CN111759801A - Levetiracetam oral solution and preparation method thereof - Google Patents
Levetiracetam oral solution and preparation method thereof Download PDFInfo
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- CN111759801A CN111759801A CN202010603175.7A CN202010603175A CN111759801A CN 111759801 A CN111759801 A CN 111759801A CN 202010603175 A CN202010603175 A CN 202010603175A CN 111759801 A CN111759801 A CN 111759801A
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- 229940058240 levetiracetam oral solution Drugs 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 40
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 claims abstract description 30
- 229960004002 levetiracetam Drugs 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 22
- 238000001914 filtration Methods 0.000 claims abstract description 19
- 238000001816 cooling Methods 0.000 claims abstract description 18
- 239000000022 bacteriostatic agent Substances 0.000 claims abstract description 17
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 16
- 239000003765 sweetening agent Substances 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 125000003118 aryl group Chemical group 0.000 claims abstract description 13
- 239000006172 buffering agent Substances 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 30
- 239000007788 liquid Substances 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 10
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- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 6
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 6
- 229960004998 acesulfame potassium Drugs 0.000 claims description 6
- 239000000619 acesulfame-K Substances 0.000 claims description 6
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- 238000002156 mixing Methods 0.000 claims description 6
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 6
- 229960003415 propylparaben Drugs 0.000 claims description 6
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 5
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- 238000004321 preservation Methods 0.000 claims description 4
- 108010011485 Aspartame Proteins 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- 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 description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000004376 Sucralose Substances 0.000 claims description 3
- 239000000605 aspartame Substances 0.000 claims description 3
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- 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 3
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- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 3
- 235000019408 sucralose Nutrition 0.000 claims description 3
- 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 3
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 claims description 3
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 claims description 3
- 240000009088 Fragaria x ananassa Species 0.000 claims 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
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- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
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- 230000009286 beneficial effect Effects 0.000 description 4
- 206010015037 epilepsy Diseases 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000220223 Fragaria Species 0.000 description 3
- 229960003965 antiepileptics Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- IODGAONBTQRGGG-ZCFIWIBFSA-N (2r)-2-(2-oxopyrrolidin-1-yl)butanoic acid Chemical compound CC[C@H](C(O)=O)N1CCCC1=O IODGAONBTQRGGG-ZCFIWIBFSA-N 0.000 description 2
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- 230000001037 epileptic effect Effects 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
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- 239000003755 preservative agent Substances 0.000 description 2
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- 108010005730 R-SNARE Proteins Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102000002215 Synaptobrevin Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
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Classifications
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- 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
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- 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
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- 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
- A61K47/26—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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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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Abstract
The invention belongs to the technical field of medicines, and particularly discloses a levetiracetam oral solution and a preparation method thereof. Each 150ml of levetiracetam oral solution comprises: 12-20 g of levetiracetam, 0.1-0.2 g of buffering agent, 0.3-0.5 g of bacteriostatic agent, 45-50 g of sweetening agent, 0.1-0.5 ml of aromatic and the balance of solvent. The preparation method comprises the following steps: dissolving a buffering agent in a solvent, heating to 70-80 ℃, sequentially adding a bacteriostatic agent and a sweetening agent, uniformly stirring, and keeping the temperature; and then cooling to 30-40 ℃, adding levetiracetam, stirring to dissolve, cooling to room temperature, adding an aromatic, uniformly stirring, fixing the volume to the full volume, uniformly stirring, and filtering. The levetiracetam oral solution disclosed by the invention is appropriate in bacteriostatic agent content, good in bacteriostatic effect and high in safety; in the preparation process, the increase of related substances of the raw material medicines can be avoided by controlling the temperature rise and the temperature reduction.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to levetiracetam oral solution and a preparation method thereof.
Background
Epilepsy is a chronic brain disease with recurrent attacks, prolonged course of disease and paroxysmal cerebral dysfunction, and is clinically manifested by symptoms of motor, sensory, consciousness and vegetative nerve dysfunction. Data from WHO statistics show that globally active epileptic patients account for approximately 8.2% of the world's general population, with 80% of patients in developing countries. The prevalence rate of epilepsy in China is about 3.5-4.8 per mill, and the lifetime prevalence rate is 7 per mill. Meanwhile, more than 40 ten thousand new cases occur each year, and the incidence rate of epilepsy of children and teenagers is the highest among the new cases.
Levetiracetam is a novel antiepileptic drug, and belongs to pyrrolidone derivatives. Levetiracetam, unlike traditional antiepileptic drugs that act on ion channels or excitatory and/or inhibitory neurotransmitter systems, is the only antiepileptic drug that has been demonstrated to date to bind synaptobrevin SV2A in presynaptic nerve terminals. The combination of levetiracetam and SV2A inhibits abnormal discharges in the epileptic circuit, thereby blocking seizures. Levetiracetam has a broad anti-epileptic spectrum and can be used for treating various types of epilepsy.
At present, most of the levetiracetam preparations on the market at home are tablets, and the dosage form can not effectively meet the requirements of different patients on divided dosage and is not beneficial to children and patients with dysphagia to take. The oral solution is suitable for children patients to take, and can also meet the requirements of different patients on the divided dose. However, the levetiracetam bulk drug has bitter taste and high drug content, and the oral liquid prepared by the common method has poor taste, so that the oral liquid can be used as an antiepileptic drug which needs to be taken for a long time, which can influence the medication compliance of patients, particularly children patients to a great extent. In addition, in the production process of the existing levetiracetam oral liquid, the temperature is improperly controlled, so that the increase of related substances of the raw material medicines is easily caused, and when the filter material is improperly used in the filtration process, the interception of active ingredients is easily caused, so that the content of active ingredients in the oral liquid is reduced.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a levetiracetam oral solution, which is used for solving the problems of poor taste, poor bacteriostatic effect and the like of the levetiracetam oral solution in the prior art.
The invention also aims to provide a preparation method of the levetiracetam oral solution, which is used for solving the problems that related substances of the bulk drugs are easily increased due to improper temperature control of the production process in the prior art, and active ingredients are easily intercepted due to improper use of filter materials.
The technical problem to be solved by the invention is realized by adopting the following technical scheme.
The invention provides a levetiracetam oral solution, wherein each 150ml of levetiracetam oral solution comprises the following components in parts by weight: 12-20 g of levetiracetam, 0.1-0.2 g of buffering agent, 0.3-0.5 g of bacteriostatic agent, 45-50 g of sweetening agent, 0.1-0.5 ml of aromatic and the balance of solvent.
Optionally, the buffering agent is at least one selected from citric acid-sodium citrate, sodium dihydrogen phosphate-disodium hydrogen phosphate, and acetic acid-sodium acetate.
Optionally, the bacteriostatic agent is selected from at least one of methyl hydroxybenzoate, propyl hydroxybenzoate, benzoic acid and sodium benzoate.
Optionally, the sweetener is at least one selected from maltitol solution, monoammonium glycyrrhizinate S, acesulfame potassium, mannitol, aspartame, and sucralose.
Optionally, the flavoring agent is selected from at least one of grape essence, orange essence, and strawberry essence.
Optionally, the solvent comprises water and glycerol.
Optionally, per 150ml of levetiracetam oral solution comprising: 12-20 g of levetiracetam, 0.1-0.2 g of buffering agent, 0.3-0.5 g of bacteriostatic agent, 45-50 g of sweetening agent, 0.1-0.5 ml of aromatic, 30-35 g of glycerol and the balance of water.
In another aspect, the present invention provides a method for preparing the levetiracetam oral solution, which comprises the following steps:
(1) dissolving a buffering agent in a solvent, heating to 70-80 ℃, adding a bacteriostatic agent, stirring to fully dissolve the bacteriostatic agent, adding a sweetening agent, stirring uniformly, and keeping the temperature to obtain a liquid medicine;
(2) and (2) cooling the liquid medicine obtained in the step (1) to 30-40 ℃, adding levetiracetam, stirring to completely dissolve the levetiracetam, cooling to room temperature, adding an aromatic, stirring and mixing uniformly, fixing the volume to the full volume by using a solvent, stirring uniformly, and filtering to obtain the levetiracetam oral solution.
Optionally, in the step (1), the heat preservation temperature is 70-80 ℃, and the heat preservation time is 5-10 minutes.
Optionally, in the step (2), the filter element made of polyether sulfone is adopted for filtering, so that the production operation is easy, and active ingredients of the liquid medicine are not easy to adsorb.
As described above, the levetiracetam oral solution and the preparation method thereof of the present invention have the following beneficial effects:
the levetiracetam oral solution disclosed by the invention has better mouthfeel under the action of various sweeteners, is higher in clinical compliance, and is more suitable for children patients.
The levetiracetam oral solution disclosed by the invention is appropriate in bacteriostatic agent content, good in bacteriostatic effect and high in safety.
In the preparation process of the levetiracetam oral solution, a heating and cooling process is adopted, wherein the cooling process is a key process step, so that the increase of related substances (levetiracetam acid) of the bulk drugs can be avoided; meanwhile, the polyether sulfone filter core adopted during filtering is easy to produce and operate, is not easy to adsorb active ingredients of the liquid medicine, and has stable product quality and good effectiveness.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The levetiracetam oral solution and the preparation method thereof according to the embodiment of the present invention will be specifically described below.
The embodiment of the invention provides levetiracetam oral solution, wherein each 150ml of levetiracetam oral solution comprises the following components in parts by weight: 12-20 g of levetiracetam, 0.1-0.2 g of buffering agent, 0.3-0.5 g of bacteriostatic agent, 45-50 g of sweetening agent, 0.1-0.5 ml of aromatic and the balance of solvent.
Wherein the buffer is at least one selected from citric acid-sodium citrate, sodium dihydrogen phosphate-disodium hydrogen phosphate, and acetic acid-sodium acetate.
Wherein the antiseptic is at least one selected from methyl hydroxybenzoate, propyl hydroxybenzoate, benzoic acid, and sodium benzoate.
Wherein the sweetener is at least one selected from maltitol solution, ammonium glycyrrhizinate S, acesulfame potassium, mannitol, aspartame, and sucralose.
Wherein the aromatic is at least one of grape essence, orange essence, and strawberry essence.
Wherein the solvent comprises water and glycerol.
Further, per 150ml levetiracetam oral solution comprises: 12-20 g of levetiracetam, 0.1-0.2 g of buffering agent, 0.3-0.5 g of preservative, 45-50 g of sweetening agent, 0.1-0.5 ml of aromatic, 30-35 g of glycerol and the balance of water.
The levetiracetam oral solution formula disclosed by the invention has the beneficial effects that:
the levetiracetam oral solution disclosed by the invention has better mouthfeel under the action of various sweeteners, is higher in clinical compliance, and is more suitable for children patients.
The levetiracetam oral solution disclosed by the invention is appropriate in bacteriostatic agent content, good in bacteriostatic effect and high in safety.
The invention also provides a preparation method of the levetiracetam oral solution, which comprises the following steps:
(1) adding a part of solvent into the liquid preparation tank, dissolving a buffering agent into the solvent, heating to 70-80 ℃, adding a preservative, stirring to fully dissolve the buffer, adding a sweetening agent, stirring uniformly, and then preserving heat at 70-80 ℃ for 5-10 minutes to obtain a liquid medicine;
(2) and (2) cooling the liquid medicine obtained in the step (1) to 30-40 ℃, adding levetiracetam, stirring to completely dissolve the levetiracetam, cooling to room temperature, adding an aromatic, stirring and mixing uniformly, metering the volume to the full volume by using a solvent, stirring uniformly, and filtering by using a polyether sulfone filter element to obtain the levetiracetam oral solution.
The preparation method of the levetiracetam oral solution has the beneficial effects that:
in the preparation process of the levetiracetam oral solution, a heating and cooling process is adopted, wherein the cooling process is a key process step, so that the increase of related substances (levetiracetam acid) of the bulk drugs can be avoided, and the product has stable quality and good effectiveness.
The features and properties of the present invention are described in further detail below with reference to examples.
Examples 1 to 4
Examples 1-4 provide a levetiracetam oral solution, respectively, and the formulation of 150ml of levetiracetam oral solution is as follows:
TABLE 1 levetiracetam oral solution formulations in examples 1-4
The levetiracetam oral solutions of examples 1-4 were prepared by the following steps:
(1) adding 40% of purified water into a liquid preparation tank, adding citric acid and sodium citrate, stirring until the citric acid and the sodium citrate are completely dissolved, adding glycerol, and stirring to uniformly mix;
(2) heating the medicinal liquid to 80 deg.C, adding methyl hydroxybenzoate and propyl hydroxybenzoate, stirring to dissolve, sequentially adding monoammonium glycyrrhizinate S, maltitol solution and acesulfame potassium, stirring, and keeping the temperature at 75 deg.C for 8 min;
(3) cooling the liquid medicine to 40 ℃, adding levetiracetam, stirring to completely dissolve the levetiracetam, cooling to room temperature, adding grape essence, stirring and uniformly mixing, fixing the volume to the full volume by using the residual purified water, and continuously stirring.
(4) And (3) filtering: filtering the mixture by a 0.8 mu m polyethersulfone filter element to obtain the levetiracetam oral solution.
Example 5
Example 5 provides a levetiracetam oral solution, the formulation of 150ml of levetiracetam oral solution is as follows:
table 2 levetiracetam oral solution formulation in example 5
The levetiracetam oral solution of example 5 is prepared by the following steps:
(1) adding purified water with the formula amount of 40% into a liquid preparation tank, adding acetic acid and sodium acetate to adjust the pH value to 5.0, stirring until the mixture is completely dissolved, adding glycerol, and stirring to uniformly mix the glycerol and the solution;
(2) heating the liquid medicine to 70 ℃, adding sodium benzoate, stirring to fully dissolve the sodium benzoate, sequentially adding monoammonium glycyrrhizinate S, maltitol solution and acesulfame potassium, stirring, and keeping the temperature at 70 ℃ for 10 minutes;
(3) cooling the medicinal liquid to below 30 ℃, adding levetiracetam, stirring to completely dissolve, cooling to room temperature, adding orange essence, stirring and mixing uniformly, adding the rest purified water to a constant volume, and continuously stirring.
(4) And (3) filtering: filtering the mixture by a 0.8 mu m polyethersulfone filter element to obtain the levetiracetam oral solution.
Example 6
Example 6 provides a levetiracetam oral solution, the formulation of 150ml of levetiracetam oral solution is as follows:
table 3 levetiracetam oral solution formulation in example 6
The levetiracetam oral solution of example 6 is prepared by the following steps:
(1) adding 40% of purified water into a liquid preparation tank, adding citric acid and sodium citrate, stirring until the citric acid and the sodium citrate are completely dissolved, adding glycerol, and stirring to uniformly mix;
(2) heating the medicinal liquid to 80 deg.C, adding methyl hydroxybenzoate and propyl hydroxybenzoate, stirring to dissolve, sequentially adding monoammonium glycyrrhizinate S, maltitol solution and acesulfame potassium, stirring, and maintaining at 80 deg.C for 2 hr;
(3) cooling the liquid medicine to 40 ℃, adding levetiracetam, stirring to completely dissolve the levetiracetam, cooling to room temperature, adding strawberry essence, stirring and uniformly mixing, fixing the volume to the full volume by using the residual purified water, and continuously stirring.
(4) And (3) filtering: filtering the mixture by a 0.8 mu m polyethersulfone filter element to obtain the levetiracetam oral solution.
Example 7
Example 7 provides a levetiracetam oral solution having the same formulation and preparation method as example 1, except that the bacteriostatic agents methylparaben and methylparaben were used in amounts of 80% of example 1.
The levetiracetam oral solutions of example 1 and example 7 were subjected to bacteriostatic efficacy tests and the results are shown in tables 4 and 5.
Table 4 results of bacteriostatic efficacy test of example 7
| Escherichia coli | Staphylococcus aureus | Pseudomonas aeruginosa | Candida albicans | Aspergillus niger | |
| Bacterium liquid set (cfu/ml) | 7.8×106 | 6.3×106 | 2.7×106 | 1.4×105 | 1.8×105 |
| Lg value of bacterial liquid group | 6.9 | 6.8 | 6.4 | 5.1 | 5.3 |
| 14d(cfu/ml) | <10 | <10 | <10 | <10 | <10 |
| 14d lg value | <1 | <1 | <1 | <1 | <1 |
| Reduction of lg value | >5.9 | >5.8 | >5.4 | >4.1 | >4.3 |
| 28d(cfu/ml) | <10 | <10 | <10 | <10 | <10 |
| 28d lg value | <1 | <1 | <1 | <1 | <1 |
| Reduction of lg value | NI | NI | NI | NI | NI |
Table 5 results of bacteriostatic efficacy test of example 1
| Escherichia coli | Staphylococcus aureus | Pseudomonas aeruginosa | Candida albicans | Aspergillus niger | |
| Bacterium liquid set (cfu/ml) | 7.8×106 | 6.3×106 | 2.7×106 | 1.4×105 | 1.8×105 |
| Lg value of bacterial liquid group | 6.9 | 6.8 | 6.4 | 5.1 | 5.3 |
| 14d(cfu/ml) | <10 | <10 | <10 | <10 | <10 |
| 14d lg value | <1 | <1 | <1 | <1 | <1 |
| Reduction of lg value | >5.9 | >5.8 | >5.4 | >4.1 | >4.3 |
| 28d(cfu/ml) | <10 | <10 | <10 | <10 | <10 |
| 28d lg value | <1 | <1 | <1 | <1 | <1 |
| Reduction of lg value | NI | NI | NI | NI | NI |
And (4) conclusion: according to the test results and by combining the antibacterial effectiveness judgment standard of the oral preparation, the antibacterial effectiveness measurement results of the levetiracetam oral liquid in the embodiments 1 and 7 both accord with the antibacterial effectiveness judgment standard of the oral preparation in an antibacterial effectiveness inspection method 1121 in the four general rules of 2015 in Chinese pharmacopoeia; and the test results show that the test results of the antibacterial effectiveness of the levetiracetam oral solutions in the embodiment 1 and the embodiment 7 are consistent, and each 150ml of levetiracetam oral solution has good antibacterial effect when the dosage of antibacterial agent methyl hydroxybenzoate is 2.16-2.7 mg/ml and the dosage of propyl hydroxybenzoate is 0.24-0.3 mg/ml.
Example 8
The final liquid medicine obtained in step (3) of example 1 was filtered by the following filtering method, and the filtering effect of different filtering materials was examined.
TABLE 6 comparative investigation data of different material filtering materials
And (4) conclusion: according to the test results, the content of the sample and the content of related substances before and after filtration are not obviously changed by adopting the filter material made of the polyether sulfone, and other filter materials (mixed cellulose ester) slightly adsorb the substances.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. A levetiracetam oral solution, characterized in that per 150ml of levetiracetam oral solution comprises: 12-20 g of levetiracetam, 0.1-0.2 g of buffering agent, 0.3-0.5 g of bacteriostatic agent, 45-50 g of sweetening agent, 0.1-0.5 ml of aromatic and the balance of solvent.
2. Levetiracetam oral solution according to claim 1, characterized in that: the buffer is at least one selected from citric acid-sodium citrate, sodium dihydrogen phosphate-disodium hydrogen phosphate, and acetic acid-sodium acetate.
3. Levetiracetam oral solution according to claim 1, characterized in that: the bacteriostatic agent is selected from at least one of methyl hydroxybenzoate, propyl hydroxybenzoate, benzoic acid, and sodium benzoate.
4. Levetiracetam oral solution according to claim 1, characterized in that: the sweetener is at least one selected from maltitol solution, ammonium glycyrrhizinate S, acesulfame potassium, mannitol, aspartame and sucralose.
5. Levetiracetam oral solution according to claim 1, characterized in that: the aromatic is at least one of grape essence, orange essence and strawberry essence.
6. Levetiracetam oral solution according to claim 1, characterized in that: the solvent comprises water and glycerol.
7. Levetiracetam oral solution according to claim 6, characterized in that: each 150ml of levetiracetam oral solution comprises: 12-20 g of levetiracetam, 0.1-0.2 g of buffering agent, 0.3-0.5 g of bacteriostatic agent, 45-50 g of sweetening agent, 0.1-0.5 ml of aromatic, 30-35 g of glycerol and the balance of water.
8. A method of preparing levetiracetam oral solution according to any of claims 1-7, characterized in that: the method comprises the following steps:
(1) dissolving a buffering agent in a solvent, heating to 70-80 ℃, adding a bacteriostatic agent, stirring to fully dissolve the bacteriostatic agent, adding a sweetening agent, stirring uniformly, and keeping the temperature to obtain a liquid medicine;
(2) and (2) cooling the liquid medicine obtained in the step (1) to 30-40 ℃, adding levetiracetam, stirring to completely dissolve the levetiracetam, cooling to room temperature, adding an aromatic, stirring and mixing uniformly, fixing the volume to the full volume by using a solvent, stirring uniformly, and filtering to obtain the levetiracetam oral solution.
9. The method of claim 8, wherein: in the step (1), the heat preservation temperature is 70-80 ℃, and the heat preservation time is 5-10 minutes.
10. The method of claim 8, wherein: in the step (2), a filter element made of polyether sulfone is adopted for filtering.
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