CN115569113A - Valganciclovir hydrochloride oral solution - Google Patents
Valganciclovir hydrochloride oral solution Download PDFInfo
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- CN115569113A CN115569113A CN202211147621.3A CN202211147621A CN115569113A CN 115569113 A CN115569113 A CN 115569113A CN 202211147621 A CN202211147621 A CN 202211147621A CN 115569113 A CN115569113 A CN 115569113A
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- valganciclovir hydrochloride
- oral solution
- valganciclovir
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- ZORWARFPXPVJLW-MTFPJWTKSA-N [2-[(2-amino-6-oxo-3h-purin-9-yl)methoxy]-3-hydroxypropyl] (2s)-2-amino-3-methylbutanoate;hydron;chloride Chemical compound Cl.N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 ZORWARFPXPVJLW-MTFPJWTKSA-N 0.000 title claims abstract description 136
- 229960004983 valganciclovir hydrochloride Drugs 0.000 title claims abstract description 135
- 229940100688 oral solution Drugs 0.000 title claims abstract description 88
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 99
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 66
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 66
- 239000003814 drug Substances 0.000 claims abstract description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 45
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims abstract description 37
- 239000000787 lecithin Substances 0.000 claims abstract description 37
- 235000010445 lecithin Nutrition 0.000 claims abstract description 37
- 229940067606 lecithin Drugs 0.000 claims abstract description 37
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims abstract description 34
- 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 abstract description 33
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 33
- 229930195725 Mannitol Natural products 0.000 claims abstract description 33
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims abstract description 33
- 239000004376 Sucralose Substances 0.000 claims abstract description 33
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000000594 mannitol Substances 0.000 claims abstract description 33
- 235000010355 mannitol Nutrition 0.000 claims abstract description 33
- 239000011780 sodium chloride Substances 0.000 claims abstract description 33
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims abstract description 33
- 239000000600 sorbitol Substances 0.000 claims abstract description 33
- 235000010356 sorbitol Nutrition 0.000 claims abstract description 33
- 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 abstract description 33
- 235000019408 sucralose Nutrition 0.000 claims abstract description 33
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 33
- 239000011975 tartaric acid Substances 0.000 claims abstract description 33
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 31
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 31
- 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 abstract description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 12
- 235000002639 sodium chloride Nutrition 0.000 claims abstract description 12
- 229960004756 ethanol Drugs 0.000 claims abstract description 8
- 229960005150 glycerol Drugs 0.000 claims abstract description 8
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims description 43
- 239000000203 mixture Substances 0.000 claims description 21
- 239000008213 purified water Substances 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 208000030507 AIDS Diseases 0.000 claims description 6
- 241000701022 Cytomegalovirus Species 0.000 claims description 6
- 206010038910 Retinitis Diseases 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000003860 storage Methods 0.000 abstract description 5
- 239000007788 liquid Substances 0.000 description 45
- 238000003756 stirring Methods 0.000 description 40
- 230000000052 comparative effect Effects 0.000 description 21
- 238000001914 filtration Methods 0.000 description 15
- 239000011259 mixed solution Substances 0.000 description 10
- 229920000139 polyethylene terephthalate Polymers 0.000 description 10
- 239000005020 polyethylene terephthalate Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- 239000012528 membrane Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000005286 illumination Methods 0.000 description 5
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 229960002149 valganciclovir Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001471 micro-filtration Methods 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- -1 polyethylene Terephthalate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000012552 review Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
Abstract
The invention relates to valganciclovir hydrochloride oral solution. Specifically, the invention provides a valganciclovir hydrochloride oral solution which comprises valganciclovir hydrochloride, ethanol, glycerol, polyethylene glycol 400, sucralose, sorbitol, mannitol, lecithin, polyvinyl alcohol, tartaric acid, sodium bisulfite, sodium chloride and water. The valganciclovir hydrochloride oral solution provided by the invention has excellent stability, so that the valganciclovir hydrochloride oral solution has excellent storage and transportation stability, the medicine quality is ensured, and the medication safety of the valganciclovir hydrochloride oral solution is further effectively ensured.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to valganciclovir hydrochloride oral solution.
Background
Valganciclovir hydrochloride (CAS number: 175865-59-5) having the following structural formula is suitable for treating patients with acquired immunodeficiency syndrome (AIDS) combined Cytomegalovirus (CMV) retinitis and preventing CMV infection in high-risk solid organ transplant patients:
the existing dosage forms of valganciclovir hydrochloride are mainly solid preparations such as tablets, however, the solid preparations such as tablets relate to the dissolution of the medicine, have slow effect and are inconvenient for patients with swallowing difficulty to administer, and the compliance of the patients is poor. The oral liquid preparation can be prepared by simple batch filling, is suitable for patients with swallowing difficulty to administer, and has strong patient compliance. However, valganciclovir hydrochloride has the problem of poor stability in water and is easily influenced by various factors such as illumination, heat and the like, so that the valganciclovir hydrochloride oral solution has poor stability and is not favorable for the storage and transportation stability of the valganciclovir hydrochloride oral solution, the quality of the valganciclovir hydrochloride oral solution is adversely affected, and the application of the valganciclovir hydrochloride oral solution is limited.
Therefore, there is a need in the art to develop an oral solution of valganciclovir hydrochloride having excellent stability.
Disclosure of Invention
The object of the present invention is to provide an oral solution of valganciclovir hydrochloride having excellent stability.
In a first aspect of the present invention, a valganciclovir hydrochloride oral solution is provided, which comprises valganciclovir hydrochloride, ethanol, glycerol, polyethylene glycol 400, sucralose, sorbitol, mannitol, lecithin, polyvinyl alcohol, tartaric acid, sodium bisulfite, sodium chloride and water.
Preferably, the valganciclovir hydrochloride is 1-10 parts by weight, preferably 3-7 parts by weight, more preferably 4-6 parts by weight, and most preferably 5.0 parts by weight.
Preferably, the valganciclovir hydrochloride content is 1-10g/100ml, preferably 3-7g/100ml, more preferably 4-6g/100ml, and most preferably 5.0g/100ml.
Preferably, the ethanol is 20 to 40 parts by weight, preferably 25 to 35 parts by weight, more preferably 28 to 32 parts by weight, most preferably 30 parts by weight.
Preferably, the ethanol is present in an amount of 20-40g/100ml, preferably 25-35g/100ml, more preferably 28-32g/100ml, most preferably 30g/100ml.
Preferably, the glycerol is present in an amount of 1 to 10 parts by weight, preferably 4 to 8 parts by weight, more preferably 5 to 7 parts by weight, most preferably 6 parts by weight.
Preferably, the glycerol is present in an amount of 1-10g/100ml, preferably 4-8g/100ml, more preferably 5-7g/100ml, most preferably 6g/100ml.
Preferably, the polyethylene glycol 400 is 1 to 10 parts by weight, preferably 3 to 7 parts by weight, more preferably 4 to 6 parts by weight, and most preferably 5.0 parts by weight.
Preferably, the polyethylene glycol 400 is present in an amount of 1-10g/100ml, preferably 3-7g/100ml, more preferably 4-6g/100ml, most preferably 5.0g/100ml.
Preferably, the sucralose is 0.02-0.15 parts by weight, preferably 0.06-0.10 parts by weight, more preferably 0.07-0.09 parts by weight, and most preferably 0.08 parts by weight.
Preferably, the sucralose is present in an amount of 0.02-0.15g/100ml, preferably 0.06-0.10g/100ml, more preferably 0.07-0.09g/100ml, and most preferably 0.08g/100ml.
Preferably, the sorbitol is present in an amount of 1 to 3 parts by weight, preferably 1.5 to 2.5 parts by weight, more preferably 1.8 to 2.2 parts by weight, most preferably 2.0 parts by weight.
Preferably, the sorbitol is present in an amount of 1 to 3g/100ml, preferably 1.5 to 2.5g/100ml, more preferably 1.8 to 2.2g/100ml, most preferably 2.0g/100ml.
Preferably, the mannitol is 0.5 to 3 parts by weight, preferably 1 to 2 parts by weight, more preferably 1.3 to 1.7 parts by weight, most preferably 1.5 parts by weight.
Preferably, the mannitol is present in an amount of 0.5-3g/100ml, preferably 1-2g/100ml, more preferably 1.3-1.7g/100ml, most preferably 1.5g/100ml.
Preferably, the lecithin is present in an amount of 0.1 to 0.5 parts by weight, preferably 0.2 to 0.3 parts by weight, more preferably 0.23 to 0.27 parts by weight, most preferably 0.25 parts by weight.
Preferably, the lecithin is present in an amount of 0.1 to 0.5g/100ml, preferably 0.2 to 0.3g/100ml, more preferably 0.23 to 0.27g/100ml, most preferably 0.25g/100ml.
Preferably, the polyvinyl alcohol is 0.2 to 3 parts by weight, preferably 0.5 to 1.5 parts by weight, more preferably 0.8 to 1.2 parts by weight, and most preferably 1.0 part by weight.
Preferably, the polyvinyl alcohol is present in an amount of 0.2 to 3g/100ml, preferably 0.5 to 1.5g/100ml, more preferably 0.8 to 1.2g/100ml, most preferably 1.0g/100ml.
Preferably, the tartaric acid is 3-5 parts by weight, preferably 3.5-4.5 parts by weight, more preferably 3.8-4.2 parts by weight, most preferably 4.0 parts by weight.
Preferably, the tartaric acid is present in an amount of 3-5g/100ml, preferably 3.5-4.5g/100ml, more preferably 3.8-4.2g/100ml, most preferably 4.0g/100ml.
Preferably, the sodium bisulfite is 0.02 to 0.2 parts by weight, preferably 0.02 to 0.1 parts by weight, more preferably 0.04 to 0.08 parts by weight, most preferably 0.06 parts by weight.
Preferably, the sodium bisulfite is present in an amount of 0.02 to 0.2g/100ml, preferably 0.02 to 0.1g/100ml, more preferably 0.04 to 0.08g/100ml, most preferably 0.06g/100ml.
Preferably, the sodium chloride is present in an amount of 0.05 to 1.0 parts by weight, preferably 0.1 to 0.5 parts by weight, more preferably 0.1 to 0.3 parts by weight, most preferably 0.2 parts by weight.
Preferably, the sodium chloride is present in an amount of 0.05 to 1.0g/100ml, preferably 0.1 to 0.5g/100ml, more preferably 0.1 to 0.3g/100ml, most preferably 0.2g/100ml.
Preferably, the water is present in an amount of 50 to 70 parts by weight, preferably 55 to 65 parts by weight, more preferably 57 to 62 parts by weight, most preferably 58 to 60 parts by weight.
Preferably, the water comprises purified water.
Preferably, the unit of parts by weight is g.
Preferably, the valganciclovir hydrochloride oral solution comprises:
preferably, the valganciclovir hydrochloride oral solution comprises:
| components | Amount of the composition |
| Valganciclovir hydrochloride | 4 to 6 parts by weight of |
| Ethanol | 28-32 parts by weight |
| Glycerol | 5 to 7 parts by weight of |
| Polyethylene glycol 400 | 4 to 6 parts by weight of |
| Sucralose | 0.06-0.10 weight portion |
| Sorbitol | 1.5-2.5 parts by weight |
| Mannitol | 1-2 parts by weight |
| Lecithin (lecithin) | 0.2 to 0.3 part by weight |
| Polyvinyl alcohol | 0.8 to 1.2 parts by weight of |
| Tartaric acid | 3 to 5 parts by weight of |
| Sodium bisulfite | 0.04-0.08 weight part |
| Sodium chloride | 0.1-0.3 weight part; and |
| water (I) | 57-62 parts by weight. |
Preferably, the valganciclovir hydrochloride oral solution comprises:
| components | Dosage of |
| Valganciclovir hydrochloride | 5.0g |
| Ethanol | 30g |
| Glycerol | 6.0g |
| Polyethylene glycol 400 | 5.0g |
| Sucralose | 0.08g |
| Sorbitol | 2.0g |
| Mannitol | 1.5g |
| Lecithin | 0.25g |
| Polyvinyl alcohol | 1.0g |
| Tartaric acid | 4.0g |
| Sodium bisulfite | 0.06g |
| Sodium chloride | 0.2g |
| Purified water | To 100ml. |
In a second aspect of the present invention, there is provided a process for preparing an oral solution of valganciclovir hydrochloride according to the first aspect of the present invention, said process comprising the steps of:
and mixing the valganciclovir hydrochloride, ethanol, glycerol, polyethylene glycol 400, sucralose, sorbitol, mannitol, lecithin, polyvinyl alcohol, tartaric acid, sodium bisulfite, sodium chloride and water to obtain the valganciclovir hydrochloride oral solution.
Preferably, the method comprises:
(1) Stirring, mixing and dissolving 75-85% of water, ethanol, glycerol and polyethylene glycol 400, adding valganciclovir hydrochloride into the mixed solution, stirring, mixing and dissolving to obtain liquid medicine 1;
(2) Adding lecithin and polyvinyl alcohol into the liquid medicine 1, stirring, mixing and dissolving, adding sucralose, sorbitol, mannitol, tartaric acid, sodium bisulfite and sodium chloride into the mixed solution, stirring, mixing and dissolving to obtain liquid medicine 2;
(3) And adding water into the liquid medicine 2 to a constant volume to a dosage volume, uniformly stirring and mixing, and filtering to obtain the valganciclovir hydrochloride oral solution.
Preferably, the method comprises:
(1) Stirring, mixing and dissolving 75-85% of water, ethanol, glycerol and polyethylene glycol 400 at 40-50 ℃, adding valganciclovir hydrochloride into the mixed solution, stirring, mixing and dissolving at 40-50 ℃ to obtain liquid medicine 1;
(2) Adding lecithin and polyvinyl alcohol into the liquid medicine 1, stirring, mixing and dissolving at 40-50 ℃, adding sucralose, sorbitol, mannitol, tartaric acid, sodium bisulfite and sodium chloride into the mixed solution, stirring, mixing and dissolving at 40-50 ℃, and obtaining liquid medicine 2.
(3) And adding water into the liquid medicine 2 to a constant volume to a dosage volume, stirring and mixing uniformly, and filtering to obtain the valganciclovir hydrochloride oral solution.
Preferably, the filtration is by microfiltration.
Preferably, said filtration comprises filtration through 0.45 μm and 0.22 μm microporous filter membranes in that order.
In a third aspect of the present invention, there is provided a kit comprising a transparent container and an oral solution of valganciclovir hydrochloride as defined in the first aspect of the invention.
Preferably, said oral solution of valganciclovir hydrochloride according to the first aspect of the invention is dispensed in said transparent container.
Preferably, the transparent container comprises a transparent plastic container or a transparent glass container.
Preferably, the transparent container comprises a transparent PET bottle.
In a fourth aspect of the present invention, there is provided the use of an oral solution of valganciclovir hydrochloride according to the first aspect of the invention in the manufacture of a medicament for the treatment of Acquired Immune Deficiency Syndrome (AIDS) combined with Cytomegalovirus (CMV) retinitis.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments.
Detailed Description
The invention provides valganciclovir hydrochloride oral solution which comprises valganciclovir, ethanol, glycerol, polyethylene glycol 400, sucralose, sorbitol, mannitol, lecithin, polyvinyl alcohol, tartaric acid, sodium bisulfite, sodium chloride and water. The valganciclovir hydrochloride oral solution provided by the invention has excellent stability, so that the valganciclovir hydrochloride oral solution has excellent storage and transportation stability, the medicine quality is ensured, and the medication safety of the valganciclovir hydrochloride oral solution is further effectively ensured.
Term(s) for
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.
As used herein, the terms "comprising," "including," "containing," and "containing" are used interchangeably and include not only closed-form definitions, but also semi-closed and open-form definitions. In other words, the term includes "consisting of (8230); 8230; composition", "consisting essentially of (8230); 8230; composition".
As used herein, the term "PET" refers to polyethylene Terephthalate, known by the english name Poly (ethylene Terephthalate).
As used herein, the term "polyethylene glycol 400" is abbreviated PEG-400, and is known by the English name Poly (ethylene glycol) 400.
As used herein, the english language of the term "Polyvinyl Alcohol" is Polyvinyl Alcohol, CAS number: 9002-89-5.
As used herein, the english language for the term "Lecithin" is Lecithin, CAS number: 8002-43-5.
As used herein, the term "part by weight" can be any fixed weight expressed in milligrams, grams, or kilograms (e.g., 1mg, 1g, or 1kg, etc.). For example, a composition consisting of 1 part by weight of component a and 9 parts by weight of component b may be a composition consisting of 1g of component a + 9g of component b, or 10g of component a +90 g of component b. In the valganciclovir hydrochloride oral solution, the percentage content of a certain component = (the weight part of the component/the sum of all the weight parts of the component) × 100%, so that in a composition consisting of 1 weight part of the component a and 9 weight parts of the component b, the content of the component a is 10%, and the content of the component b is 90%.
Oral solution
The present invention provides an oral solution of valganciclovir hydrochloride having excellent stability.
The valganciclovir hydrochloride oral solution comprises valganciclovir hydrochloride, ethanol, glycerol, polyethylene glycol 400, sucralose, sorbitol, mannitol, lecithin, polyvinyl alcohol, tartaric acid, sodium bisulfite, sodium chloride and water.
In a preferred embodiment of the present invention, the valganciclovir hydrochloride is 1-10 parts by weight, preferably 3-7 parts by weight, more preferably 4-6 parts by weight, and most preferably 5.0 parts by weight.
Preferably, the valganciclovir hydrochloride content is 1-10g/100ml, preferably 3-7g/100ml, more preferably 4-6g/100ml, and most preferably 5.0g/100ml.
In a preferred embodiment of the present invention, the amount of ethanol is 20 to 40 parts by weight, preferably 25 to 35 parts by weight, more preferably 28 to 32 parts by weight, and most preferably 30 parts by weight.
Preferably, the ethanol is present in an amount of 20-40g/100ml, preferably 25-35g/100ml, more preferably 28-32g/100ml, most preferably 30g/100ml.
In a preferred embodiment of the present invention, the glycerol is 1 to 10 parts by weight, preferably 4 to 8 parts by weight, more preferably 5 to 7 parts by weight, and most preferably 6 parts by weight.
Preferably, the glycerol is present in an amount of 1-10g/100ml, preferably 4-8g/100ml, more preferably 5-7g/100ml, most preferably 6g/100ml.
In a preferred embodiment of the present invention, the polyethylene glycol 400 is 1 to 10 parts by weight, preferably 3 to 7 parts by weight, more preferably 4 to 6 parts by weight, and most preferably 5.0 parts by weight.
Preferably, the polyethylene glycol 400 is present in an amount of 1-10g/100ml, preferably 3-7g/100ml, more preferably 4-6g/100ml, most preferably 5.0g/100ml.
In a preferred embodiment of the present invention, the sucralose is 0.02-0.15 parts by weight, preferably 0.06-0.10 parts by weight, more preferably 0.07-0.09 parts by weight, and most preferably 0.08 parts by weight.
Preferably, the sucralose is present in an amount of 0.02-0.15g/100ml, preferably 0.06-0.10g/100ml, more preferably 0.07-0.09g/100ml, and most preferably 0.08g/100ml.
In a preferred embodiment of the present invention, the sorbitol is 1 to 3 parts by weight, preferably 1.5 to 2.5 parts by weight, more preferably 1.8 to 2.2 parts by weight, and most preferably 2.0 parts by weight.
Preferably, the sorbitol is present in an amount of 1 to 3g/100ml, preferably 1.5 to 2.5g/100ml, more preferably 1.8 to 2.2g/100ml, most preferably 2.0g/100ml.
In a preferred embodiment of the present invention, the mannitol is 0.5 to 3 parts by weight, preferably 1 to 2 parts by weight, more preferably 1.3 to 1.7 parts by weight, and most preferably 1.5 parts by weight.
Preferably, the mannitol is present in an amount of 0.5-3g/100ml, preferably 1-2g/100ml, more preferably 1.3-1.7g/100ml, most preferably 1.5g/100ml.
In a preferred embodiment of the present invention, the lecithin is 0.1 to 0.5 parts by weight, preferably 0.2 to 0.3 parts by weight, more preferably 0.23 to 0.27 parts by weight, most preferably 0.25 parts by weight.
Preferably, the lecithin is present in an amount of 0.1 to 0.5g/100ml, preferably 0.2 to 0.3g/100ml, more preferably 0.23 to 0.27g/100ml, most preferably 0.25g/100ml.
In a preferred embodiment of the present invention, the polyvinyl alcohol is 0.2 to 3 parts by weight, preferably 0.5 to 1.5 parts by weight, more preferably 0.8 to 1.2 parts by weight, and most preferably 1.0 part by weight.
Preferably, the polyvinyl alcohol is present in an amount of 0.2 to 3g/100ml, preferably 0.5 to 1.5g/100ml, more preferably 0.8 to 1.2g/100ml, most preferably 1.0g/100ml.
In a preferred embodiment of the present invention, the tartaric acid is 3 to 5 parts by weight, preferably 3.5 to 4.5 parts by weight, more preferably 3.8 to 4.2 parts by weight, and most preferably 4.0 parts by weight.
Preferably, the tartaric acid is present in an amount of 3-5g/100ml, preferably 3.5-4.5g/100ml, more preferably 3.8-4.2g/100ml, most preferably 4.0g/100ml.
In a preferred embodiment of the present invention, the sodium bisulfite is 0.02 to 0.2 parts by weight, preferably 0.02 to 0.1 parts by weight, more preferably 0.04 to 0.08 parts by weight, and most preferably 0.06 parts by weight.
Preferably, the sodium bisulfite is present in an amount of 0.02 to 0.2g/100ml, preferably 0.02 to 0.1g/100ml, more preferably 0.04 to 0.08g/100ml, most preferably 0.06g/100ml.
In a preferred embodiment of the present invention, the sodium chloride is 0.05 to 1.0 part by weight, preferably 0.1 to 0.5 part by weight, more preferably 0.1 to 0.3 part by weight, and most preferably 0.2 part by weight.
Preferably, the sodium chloride is present in an amount of 0.05 to 1.0g/100ml, preferably 0.1 to 0.5g/100ml, more preferably 0.1 to 0.3g/100ml, most preferably 0.2g/100ml.
In a preferred embodiment of the present invention, the amount of water is 50 to 70 parts by weight, preferably 55 to 65 parts by weight, more preferably 57 to 62 parts by weight, most preferably 58 to 60 parts by weight.
Preferably, the water comprises purified water.
Preferably, the unit of parts by weight is g.
Typically, the valganciclovir hydrochloride oral solution comprises:
typically, the valganciclovir hydrochloride oral solution comprises:
| components | Dosage of |
| Valganciclovir hydrochloride | 4-6 parts by weight of |
| Ethanol | 28-32 parts by weight |
| Glycerol | 5 to 7 parts by weight of |
| Polyethylene glycol 400 | 4 to 6 parts by weight of |
| Sucralose | 0.06-0.10 weight portion |
| Sorbitol | 1.5-2.5 parts by weight |
| Mannitol | 1 to 2 parts by weight of |
| Lecithin (lecithin) | 0.2 to 0.3 part by weight |
| Polyvinyl alcohol | 0.8 to 1.2 parts by weight of |
| Tartaric acid | 3 to 5 portions of |
| Sodium bisulfite | 0.04-0.08 part by weight |
| Sodium chloride | 0.1-0.3 weight parts; and |
| water (W) | 57-62 parts by weight. |
Typically, the valganciclovir hydrochloride oral solution comprises:
Method
the invention provides a preparation method of valganciclovir hydrochloride oral solution, which comprises the following steps:
and mixing the valganciclovir hydrochloride, ethanol, glycerol, polyethylene glycol 400, sucralose, sorbitol, mannitol, lecithin, polyvinyl alcohol, tartaric acid, sodium bisulfite, sodium chloride and water to obtain the valganciclovir hydrochloride oral solution.
In a preferred embodiment of the present invention, the method comprises:
(1) Stirring, mixing and dissolving 75-85% of water, ethanol, glycerol and polyethylene glycol 400, adding valganciclovir hydrochloride into the mixed solution, stirring, mixing and dissolving to obtain liquid medicine 1;
(2) Adding lecithin and polyvinyl alcohol into the liquid medicine 1, stirring, mixing and dissolving, adding sucralose, sorbitol, mannitol, tartaric acid, sodium bisulfite and sodium chloride into the mixed solution, stirring, mixing and dissolving to obtain liquid medicine 2;
(3) And adding water into the liquid medicine 2 to a constant volume to a dosage volume, uniformly stirring and mixing, and filtering to obtain the valganciclovir hydrochloride oral solution.
Typically, the method comprises:
(1) Stirring, mixing and dissolving 75-85% of water, ethanol, glycerol and polyethylene glycol 400 at 40-50 ℃, adding valganciclovir hydrochloride into the mixed solution, stirring, mixing and dissolving at 40-50 ℃ to obtain liquid medicine 1;
(2) Adding lecithin and polyvinyl alcohol into the liquid medicine 1, stirring and mixing at 40-50 ℃ for dissolving, adding sucralose, sorbitol, mannitol, tartaric acid, sodium bisulfite and sodium chloride into the mixed solution, stirring and mixing at 40-50 ℃ for dissolving, and obtaining liquid medicine 2.
(3) And adding water into the liquid medicine 2 to a constant volume to the dosage volume, stirring and mixing uniformly, and filtering to obtain the valganciclovir hydrochloride oral solution.
Preferably, the filtration is by microfiltration.
Preferably, said filtration comprises filtration through 0.45 μm and 0.22 μm microporous filter membranes in that order.
Medicine box
The invention also provides a kit comprising a transparent container and the valganciclovir hydrochloride oral solution.
In a preferred embodiment of the present invention, the valganciclovir hydrochloride oral solution of the present invention is dispensed in the transparent container.
The transparent container according to the present invention may comprise a transparent plastic container or a transparent glass container. For example, the transparent container comprises a transparent PET bottle.
The main excellent technical effects of the invention comprise:
1. the valganciclovir hydrochloride oral solution has excellent stability, so that the valganciclovir hydrochloride oral solution has excellent storage and transportation stability, the medicine quality is ensured, and the medication safety of the valganciclovir hydrochloride oral solution is further effectively ensured.
2. The valganciclovir hydrochloride oral solution developed by the invention has high safety and strong oral compliance of patients.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specifying specific conditions in the following examples are generally carried out under conventional conditions.
Example 1 oral solution of valganciclovir hydrochloride
The formula of valganciclovir hydrochloride oral solution of this example 1 is shown in table 1:
TABLE 1 prescription composition of valganciclovir hydrochloride oral solution (specification: 5g/100 ml)
| Components | Dosage of |
| Valganciclovir hydrochloride | 5.0g |
| Ethanol | 30g |
| Glycerol | 6.0g |
| Polyethylene glycol 400 | 5.0g |
| Sucralose | 0.08g |
| Sorbitol | 2.0g |
| Mannitol | 1.5g |
| Lecithin | 0.25g |
| Polyvinyl alcohol | 1.0g |
| Tartaric acid | 4.0g |
| Sodium bisulfite | 0.06g |
| Sodium chloride | 0.2g |
| Purified water | To 100ml |
The valganciclovir hydrochloride oral solution of this example 1 is prepared as follows:
(1) After the purified water with the prescription amount of 80 percent after boiling and cooling, the ethanol with the prescription amount, the glycerol with the prescription amount and the polyethylene glycol 400 with the prescription amount are stirred, mixed and dissolved at the temperature of 45 ℃, the valganciclovir hydrochloride with the prescription amount is added into the mixed liquid, and the liquid medicine 1 is obtained after stirring, mixing and dissolving at the temperature of 45 ℃.
(2) Adding prescription amount of lecithin and prescription amount of polyvinyl alcohol into the liquid medicine 1, stirring, mixing and dissolving at 45 ℃, adding prescription amount of sucralose, prescription amount of sorbitol, prescription amount of mannitol, prescription amount of tartaric acid, prescription amount of sodium bisulfite and prescription amount of sodium chloride into the mixed liquid, stirring, mixing and dissolving at 45 ℃, and obtaining liquid medicine 2.
(3) Adding boiled and cooled purified water into the liquid medicine 2 to fix the volume to the dosage volume, stirring and mixing uniformly, filtering by 0.45 mu m and 0.22 mu m microporous filter membranes in sequence to obtain valganciclovir hydrochloride oral solution, and subpackaging in transparent PET bottles, wherein the specification of each bottle of valganciclovir hydrochloride is 5g/100ml.
Comparative example 1 valganciclovir hydrochloride oral solution
The formulation of valganciclovir hydrochloride oral solution of this comparative example 1 is shown in table 2:
TABLE 2 prescription composition of valganciclovir hydrochloride oral solution (specification: 5g/100 ml)
| Components | Dosage of |
| Valganciclovir hydrochloride | 5.0g |
| Ethanol | 30g |
| Glycerol | 6.0g |
| Polyethylene glycol 400 | 5.0g |
| Sucralose | 0.08g |
| Sorbitol | 4.0g |
| Mannitol | 1.5g |
| Lecithin | 0.25g |
| Polyvinyl alcohol | 1.0g |
| Tartaric acid | 2.0g |
| Sodium bisulfite | 0.06g |
| Sodium chloride | 0.2g |
| Purified water | To 100ml |
The preparation method of valganciclovir hydrochloride oral solution of comparative example 1 is as follows:
(1) After the purified water with the prescription amount of 80 percent after boiling and cooling, the ethanol with the prescription amount, the glycerol with the prescription amount and the polyethylene glycol 400 with the prescription amount are stirred, mixed and dissolved at the temperature of 45 ℃, the valganciclovir hydrochloride with the prescription amount is added into the mixed liquid, and the liquid medicine 1 is obtained after stirring, mixing and dissolving at the temperature of 45 ℃.
(2) Adding prescription amount of lecithin and prescription amount of polyvinyl alcohol into the liquid medicine 1, stirring, mixing and dissolving at 45 ℃, adding prescription amount of sucralose, prescription amount of sorbitol, prescription amount of mannitol, prescription amount of tartaric acid, prescription amount of sodium bisulfite and prescription amount of sodium chloride into the mixed solution, stirring, mixing and dissolving at 45 ℃, and obtaining the liquid medicine 2.
(3) Adding boiled and cooled purified water into the liquid medicine 2 to a constant volume to a dosage volume, stirring and mixing uniformly, filtering through 0.45 mu m and 0.22 mu m microporous filter membranes in sequence to obtain valganciclovir hydrochloride oral solution, and subpackaging in transparent PET bottles, wherein the specification of valganciclovir hydrochloride in each bottle is 5g/100ml.
Comparative example 2 oral solution of valganciclovir hydrochloride
The formulation of valganciclovir hydrochloride oral solution of this comparative example 2 is shown in table 3:
TABLE 3 prescription composition of valganciclovir hydrochloride oral solution (specification: 5g/100 ml)
| Components | Dosage of |
| Valganciclovir hydrochloride | 5.0g |
| Ethanol | 30g |
| Glycerol | 6.0g |
| Polyethylene glycol 400 | 5.0g |
| Sucralose | 0.08g |
| Sorbitol | 2.0g |
| Mannitol | 1.5g |
| Polyvinyl alcohol | 1.0g |
| Tartaric acid | 4.0g |
| Sodium bisulfite | 0.06g |
| Sodium chloride | 0.2g |
| Purified water | To 100ml |
The preparation method of valganciclovir hydrochloride oral solution of comparative example 2 is as follows:
(1) After the purified water with the prescription amount of 80 percent after boiling and cooling, the ethanol with the prescription amount, the glycerol with the prescription amount and the polyethylene glycol 400 with the prescription amount are stirred, mixed and dissolved at the temperature of 45 ℃, the valganciclovir hydrochloride with the prescription amount is added into the mixed liquid, and the liquid medicine 1 is obtained after stirring, mixing and dissolving at the temperature of 45 ℃.
(2) Adding the polyvinyl alcohol with the prescription amount into the liquid medicine 1, stirring, mixing and dissolving at 45 ℃, adding the sucralose with the prescription amount, the sorbitol with the prescription amount, the mannitol with the prescription amount, the tartaric acid with the prescription amount, the sodium bisulfite with the prescription amount and the sodium chloride with the prescription amount into the mixed liquid, stirring, mixing and dissolving at 45 ℃, and obtaining liquid medicine 2.
(3) Adding boiled and cooled purified water into the liquid medicine 2 to fix the volume to the dosage volume, stirring and mixing uniformly, filtering by 0.45 mu m and 0.22 mu m microporous filter membranes in sequence to obtain valganciclovir hydrochloride oral solution, and subpackaging in transparent PET bottles, wherein the specification of each bottle of valganciclovir hydrochloride is 5g/100ml.
Comparative example 3 oral solution of valganciclovir hydrochloride
The formulation of the valganciclovir hydrochloride oral solution of this comparative example 3 is shown in table 4:
TABLE 4 prescription composition of valganciclovir hydrochloride oral solution (specification: 5g/100 ml)
| Components | Amount of the composition |
| Valganciclovir hydrochloride | 5.0g |
| Ethanol | 30g |
| Glycerol | 6.0g |
| Polyethylene glycol 400 | 5.0g |
| Sucralose | 0.08g |
| Sorbitol | 2.0g |
| Mannitol | 1.5g |
| Lecithin (lecithin) | 0.25g |
| Tartaric acid | 4.0g |
| Sodium bisulfite | 0.06g |
| Sodium chloride | 0.2g |
| Purified water | To 100ml |
The preparation method of valganciclovir hydrochloride oral solution of comparative example 3 is as follows:
(1) After the purified water with the prescription amount of 80 percent after boiling and cooling, the ethanol with the prescription amount, the glycerol with the prescription amount and the polyethylene glycol 400 with the prescription amount are stirred, mixed and dissolved at the temperature of 45 ℃, the valganciclovir hydrochloride with the prescription amount is added into the mixed liquid, and the liquid medicine 1 is obtained after stirring, mixing and dissolving at the temperature of 45 ℃.
(2) Adding prescription amount of lecithin into the liquid medicine 1, stirring, mixing and dissolving at 45 ℃, adding prescription amount of sucralose, prescription amount of sorbitol, prescription amount of mannitol, prescription amount of tartaric acid, prescription amount of sodium bisulfite and prescription amount of sodium chloride into the mixed solution, stirring, mixing and dissolving at 45 ℃, and obtaining liquid medicine 2.
(3) Adding boiled and cooled purified water into the liquid medicine 2 to fix the volume to the dosage volume, stirring and mixing uniformly, filtering by 0.45 mu m and 0.22 mu m microporous filter membranes in sequence to obtain valganciclovir hydrochloride oral solution, and subpackaging in transparent PET bottles, wherein the specification of each bottle of valganciclovir hydrochloride is 5g/100ml.
Comparative example 4 valganciclovir hydrochloride oral solution
The formulation of valganciclovir hydrochloride oral solution of this comparative example 4 is shown in table 5:
TABLE 5 prescription composition of valganciclovir hydrochloride oral solution (specification: 5g/100 ml)
| Components | Amount of the composition |
| Valganciclovir hydrochloride | 5.0g |
| Ethanol | 30g |
| Glycerol | 6.0g |
| Polyethylene glycol 400 | 5.0g |
| Sucralose | 0.08g |
| Sorbitol | 0.5g |
| Mannitol | 1.5g |
| Lecithin | 0.25g |
| Tartaric acid | 4.0g |
| Sodium bisulfite | 0.06g |
| Sodium chloride | 0.2g |
| Purified water | To 100ml |
The preparation method of valganciclovir hydrochloride oral solution of comparative example 4 is as follows:
(1) After the purified water with the prescription amount of 80 percent after boiling and cooling, the ethanol with the prescription amount, the glycerol with the prescription amount and the polyethylene glycol 400 with the prescription amount are stirred, mixed and dissolved at the temperature of 45 ℃, the valganciclovir hydrochloride with the prescription amount is added into the mixed liquid, and the liquid medicine 1 is obtained after stirring, mixing and dissolving at the temperature of 45 ℃.
(2) Adding prescription amount of lecithin into the liquid medicine 1, stirring, mixing and dissolving at 45 ℃, adding prescription amount of sucralose, prescription amount of sorbitol, prescription amount of mannitol, prescription amount of tartaric acid, prescription amount of sodium bisulfite and prescription amount of sodium chloride into the mixed liquid, stirring, mixing and dissolving at 45 ℃, and obtaining liquid medicine 2.
(3) Adding boiled and cooled purified water into the liquid medicine 2 to a constant volume to a dosage volume, stirring and mixing uniformly, filtering through 0.45 mu m and 0.22 mu m microporous filter membranes in sequence to obtain valganciclovir hydrochloride oral solution, and subpackaging in transparent PET bottles, wherein the specification of valganciclovir hydrochloride in each bottle is 5g/100ml.
Examination of the stability of the oral solution of valganciclovir hydrochloride prepared in example 1 and comparative examples 1-4
1. Stability study of illumination factors
The valganciclovir hydrochloride oral solutions prepared in example 1 and comparative examples 1-4 were placed under light conditions (4500lx, 25 ℃) for 0 day, 10 days and 30 days, and the light stability of the valganciclovir hydrochloride oral solutions prepared in example 1 and comparative examples 1-4 was examined according to the guidelines of the Chinese pharmacopoeia formulation stability test.
The stability inspection indexes of the illumination factors are as follows: the content (%) of valganciclovir and related substances of the valganciclovir hydrochloride oral solution at different investigation time points under the illumination condition are measured by high performance liquid chromatography.
The results of the light factor examination of the valganciclovir hydrochloride oral solutions prepared in example 1 and comparative examples 1-4 at different examination time points are shown in table 6:
TABLE 6 stability examination of light factors (4500lx, 25 deg.C.) for valganciclovir hydrochloride oral solutions prepared in example 1 and comparative examples 1-4
As seen from table 6, the valganciclovir hydrochloride oral solution prepared in example 1 has excellent light stability and strong light stability, and can be simply stored and transported in transparent containers.
2. Accelerated stability review
The valganciclovir hydrochloride oral solutions prepared in example 1 and comparative examples 1-4 were placed under conditions of 40 ± 2 ℃ temperature and RH75 ± 5% relative humidity for 0 day, 1, 3 and 6 months, and the accelerated stability of the valganciclovir hydrochloride oral solutions prepared in example 1 and comparative examples 1-4 was examined according to the chinese pharmacopoeia formulation stability test guidelines.
Accelerated stability survey indexes: the content (%) of valganciclovir and related substances of the valganciclovir hydrochloride oral solution at different investigation time points under the illumination condition are measured by high performance liquid chromatography.
The results of accelerated stability studies of valganciclovir hydrochloride oral solutions prepared in example 1 and comparative examples 1-4 at different study time points are shown in table 7:
TABLE 7 accelerated stability Studies of oral solutions of valganciclovir hydrochloride prepared in example 1 and comparative examples 1-4 at 40 + -2 deg.C and RH75 + -5%
It is seen from table 7 that the valganciclovir hydrochloride oral solution prepared in example 1 has excellent high-temperature and high-humidity accelerated stability, thus having excellent storage and transportation stability, ensuring the quality of the drug, and further effectively ensuring the medication safety of the valganciclovir hydrochloride oral solution.
While the invention has been described in terms of a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the spirit and scope of the invention.
Claims (7)
1. The valganciclovir hydrochloride oral solution is characterized by comprising valganciclovir hydrochloride, ethanol, glycerol, polyethylene glycol 400, sucralose, sorbitol, mannitol, lecithin, polyvinyl alcohol, tartaric acid, sodium bisulfite, sodium chloride and water.
2. The valganciclovir hydrochloride oral solution of claim 1, wherein the valganciclovir hydrochloride is present in an amount of 1 to 10 parts by weight, preferably 3 to 7 parts by weight, more preferably 4 to 6 parts by weight, most preferably 5.0 parts by weight;
the ethanol accounts for 20-40 parts by weight, preferably 25-35 parts by weight, more preferably 28-32 parts by weight, and most preferably 30 parts by weight;
1-10 parts by weight of glycerol, preferably 4-8 parts by weight, more preferably 5-7 parts by weight, and most preferably 6 parts by weight;
1-10 parts of polyethylene glycol 400, preferably 3-7 parts, more preferably 4-6 parts, and most preferably 5.0 parts;
the sucralose is 0.02-0.15 part by weight, preferably 0.06-0.10 part by weight, more preferably 0.07-0.09 part by weight, and most preferably 0.08 part by weight;
1-3 parts of sorbitol, preferably 1.5-2.5 parts, more preferably 1.8-2.2 parts, and most preferably 2.0 parts;
the mannitol is 0.5-3 parts by weight, preferably 1-2 parts by weight, more preferably 1.3-1.7 parts by weight, most preferably 1.5 parts by weight;
the lecithin accounts for 0.1 to 0.5 weight part, preferably 0.2 to 0.3 weight part, more preferably 0.23 to 0.27 weight part, and most preferably 0.25 weight part;
the polyvinyl alcohol is 0.2 to 3 parts by weight, preferably 0.5 to 1.5 parts by weight, more preferably 0.8 to 1.2 parts by weight, and most preferably 1.0 part by weight;
3-5 parts by weight of tartaric acid, preferably 3.5-4.5 parts by weight, more preferably 3.8-4.2 parts by weight, and most preferably 4.0 parts by weight;
the sodium bisulfite is 0.02-0.2 weight parts, preferably 0.02-0.1 weight parts, more preferably 0.04-0.08 weight parts, most preferably 0.06 weight parts;
the sodium chloride is 0.05 to 1.0 weight part, preferably 0.1 to 0.5 weight part, more preferably 0.1 to 0.3 weight part, and most preferably 0.2 weight part; and
the amount of the water is 50 to 70 parts by weight, preferably 55 to 65 parts by weight, more preferably 57 to 62 parts by weight, most preferably 58 to 60 parts by weight.
3. The valganciclovir hydrochloride oral solution of claim 1, wherein the valganciclovir hydrochloride oral solution comprises:
4. The valganciclovir hydrochloride oral solution of claim 1, wherein the valganciclovir hydrochloride oral solution comprises:
5. The valganciclovir hydrochloride oral solution of claim 1, wherein the valganciclovir hydrochloride oral solution comprises:
6. A method of preparing the oral solution of valganciclovir hydrochloride of claim 1, said method comprising the steps of:
and mixing the valganciclovir hydrochloride, ethanol, glycerol, polyethylene glycol 400, sucralose, sorbitol, mannitol, lecithin, polyvinyl alcohol, tartaric acid, sodium bisulfite, sodium chloride and water to obtain the valganciclovir hydrochloride oral solution.
7. Use of valganciclovir hydrochloride in oral solution according to claim 1 for the preparation of a medicament for the treatment of Acquired Immune Deficiency Syndrome (AIDS) combined Cytomegalovirus (CMV) retinitis.
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| CN202211147621.3A Active CN115569113B (en) | 2022-09-19 | 2022-09-19 | Valganciclovir hydrochloride oral solution |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190117775A1 (en) * | 2006-12-13 | 2019-04-25 | Hoffmann-La Roche Inc. | Novel pharmaceutical dosage forms comprising valganciclovir hydrochloride |
| CN110934823A (en) * | 2019-12-27 | 2020-03-31 | 湖北康源药业有限公司 | Valganciclovir hydrochloride oral solution and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190117775A1 (en) * | 2006-12-13 | 2019-04-25 | Hoffmann-La Roche Inc. | Novel pharmaceutical dosage forms comprising valganciclovir hydrochloride |
| CN110934823A (en) * | 2019-12-27 | 2020-03-31 | 湖北康源药业有限公司 | Valganciclovir hydrochloride oral solution and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| NASR H. ANAIZI, ET AL.: "Stability of valganciclouir in an extemporaneously compounded oral liquid", AM J HEALTH-SYST PHARM, vol. 59, pages 1267 - 1270, XP009105972 * |
| 安富荣, 曹惠明: "口服抗病毒新药――缬更昔洛韦", 中国新药与临床杂志, no. 10, pages 612 - 614 * |
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