablet (5 mg) original grinding information
| Chinese name | Nebivolol hydrochloride tablet |
| English name | NebivololHydrochlorideTablets |
| Trade name | Bystolic |
| Specification of specification | 5mg (calculated as nebivolol) |
| Manufacturer' s | AllerganUSA,lnc |
| Lot number | W05647 |
The films and the raw tablets of the prescriptions 15, 18-20 were placed in stability test boxes at 40 ℃ ± 2 ℃ and 75% ± 5% relative humidity for 30 days, respectively, and samples were taken for 0 day and 30 days to detect nitrosamine impurities using LC-MS, and the results are shown in table 17 below.
TABLE 17 detection results of nitrosamine impurities from homemade film preparation and original ground sheet stability samples
The self-made film agent nebivolol nitrosamine impurity of the invention is lower than the original grinding tablet in 0 day and 1 month under the acceleration condition (40 ℃ +/-2 ℃ 75% +/-5% RH), and the problems of nitrosamine impurity preparation process and growth during the stability period can be more strictly controlled by adopting the drying parameters of low temperature drying not exceeding 35 ℃ and preferably 30 ℃ to prepare the film agent.
2. In vitro dissolution
According to the second method (oar method) of dissolution and release measurement of Chinese pharmacopoeia (2020 edition of four general rule 0931), respectively preparing pH 2.0 hydrochloric acid medium, pH 4.5 acetate buffer medium and pH 6.8 phosphate buffer medium, 900ml of dissolution medium needs to be subjected to degassing treatment, the temperature is 37+/-0.5 ℃, the rotating speed is 50rpm, 6 samples of the sample are put into a dissolution cup for dissolution test, and are respectively sampled at 10, 20, 30 and 45 minutes, and measured according to high performance liquid chromatography (2020 edition of four general rule 0512), and the dissolution conditions of self-made film agents and original grinding tablets in different media are respectively examined, and the results are shown in tables 18-20 and figures 1-3.
TABLE 18 comparison of dissolution curves of self-made film and raw ground tablets in pH 2.0 hydrochloric acid medium
| Dissolution time | 10min | 20min | 30min | 45min |
| Original grinding tablet | 72.3％ | 85.3％ | 91.3％ | 94.9％ |
| Prescription 18 | 88.2％ | 99.2％ | 98.8％ | 99.5％ |
| Prescription 19 | 86.2％ | 96.8％ | 97.2％ | 98.8％ |
| Prescription 20 | 86.8％ | 98.2％ | 99.0％ | 99.3％ |
TABLE 19 comparison of dissolution curves of self-made film and raw ground tablets in acetate medium pH 4.5
| Dissolution time | 10min | 20min | 30min | 45min |
| Original grinding tablet | 53.5％ | 69.8％ | 77.9％ | 86.0％ |
| Prescription 18 | 88.6％ | 96.2％ | 98.9％ | 99.3％ |
| Prescription 19 | 86.9％ | 97.0％ | 97.2％ | 98.8％ |
| Prescription 20 | 88.5％ | 98.2％ | 99.6％ | 99.6％ |
TABLE 20 comparison of dissolution curves of self-made film and raw ground tablets in phosphate Medium at pH 6.8
| Dissolution time | 10min | 20min | 30min | 45min |
| Original grinding tablet | 57.0％ | 69.4％ | 81.5％ | 92.9％ |
| Prescription 18 | 85.4％ | 95.6％ | 97.2％ | 97.6％ |
| Prescription 19 | 82.6％ | 94.2％ | 98.1％ | 98.5％ |
| Prescription 20 | 87.0％ | 93.5％ | 96.5％ | 99.2％ |
In conclusion, the dissolution rate of the film agent designed by the invention in different dissolution media (pH 2.0 hydrochloric acid medium, pH 4.5 acetate buffer solution medium and pH 6.8 phosphate buffer solution medium) is far higher than that of the original grinding sheet, the dissolution amount of the film agent in 10min can be more than 80%, and the release of the prepared oral dissolution film agent medicine is superior to that of the original grinding sheet.
The nebivolol hydrochloride is an oral film, belongs to a low-dissolution high-permeability medicine, is easy to absorb after being disintegrated and dissolved in the body, and provides a new solution for patients with hypertension (especially the elderly with chewing or swallowing difficulties).
Claims (10)
1. A pharmaceutical composition containing nebivolol hydrochloride, which is characterized by comprising 7-14% of nebivolol hydrochloride, 50-80% of film forming material, not more than 20% of plasticizer, not more than 10% of flavoring agent and 2-10% of absorption enhancer by weight.
2. The pharmaceutical composition of claim 1, wherein the film-forming material is selected from at least one of polyvinyl alcohol PVA, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyacrylic acid and polyacrylate, polyvinyl acetate copolymer and polycycloacid, phthalate-formed gelatin, cross-linked gelatin, shellac, water-soluble chemical derivatives of starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium alginate, polyoxyethylene, vinyl acetate, trimethylpentanediol/adipic acid/glycerin cross-linked polymer, vinylpyrrolidone/vinyl acetate copolymer, carboxylated vinyl acetate copolymer.
3. The pharmaceutical composition of claim 1, wherein the plasticizer is at least one selected from the group consisting of glycerin, polyethylene glycol 200, polyethylene glycol 400, propylene glycol, butylene glycol, sorbitol, polysorbate, diethyl phthalate, ethyl citrate, and triacetin.
4. The pharmaceutical composition of claim 1, wherein the flavoring agent is at least one selected from the group consisting of sucralose, ammonium monoglycyrrhetate, aspartame, eucalyptus oil, orange oil, peppermint oil, menthol.
5. The pharmaceutical composition of claim 1, wherein the absorption enhancer is selected from at least one of polyethylene glycol 1000 vitamin E succinate, poloxamer, sodium docusate, benzalkonium chloride, cyclodextrin, polysorbate, chitosan, edetic acid.
6. The pharmaceutical composition according to claim 1, wherein the preparation is in the form of an orosol film having a thickness of 30-80 μm and a specification of 2X 10cm 2 。
7. The pharmaceutical composition of claim 6, wherein the orolytic film agent is fully dissolved in water at 25 ℃ within 60 seconds.
8. The pharmaceutical composition of claim 6, wherein the stretch-break force of the orolytic film agent is greater than 10N.
9. A method of preparing the pharmaceutical composition of claim 1, comprising the steps of:
(1) Dissolving a film forming agent in water;
(2) Adding a plasticizer into the solution prepared in the step (1) for dissolution; then adding nebivolol hydrochloride, a flavoring agent and an absorption accelerator, dissolving and defoaming;
(3) And (3) coating the liquid medicine prepared in the step (2) on a substrate, and drying the liquid medicine at the temperature of not more than 35 ℃ to form a film, thus obtaining the pharmaceutical composition.
10. The method of claim 9, wherein the drying temperature is no more than 30 ℃.
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