CN108066344A - A kind of oral mixed suspension preparation comprising Lopinavir and Ritonavir - Google Patents
A kind of oral mixed suspension preparation comprising Lopinavir and Ritonavir Download PDFInfo
- Publication number
- CN108066344A CN108066344A CN201611006360.8A CN201611006360A CN108066344A CN 108066344 A CN108066344 A CN 108066344A CN 201611006360 A CN201611006360 A CN 201611006360A CN 108066344 A CN108066344 A CN 108066344A
- Authority
- CN
- China
- Prior art keywords
- lopinavir
- ritonavir
- suspension
- solubilizer
- compound oral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
Abstract
The present invention provides compound oral suspension containing Lopinavir and Ritonavir and preparation method thereof, the oral administration mixed suspension includes Lopinavir and Ritonavir active ingredient and pharmaceutically acceptable auxiliary material.The Lopinavir of the present invention and Ritonavir compound oral suspension stable quality place phenomena such as being not in sedimentation, caking, can be uniformly dispersed rapidly after shaking, good mouthfeel, patient compliance is preferable for a long time.The Lopinavir and Ritonavir compound oral suspension dissolution rate of the present invention is high, improves bioavilability.The formulation preparation method of the present invention is simple, is suitable for industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of compound oral suspension containing Lopinavir and Ritonavir
And preparation method thereof.
Background technology
Human immunodeficiency virus（HIV）It is pathogenic retrovirus, and is acquired immunodeficiency syndrome
（AIDS）And the pathogen of associated conditions.2011, global more than 3,400 ten thousand people of HIV/AIDS Patients, wherein newly-increased 2,500,000, have
1700000 die of relative disease.It is shown according to the Ministry of Public Health of China data, China's AIDS number in 2011 is up to 20450, on year-on-year basis
Increase by 27.96% within 2010,9224 people of death toll increases by 19.13% on a year-on-year basis.
At present, the design of inverase is mainly for three key enzymes in HIV replicative cycles, i.e. reverse transcriptase, albumen
Enzyme, integrase and HIV invasion procedures.According to the difference of drug target, divide six major classes, i.e.,：Nucleoside reverse transcriptase presses down
Preparation（NRTIs）, non-nucleoside reverse transcriptase inhibitor（NNRTIs）, protease inhibitors（PIs）, entry inhibitor（EIs）、
Integrase inhibitor（IIs）With CCR5 receptor antagonists etc..Zidovidine（AZT）It was obtained as first inverase in 1987
It must list, it belongs to efabirenz, and inverase is then global first granted protease inhibitors, by
Roche in nineteen ninety-five develop and by FDA ratify list, clinically with efabirenz（NRTIs）Therapeutic alliance
Full-blown AIDS patient shows good effect, has thus started the drug combination epoch of anti-AIDS treatment.
Lopinavir Ritonavir is the compound protein enzyme inhibitor of first treatment AIDS in the world, is American-European AIDS
One of protease inhibitors preferred in initial antiretroviral therapy scheme for combining in practice guidelines, potent lasting, side effect is mild.
The patent of domestic applications at present relates generally to solid pharmaceutical preparation, and the only patent disclosure of Application No. CN103655571A one kind contains
The compound high evenness nanometer of Lopinavir and Ritonavir is divided into granular media, but the process is more complicated, and to equipment requirement
It is higher, need to sample be ground to by nanoscale using nano dispersion mill, be unfavorable for industrialization production.The present invention develops preparation
Oral administration mixed suspension simple for process, for solid pharmaceutical preparation, oral suspension formulations drug absorption is fast, works rapid, suffers from
Person is convenient to take, but for compound preparation since its drug component is complicated, between each raw material, there is interaction, medicine between auxiliary material
Object stability is bad, and medicine stability but will be negatively affected under solution state.Therefore the present invention uses preparation hand
Section solves problem above, on the one hand adds in the suitable solubilizer of HLB, adds the solubility of active ingredient, on the other hand logical
Addition dispersible cellulose is crossed, solves the problems, such as sample physical stability, compound oral suspension is made, is suitble to children and tool
There is the patient of dysphagia, and greatly improve the bioavilability of sample.
The content of the invention
The present invention provides a kind of compound oral mixed suspension preparations containing Lopinavir and Ritonavir and preparation method thereof.
Compound oral mixed suspension preparation containing Lopinavir and Ritonavir, which is characterized in that including：Lopinavir and profit support
That Wei and pharmaceutically acceptable auxiliary material, wherein, the pharmaceutically acceptable auxiliary material includes solubilizer and dispersed fiber
Element.
The solubilizer is selected from：Polyoxyethylene alkyl ether, polyoxyethylene alkylaryl ether, cithrol, Asia
Alkyl diol fatty-acid monoester, sucrose fatty ester or sorbitan fatty acids monoesters, HLB value is in the range of 4 to 10.
The dispersible cellulose be sodium carboxymethylcellulose and microcrystalline cellulose mixt, ratio 1:5.67-1:
8.09。
The dispersible cellulose is Avicel.
The compound oral suspension of the Lopinavir and Ritonavir, it is characterised in that：Lip river is included per 100mL suspensions
That Wei 2g-20g, Ritonavir 0.5g-5g, solubilizer 1g-30g, dispersible cellulose 40g-80g, wherein, Lopinavir and
The weight ratio of both Ritonavirs is 2:1-6:1.
The particle size range of the active ingredient Lopinavir and Ritonavir is in 1 μm of -100 μ m.
The pharmaceutically acceptable auxiliary material includes：Corrigent, cosolvent, pH adjusting agent and preservative.
The corrigent be selected from sucrose, Aspartame, saccharin sodium, Sucralose, acesulfame potassium, strawberry essence, fragrant citrus essence,
At least one of vanilla；The cosolvent is selected from least one of propylene glycol, ethyl alcohol, glycerine；The pH adjusting agent
In sodium acetate, acetic acid, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, citric acid, sodium citrate, tartaric acid, sodium tartrate
One or more；The preservative is selected from benzoic acid and sodium benzoate, sorbic acid and its sylvite, methyl hydroxybenzoate, ethyl hydroxy benzoate, hydroxyl
At least one of phenylpropyl alcohol ester.
The compound oral suspension containing Lopinavir and Ritonavir described in any of the above item, which is characterized in that include
Following steps：
（1）Glycerine is heated to 50-55 DEG C, adds in preservative, antiseptic solution is made in dissolving；
（2）Dispersible cellulose is added to the water, using High shear device, is uniformly dispersed, uniform suspending system is presented；
（3）The purified water and solubilizer that will warm up 50-55 DEG C are prepared by mixing into dispersion liquid；
（4）By corrigent, step（1）Antiseptic solution obtained and step（2）The suspending system of gained is uniformly mixed, spare；
（5）By the Lopinavir of micronizing and Ritonavir and step（3）In dispersion liquid be uniformly mixed, be added to step（4）
In the mixture of gained, using the violent high-speed stirred of High shear device；
（6）It is appropriate to add in pH adjusting agent, regulating step（5）Suspension pH value to 5.0-6.0 to get.
The present invention can reach following technique effect：
The active ingredient in suspension is disperseed using dispersible cellulose, dispersible cellulose is scattered in liquid can shape
Into thixotropy colloid, it is ensured that Lopinavir and Ritonavir particle in oral administration mixed suspension are scattered in colloid, will not be settled,
Stability is good.And when taking, it shakes 10-20 seconds, colloid disappears, and viscosity declines, convenient for children and the trouble with dysphagia
Person uses.
Specific embodiment
Technical scheme is described in detail in following embodiment, but the present invention is not restricted to the implementation
Example.
Composition：
Preparation process：
（1）Glycerine, propylene glycol are heated to 50-55 DEG C, add in methyl hydroxybenzoate, Nipasol, antiseptic solution is made in dissolving；
（2）By Avicel CL-611（Comparative example 1 is added without）It is added to the water, using High shear device, is uniformly dispersed,
Uniform suspending system is presented；
（3）It will warm up 50-55 DEG C of purified water and polyoxyethylene alkyl ether（Comparative example 2 is added without）It is mixed with ingredient
Dispersion liquid；
（4）By Aspartame, fragrant citrus essence, step（1）Antiseptic solution obtained and step（2）The suspending system mixing of gained
Uniformly, it is spare；
（5）By the Lopinavir of micronizing and Ritonavir and step（3）In dispersion liquid be uniformly mixed, be added to step（4）
In the mixture of gained, using the violent high-speed stirred of High shear device；
（6）Add in citric acid, appropriate sodium citrate, regulating step（5）Suspension pH value to 5.0-6.0 to get.
Evaluation result
（1）Physicochemical property
The different sample physicochemical property evaluation results of table 1
According to the evaluation criterion of oral administration mixed suspension, it is more uniform then to show that drug disperses, generally takes orally closer to 1 for sedimentation volume ratio
The sedimentation volume ratio of suspension is not lower than 0.9, and as shown in Table 1, the comparative example 1 for being not added with dispersible cellulose settles body
For product than unqualified, sample physical stability is poor, will therefore, in prescription be added scattered without follow-up property and study on the stability
Property cellulose can significantly improve sample sedimentation stability, and sample viscosity is moderate, and be uniformly dispersed the period, facilitates administration.
（2）Dissolution rate is investigated
The 0 day dissolution rate of different samples of table 2 is investigated
Table 2 the result shows that, it is relatively low not add the 2 sample 30min stripping quantities of comparative example of solubilizer, therefore, is added in prescription
Solubilizer can preferably improve the dissolution rate of sample.
Claims (8)
1. a kind of compound oral mixed suspension preparation containing Lopinavir and Ritonavir, which is characterized in that including：Lopinavir and profit
Tuo Nawei and pharmaceutically acceptable auxiliary material, wherein, the pharmaceutically acceptable auxiliary material includes solubilizer and dispersiveness is fine
Dimension element.
2. solubilizer is selected from according to claim 1：Polyoxyethylene alkyl ether, polyoxyethylene alkylaryl ether, polyethylene glycol
Aliphatic ester, aklylene glycol fatty-acid monoester, sucrose fatty ester or sorbitan fatty acids monoesters, HLB value is 4
To in the range of 10.
3. dispersible cellulose is sodium carboxymethylcellulose and microcrystalline cellulose mixt according to claim 1, ratio is
1:5.67-1:8.09。
4. dispersible cellulose is Avicel, preferably Avicel RC-591 or Avicel CL-611 according to claim 1.
5. the compound oral suspension of Lopinavir and Ritonavir according to claim 1, it is characterised in that：Per 100mL
Suspension includes Lopinavir 2g-20g, Ritonavir 0.5g-5g, solubilizer 1g-30g, dispersible cellulose 40g-80g,
In, the weight ratio of both Lopinavir and Ritonavir is 2:1-6:1, preferably 4:1.
6. according to claim 1, the particle size range of active ingredient Lopinavir and Ritonavir is in 1 μm of -100 μ m
It is interior, preferably 1 μm -50 μm.
7. pharmaceutically acceptable auxiliary material includes according to claim 1：Corrigent, cosolvent, pH adjusting agent and preservative.
8. prepare compound oral suspension of the claim 1-7 any one of them containing Lopinavir and Ritonavir, feature
It is, comprises the following steps：
（1）Glycerine is heated to 50-55 DEG C, adds in preservative, antiseptic solution is made in dissolving；
（2）Dispersible cellulose is added to the water, using High shear device, is uniformly dispersed, uniform suspending system is presented；
（3）The purified water and solubilizer that will warm up 50-55 DEG C are prepared by mixing into dispersion liquid；
（4）By corrigent, step（1）Antiseptic solution obtained and step（2）The suspending system of gained is uniformly mixed, spare；
（5）By the Lopinavir of micronizing and Ritonavir and step（3）In dispersion liquid be uniformly mixed, be added to step（4）
In the mixture of gained, using the violent high-speed stirred of High shear device；
（6）It is appropriate to add in pH adjusting agent, regulating step（5）Suspension pH value to 5.0-6.0 to get.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611006360.8A CN108066344A (en) | 2016-11-16 | 2016-11-16 | A kind of oral mixed suspension preparation comprising Lopinavir and Ritonavir |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611006360.8A CN108066344A (en) | 2016-11-16 | 2016-11-16 | A kind of oral mixed suspension preparation comprising Lopinavir and Ritonavir |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108066344A true CN108066344A (en) | 2018-05-25 |
Family
ID=62163087
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611006360.8A Pending CN108066344A (en) | 2016-11-16 | 2016-11-16 | A kind of oral mixed suspension preparation comprising Lopinavir and Ritonavir |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108066344A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101991531A (en) * | 2010-11-09 | 2011-03-30 | 武汉人福药业有限责任公司 | Ibuprofen oral suspension and preparation method thereof |
| CN102274231A (en) * | 2011-06-27 | 2011-12-14 | 黑龙江福和华星制药集团股份有限公司 | Capsules filled with lopinavir tablets and ritonavir tablets |
| CN103655571A (en) * | 2012-09-11 | 2014-03-26 | 上海星泰医药科技有限公司 | Lopinavir and ritonavir compound high-uniformity nano co-dispersion body and preparation method thereof |
| EP2753308A1 (en) * | 2011-09-09 | 2014-07-16 | The University of Liverpool | Compositions of lopinavir and ritonavir |
-
2016
- 2016-11-16 CN CN201611006360.8A patent/CN108066344A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101991531A (en) * | 2010-11-09 | 2011-03-30 | 武汉人福药业有限责任公司 | Ibuprofen oral suspension and preparation method thereof |
| CN102274231A (en) * | 2011-06-27 | 2011-12-14 | 黑龙江福和华星制药集团股份有限公司 | Capsules filled with lopinavir tablets and ritonavir tablets |
| EP2753308A1 (en) * | 2011-09-09 | 2014-07-16 | The University of Liverpool | Compositions of lopinavir and ritonavir |
| US20140220141A1 (en) * | 2011-09-09 | 2014-08-07 | The University Of Liverpool | Compositions of lopinavir and ritonavir |
| CN103655571A (en) * | 2012-09-11 | 2014-03-26 | 上海星泰医药科技有限公司 | Lopinavir and ritonavir compound high-uniformity nano co-dispersion body and preparation method thereof |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180525 |