CN106466307A - Ibuprofen and glycine betaine pharmaceutical composition and preparation method thereof - Google Patents
Ibuprofen and glycine betaine pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN106466307A CN106466307A CN201510507138.5A CN201510507138A CN106466307A CN 106466307 A CN106466307 A CN 106466307A CN 201510507138 A CN201510507138 A CN 201510507138A CN 106466307 A CN106466307 A CN 106466307A
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- ibuprofen
- glycine betaine
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Abstract
The invention belongs to field of medicaments is and in particular to a kind of have ibuprofen medicinal composition that pipe intestinal protection acts on and preparation method thereof.Technical problem solved by the invention is the ibuprofen and glycine betaine pharmaceutical composition providing and having pipe intestinal protection effect, and it comprises ibuprofen and glycine betaine, and the weight portion of ibuprofen is 1 part, and the weight portion of glycine betaine is 1-12 part.Present invention also offers ibuprofen and glycine betaine drug combination preparation, it is that clinical safety effectively applies ibuprofen to provide a kind of new selection.
Description
Technical field
The present invention relates to field of pharmaceutical preparations and in particular to a kind of have pipe intestinal protection effect ibuprofen medicinal composition and its
Preparation method.
Background technology
Active component in the present invention is ibuprofen (ibuprofen), and its chemical structural formula is as follows：
From it, in nineteen sixties, invention starts to become very famous medicine to ibuprofen (ibuprofen), and at present
With various trade names, sell for oral and intravenous administration medicament forms, for treatment pain, inflammation
Disease and heating.But ibuprofen has gastrointestinal side effect, may occur in which epigastric discomfort, dull pain, Nausea and vomiting, glutted,
The indigestion symptoms such as gas, loss of appetite.In the patient of Long-term Oral ibuprofen, about 30% patient occurs digestibility to burst
Infectionss, or even have patient that serious complication such as bleeding or perforation occurs.So, need when taking ibuprofen to add gastrointestinal tract guarantor
The medicine of shield property.
In the present invention, another composition is glycine betaine (betaine), and its chemical structural formula is as follows：
Glycine betaine (betaine), no strong hygroscopicity, nontoxic, physico-chemical property is stable, high temperature resistant (200 DEG C), extensively
General it is distributed in nature.Glycine betaine can participate in methyl circulation in animal body, can replace as nutrient feed additive part
Methionine, reduces the production cost of feedstuff.Meanwhile, glycine betaine is to human body cardiovascular diseases, neural class, liver class and high half Guang
The diseases such as acidaminuria disease have certain therapeutical effect, can alternately medicine use.Glycine betaine is used for treating homocysteinuria
Disease, early in 1996 in U.S.'s listing, and in 2007 in European Union's listing.
Have not yet to see the relevant report that ibuprofen and glycine betaine are used in combination.
Content of the invention
Technical problem solved by the invention is to provide the pharmaceutical composition of the ibuprofen with pipe intestinal protection effect and glycine betaine.
In described ibuprofen glycine betaine pharmaceutical composition, the weight portion of ibuprofen is 1 part, and the weight portion of glycine betaine is 1-12 part.
The weight portion being preferably ibuprofen is 1 part, and the weight portion of glycine betaine is 1-6 part.
The weight portion of most preferably ibuprofen is 1 part, and the weight portion of glycine betaine is 2.5 parts.
The preparation that above-mentioned ibuprofen and betaine group compound are made, dosage form is hard capsule, tablet, granule, oral liquid.
Inventor, through a series of investigations, has been surprisingly found that glycine betaine when with ibuprofen use in conjunction, the damage of gastric mucosa and ulcer
More alone ibuprofen substantially mitigates.
Secondly, ibuprofen would generally cause stomach permeability to increase, and this often betides the sign before ulcer, therefore investigates penetrating
Performance reflects stomach early lesion.Compared with alone ibuprofen, ibuprofen and glycine betaine drug combination significantly reduce the penetrating of sucrose
Rate.Show, ibuprofen and glycine betaine use in conjunction are capable of the generation of pre- ulcer.
Finally, have been surprisingly found that in research, when ibuprofen and glycine betaine drug combination, the relative bioavailability of ibuprofen has bright
Aobvious raising.
Specific embodiment
Test case 1
The inhibition that the alimentary canal mucous membrane that the different consumption of glycine betaine causes to ibuprofen damages
1. reagent
Ibuprofen is bought from Zibo Xinhua-hundred Li Gao Pharmaceutical Co, and glycine betaine is from the limited public affairs of Shanghai promise occasion biotechnology
Department buys.
2. animal
Buy the male Wistar rat of 8 week old, weight is in 220-250g.By rat put into 20～26 DEG C of temperature, humidity 30～
70% raise in case so as to freely taking food feedstuff and the tap water by water filter and being raised.Through 7
After it preparation is raised, tested with 10 for one group.
3 methods
Extracting male Wistar rat is randomly divided into 7 groups, continuously gives following samples respectively 6 days, and medicine is all with carboxymethyl cellulose
Sodium (1%) is as disperse medium.Successive administration puts to death rat in 6 days later, takes gastric tissue, clean with normal saline flushing, uses
Guth method counts ulcer.As follows by Guth standard scoring system：Speckle is rotten to the corn：1 point of note；Rotten to the corn length<1mm：2 points of note；
Rotten to the corn length 1-2mm：3 points of note；Rotten to the corn length 2-3mm：4 points of note；Rotten to the corn length>3mm：5 points of note, rotten to the corn width>
1mm：Score value × 2.Result such as table 2.
4. result of the test
The result that obtained and the group of garden beet alkali ulcer is scored is as shown in table 1.
The different glycine betaine consumption ulcer of table 1 is scored result
As shown in Table 1, glycine betaine consumption, in the range of 200mg/kg-3000mg/kg, has stomach protective effect；But work as glycine betaine
When consumption is 2800mg/kg, all the symptom of irritable in wherein 7 rats.
Test case 2
Gastric injury is typically not only embodied in ulcer, and the generation that gastrointestinal tract permeability increases, prior to the generation of ulcer, is therefore gastrointestinal
One pointer of road early lesion.Ibuprofen can cause gastrointestinal tract permeability to increase, and then forms ulcer.Sucrose as people and moves
The probe of thing gastrointestinal tract permeability, has been used for the labelling of the upper digestive tract side effect that NSAID (non-steroidal anti-inflammatory drug) causes.Sucrose is in health
Permeability on the upper digestive tract path of body is very little, and is hydrolyzed in small intestinal.Therefore after sucrose is administered orally, detect in urine
Caused by the sucrose arriving is the increase of upper digestive tract permeability, by measuring the percolation ratio of sucrose in urine as evaluation stomach permeability
Mark.
1. reagent
Ibuprofen is bought from Zibo Xinhua-hundred Li Gao Pharmaceutical Co, and glycine betaine is from the limited public affairs of Shanghai promise occasion biotechnology
Department buys.
2. animal
Buy the male Wistar rat of 8 week old, weight is in 220-250g.By rat put into 20～26 DEG C of temperature, humidity 30～
70% raise in case so as to freely taking food feedstuff and the tap water by water filter and being raised.Through 7
After it preparation is raised, tested with 10 for one group.
3 methods
Extracting male Wistar rat is randomly divided into 3 groups, continuously gives following samples respectively 6 days, and medicine is all with sodium carboxymethyl cellulose
(1%) as disperse medium, blank control group is given only the disperse medium (group 1) of not pastille, ibuprofen group (200mg/kg)
(group 2), ibuprofen and betaine group (two kinds of medicine difference dosages are 200mg/kg and 500mg/kg) (group 3).Continuously
After administration 6 days, rat is positioned in metabolic cage, is often only given 1ml saturation aqueous sucrose solution, continuous collection urine 8 hours.
Sucrose in urine can generate glucose using the sucrose in hydrolysis urine, adopts trinder reaction method to measure further.
4. result of the test
Obtained and the sucrose Penetration ration of group of garden beet alkali result is as shown in table 3.
Table 2 sucrose Penetration ration result
* ibuprofen group compares P with blank group<0.01
* ibuprofen combination betaine group compares P with ibuprofen group<0.01
As table 3, result show ibuprofen process after the permeability of rat gastric tissue dramatically increase (p<0.01), simultaneously ibuprofen with
Glycine betaine combination group all significantly reduces the Penetration ration (p of sucrose<0.01).It is known that it is to evaluate gastric injury that ulcer is scored
Index directly perceived, and be then the assessment to the damage also intuitively not showed to the evaluation of permeability, from this aspect,
Glycine betaine has the protective effect to initial stage gastric injury.
Test case 3
Ibuprofen combination glycine betaine can improve bioavailability in rat body for the ibuprofen
1. reagent
Ibuprofen is bought from Zibo Xinhua-hundred Li Gao Pharmaceutical Co, and glycine betaine is from the limited public affairs of Shanghai promise occasion biotechnology
Department buys.
2. animal
Buy the male Wistar rat of 8 week old, weight is in 220-250g.By rat put into 20～26 DEG C of temperature, humidity 30～
70% raise in case so as to freely taking food feedstuff and the tap water by water filter and being raised.Through 7
After it preparation is raised, tested with 10 for one group.
3 methods
Extracting male Wistar rat is randomly divided into 2 groups, and empty stomach single dose intersects oral ibuprofen group (200mg/kg) and ibuprofen
Combination betaine group (ibuprofen (200mg/kg)+glycine betaine (500mg/kg)).0.25h after 24h is administered on an empty stomach before medication,
Extracting vein blood 0.5ml isolates serum with centrifuge immediately and puts -40 DEG C of ice respectively for 0.5h, 1h, 2h, 4h, 8h and 12h
To be measured, intertrial interval 1 week twice is preserved in case.
Serum-concentration measures：Blood serum sample 0.1ml is taken to be placed in the indomethacin internal standard in 1ml plastic centrifuge tube plus with acetontrile
After liquid 0.1ml (10 μ g/ml), put 0.5min at water bath sonicator in ultrasonic cleaner, high speed centrifugation (15000rpm, 10min),
Take supernatant 20 μ l.HPLC analysis method：Chromatographic column：Dikma Diamonsil C18 (4.6mm × 250mm, 5 μm)；
Mobile phase：Acetonitrile -0.02mol/L potassium dihydrogen phosphate (uses H3PO4Adjust pH 3.8) (85：15)；Detection wavelength：221nm；
Flow velocity：1.0mL/min；Column temperature：30℃；Sample size：20μL.
4. result of the test
Single dose intersects oral ibuprofen group (group 1) and ibuprofen combination betaine group (group 2), with 3P97 software automatic Iterative
Matching, calculates pharmacokinetic parameter.Result shows：The data fitting result of mean blood plasma concentration-time meets a Room and opens mould
Type, pharmacokinetic parameter result is as shown in table 3.
Table 3 pharmacokinetic parameter result
Application new drug design program NDST5.0 is to AUC0-∞Carry out variance analyses and Doubled haploid population, evaluate both biological profits
Expenditure.Result shows between two groups that there were significant differences (P<0.05), ibuprofen combination betaine group relative bioavailability is better than cloth
Ibuprofen group.
Embodiment 1
Ibuprofen glycine betaine hard capsule
Prescription：
Table 4 ibuprofen glycine betaine capsule prescription
Preparation technology
Tablet is prepared by procedure below, and described item 1-10 is table 4 prescription item.
(1) item 1-4 (glycine betaine, Microcrystalline Cellulose, Pregelatinized Starch, carboxymethyl starch sodium) crosses 100 mesh sieves, adopts
The method that equivalent is progressively increased is mixed uniformly.
(2) in the mixture that item 5 (HPMC 5% aqueous solution) progressively increases in step (1), soft material processed.
(3) soft material in step (2) passes through 20 eye mesh screens granulations.
(4) dry at 60 DEG C in drying baker of granule by being obtained in step (3), when water content is less than 3%, stop dry
Dry.
(5) granule being dried crosses 20 eye mesh screen granulate.
(6) item 6-8 (ibuprofen, Microcrystalline Cellulose, carboxymethyl starch sodium) sieves 100 mesh, the side progressively increased using equivalent
Method is mixed uniformly.
(7) in the mixture that item 9 (HPMC 5% aqueous solution) progressively increases in step (6), soft material processed.
(8) soft material in step (7) passes through 20 eye mesh screens granulations.
(9) dry at 60 DEG C in drying baker of granule by being obtained in step (8), when water content is less than 3%, it is dried
Stop.
(10) granule being dried is crossed 20 eye mesh screens and is arranged.
(11) by step (5) and step (10) gained granule mix homogeneously respectively.
(12) fill becomes capsule.
Embodiment 2
Ibuprofen glycine betaine piece
Prescription：
Table 5 ibuprofen glycine betaine tablet recipe
Preparation method：
Tablet is prepared by procedure below, and described item 1-10 is table 5 prescription item.
(1) item 1-4 (glycine betaine, Microcrystalline Cellulose, Pregelatinized Starch, carboxymethyl starch sodium) sieves 100 mesh, adopts
The method that equivalent is progressively increased is mixed uniformly.
(2) in the mixture that item 5 (HPMC 5% aqueous solution) progressively increases in step (1), soft material processed.
(3) soft material in step (2) passes through 20 eye mesh screens granulations.
(4) dry at 60 DEG C in drying baker of granule by being obtained in step (3), when water content is less than 3%, it is dried
Stop.
(5) granule being dried crosses 20 eye mesh screen granulate.
(6) item 6-8 (ibuprofen, Microcrystalline Cellulose, carboxymethyl starch sodium) sieves 100 mesh, the side progressively increased using equivalent
Method is mixed uniformly.
(7) in the mixture that item 9 (HPMC 5% aqueous solution) progressively increases in step (6), soft material processed.
(8) soft material in step (7) passes through 20 eye mesh screens granulations.
(9) dry at 60 DEG C in drying baker of granule by being obtained in step (8), when water content is less than 3%, it is dried
Stop.
(10) granule being dried is crossed 20 eye mesh screens and is arranged.
(11) by step (5) and step (10) gained granule mix homogeneously respectively.
(12) item 10 (magnesium stearate) is added to step (11) gained granule, mix homogeneously.
(13) tabletting.
Embodiment 3
Ibuprofen glycine betaine granule
Prescription：
Table 6 ibuprofen glycine betaine granule prescription
Preparation method：
Granule is prepared by procedure below, and described item 1-6 is table 6 prescription item.
(1) item 1-2 (ibuprofen, glycine betaine) crosses 100 mesh sieves, after item 3-4 (sucrose, Polyvinylpyrrolidone) pulverizes
Cross 80 mesh sieves, standby.
(2) ibuprofen obtaining and glycine betaine in step (1) are mixed uniformly using the method that equivalent is progressively increased.
(3) item 3 and item 5 are dissolved in boiling water, stir, be configured to filler aqueous solution, standby.
(4) Polyvinylpyrrolidone is dissolved in 50% ethanol water, stirs, be configured to 3% Polyvinylpyrrolidone
50% ethanol water, standby.
(5) take the ibuprofen of mix homogeneously that step 2 obtains and glycine betaine mixture, the filling aqueous solution of spray step 3 gained and
3% Polyvinylpyrrolidone 50% ethanol water of step 4 gained, pelletizes.And material is crossed 40 mesh and 30 mesh sieves, obtain
Master batch to 30-40 mesh.
(6) master batch taking step 5 to be obtained, sprays into the remaining filling aqueous solution of step 3 and the remaining 3% poly- second of step 4
Alkene pyrrolidone 50% ethanol water, obtains the wet ball of 18-30 purpose and puts into 60 DEG C of dryings in hot air circulation drying oven, obtain final product micro-
Ball.
(7) take micropill and remaining sucrose and the sodium cyclamate of step 6 gained, be mixed uniformly using the method that equivalent is progressively increased.
(8), after mixing terminates, remaining 3% Polyvinylpyrrolidone 50% ethanol water is slowly added to soft material processed.
(9) soft material is crossed 18 mesh sieves to pelletize, be dried, add sodium citrate mix homogeneously, subpackage obtains final product.
Embodiment 4
Ibuprofen glycine betaine oral liquid
Prescription：
Table 7 ibuprofen glycine betaine oral liquid prescription
Preparation method：
Oral liquid is prepared by procedure below, and described item 1-4 is table 7 prescription item.
(1) take Mentholum to add glycerol, be stirred well to entirely molten, standby.
(2) take ibuprofen, glycine betaine add 1/2-3/4 purification water dissolution, add sucrose, sodium benzoate, Fructus Citri Limoniae essence,
Pigment, is sufficiently stirred for, dissolving.
(3) step 1 resulting solution is added in step 2 resulting solution, is sufficiently stirred for, filter.
(4) recipe quantity, mix homogeneously are added water to, packaging obtains final product.
The preferred embodiment of the present invention described in detail above.But, the present invention is not limited to concrete in above-mentioned embodiment
Details, in the range of the technology design of the present invention, can carry out multiple simple variant to technical scheme.These are simple
Modification belongs to protection scope of the present invention, and such as ibuprofen can be substituted for ibuprofen sodium salt by equimolar.
It is further to note that each particular technique feature described in above-mentioned specific embodiment, in reconcilable feelings
Under condition, can be combined by any mode.In order to avoid unnecessary repetition, the present invention is to various possible compound modes
No longer separately illustrate.
Additionally, combination in any can also be carried out between the various different embodiment of the present invention, without departing from the think of of the present invention
Think, it equally should be considered as content disclosed in this invention.
Claims (7)
1. a kind of ibuprofen with pipe intestinal protection effect and glycine betaine pharmaceutical composition, it comprises ibuprofen and glycine betaine, and the weight portion of ibuprofen is 1 part, and the weight portion of glycine betaine is 1-12 part.
2., it is characterised in that the weight portion of ibuprofen is 1 part, the weight portion of glycine betaine is 1-6 part for ibuprofen according to claim 1 and glycine betaine pharmaceutical composition.
3., it is characterised in that the weight portion of ibuprofen is 1 part, the weight portion of glycine betaine is 2.5 parts for ibuprofen according to claim 1 and glycine betaine pharmaceutical composition.
4. the ibuprofen according to claims 1 to 3 any claim and glycine betaine pharmaceutical composition are it is characterised in that described ibuprofen is selected from（RS）- ibuprofen,（S）- ibuprofen and its pharmaceutically acceptable salt class.
5. the ibuprofen according to claims 1 to 3 any claim and glycine betaine pharmaceutical composition are it is characterised in that glycine betaine is selected from glycine betaine, the glycine betaine of synthesis and its pharmaceutically acceptable salt class of natural origin.
6. the ibuprofen according to claim 1 to 5 any claim and glycine betaine drug combination preparation are it is characterised in that described preparation is oral formulations.
7. ibuprofen according to claim 6 and glycine betaine drug combination preparation are it is characterised in that described oral formulations are capsule, tablet, granule or oral liquid.
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| CN201510507138.5A CN106466307A (en) | 2015-08-18 | 2015-08-18 | Ibuprofen and glycine betaine pharmaceutical composition and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1863540A (en) * | 2003-10-01 | 2006-11-15 | 丹尼斯科公司 | Method to treat the side effects associated with non steroidal anti-inflammatory drugs using microorganisms of the genus bifidobacterium |
| CN103083314A (en) * | 2011-10-28 | 2013-05-08 | 四川大学 | Compound ibuprofen having gastrointestinal protective effect |
| CN105412038A (en) * | 2015-12-11 | 2016-03-23 | 北京阜康仁生物制药科技有限公司 | Compound preparation containing vonoprazan and non-steroidal anti-inflammatory drugs |
-
2015
- 2015-08-18 CN CN201510507138.5A patent/CN106466307A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1863540A (en) * | 2003-10-01 | 2006-11-15 | 丹尼斯科公司 | Method to treat the side effects associated with non steroidal anti-inflammatory drugs using microorganisms of the genus bifidobacterium |
| CN103083314A (en) * | 2011-10-28 | 2013-05-08 | 四川大学 | Compound ibuprofen having gastrointestinal protective effect |
| CN105412038A (en) * | 2015-12-11 | 2016-03-23 | 北京阜康仁生物制药科技有限公司 | Compound preparation containing vonoprazan and non-steroidal anti-inflammatory drugs |
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