CN103083314A - Compound ibuprofen having gastrointestinal protective effect - Google Patents
Compound ibuprofen having gastrointestinal protective effect Download PDFInfo
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- CN103083314A CN103083314A CN2012104182404A CN201210418240A CN103083314A CN 103083314 A CN103083314 A CN 103083314A CN 2012104182404 A CN2012104182404 A CN 2012104182404A CN 201210418240 A CN201210418240 A CN 201210418240A CN 103083314 A CN103083314 A CN 103083314A
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Abstract
The invention belongs to the field of medicines, in particular to a brand-new compound ibuprofen having a gastrointestinal protective effect. The technical problem to be solved is to provide the compound ibuprofen having the gastrointestinal protective effect; by utilizing the stomach protective effect of nizatidine after taking ibuprofen, gastric side effects of ibuprofen can be improved; the purpose of protecting stomach is achieved; and the compound ibuprofen comprises 15-120 parts of ibuprofen or pharmaceutical salts thereof by weight and 1-40 parts of nizatidine by weight. Furthermore, according to the invention, the technical disadvantages of being easy to degrade nizatidine and poor in stability caused by compatible application of nizatidine and ibuprofen are also overcome; an available solution is provided; and a novel selection for applying ibuprofen safely and effectively in clinical application is provided.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of brand-new compound iuprofen with pipe intestinal protection effect.
Background technology
Ibuprofen (ibuprofen) is a line medicine of the acute and chronic rheumatism for the treatment of.Rheumatic arthritis is a kind of autoimmune disease, and disease condition needs long-term prescription for outbreak repeatedly.Osteoarthritis is a kind of arthralgia that causes due to the articular cartilage degeneration and person in middle and old age's common disease of joint function disturbance (comprising joint deformity), and the number of China's osteoarthritis is 100,000,000 people left and right.Osteoarthritis is the performance that the osteoarthrosis physiological is degenerated, and there is no the medicine that reverses or end this disease progression, so also need long-term prescription.But ibuprofen has the gastrointestinal side effect, epigastric discomfort, dull pain can occur, feels sick, the indigestion symptoms such as vomiting, glutted, belch, loss of appetite.In the patient of Long-term Oral ibuprofen, peptic ulcer occurs in nearly 30% patient, even has the patient serious complication such as hemorrhage or perforation to occur.So, need to add the medicine of pipe intestinal protection when taking ibuprofen.
The histamine H2-receptor selective antagonist is the prevention of present definite effect and treats gastrointestinal ulceration, dyspeptic medicine.Mainly comprise cimetidine, ebrotidine, ranitidine, nizatidine, famotidine, roxatidine acetate and lafutidine etc.Wherein nizatidine can suppress the combination of histamine and gastric mucosa parietal cell histamine H2-receptor, has the effect of gastric acid secretion inhibiting very doughtily.This medical instrument has Drug tolerance preferably, and it does not suppress the hepatomicrosome cytochrome P 450 Enzyme, and without the effect of antiandrogen.Lafutidine is long-acting, potent bisfentidine.The Acidinhibitor of roxatidine acetate is strong, also has mucosa, also without the antiandrogen effect, does not hinder the drug metabolism of liver.In existing report, existing ibuprofen and famotidine, the report that ibuprofen and lafutidine, ibuprofen and ranitidine compatibility are used, as CN101516368A, CN101257800A, CN102247371A.
Based on above-mentioned bibliographical information; the present inventor is investigating ibuprofen and famotidine, lafutidine, discovery when ranitidine is used in conjunction with, and famotidine and lafutidine are not all the best H2 receptor-selective antagonisies of gastric injury protection effect that ibuprofen is caused.The present invention causes the mechanism of the protection of gastric injury according to H2 receptor-selective antagonist to ibuprofen, assessed from many aspects the effect of several typical H2 receptor-selective antagonisies.For ranitidine, its major side effects is infringement liver function and antiandrogen effect.And when investigating cimetidine, because cimetidine is histamine H2-receptor selective antagonist first generation medicine, Acidinhibitor a little less than, and suppress liver drug enzyme, side effect is many, the effect that acts in similar antagonist is the most weak, is not ideal selection.Ebrotidine is that the dosage that reaches therapeutical effect and need is 800mg/ time, and dosage is too large, can cause difficulty to preparation.Therefore the inventor abandons screening ranitidine, cimetidine and ebrotidine.The inventor has compared the protection of the gastric injury that several typical H2 receptor-selective antagonisies such as nizatidine, famotidine, lafutidine and roxatidine acetate cause ibuprofen.
The inventor is through a series of investigations; unexpected discovery nizatidine is when using with the ibuprofen compatibility; obviously be better than other histamine H2-receptor selective antagonists aspect antiulcer, therefore the present inventor adopts nizatidine to investigate it to the protection of the gastrointestinal side effect taking ibuprofen and cause.
Summary of the invention
First technical problem solved by the invention is to provide the compound iuprofen with pipe intestinal protection effect, utilizes nizatidine to taking the stomach protective effect after ibuprofen.
Nizatidine nizatidine is the gastric acid secretion inhibitor that histamine is incorporated into the gastric acid secretion cell, can stop gastric mucosa parietal cell histamine H2-receptor, thereby have gastric acid secretion inhibiting effect very doughtily, belongs to the selective antagonist of H2 receptor.Adopt nizatidine can reduce the incidence rate of patient's digestive tract ulcer; Simultaneously nizatidine has Drug tolerance preferably, and it does not suppress the hepatomicrosome cytochrome P 450 Enzyme, and without the effect of antiandrogen.It is used for active duodenal ulcer, consumption per day 300mg, benign gastric ulcer consumption per day 300mg, prevention duodenal ulcer consumption per day 150mg.
When estimating the stomach protective effect, after having estimated the different H2 receptor-selective of coupling antagonist, the degree that the more alone ibuprofen of the damage of gastric mucosa and ulcer alleviates.Result shows that nizatidine has best gastric mucosal protective effect, and famotidine takes second place, and both all can significantly alleviate gastric ulcer.This result demonstration, nizatidine comprises lafutidine and roxatidine acetate than other several typical H2 receptor-selective antagonisies, can reduce better the ulcer generation that ibuprofen causes, and even is better than famotidine.
Ibuprofen can cause the stomach permeability to increase usually, and this betides the sign before ulcer often, therefore investigate transparent performance reflection stomach early lesion.Result shows, nizatidine and famotidine have all significantly reduced the penetrating rate (p＜0.01) of sucrose, and lafutidine and roxatidine acetate do not improve this symptom.It is worth mentioning that, nizatidine group energy famotidine group is compared also has significant difference (p＜0.01), and namely nizatidine can prevent better than famotidine the variation of gastric tissue permeability.Known to us, the degree that ulcer alleviates is to estimate the index directly perceived of H2 receptor-selective antagonist, evaluation to permeability is to the also not assessment of visualize damage out, and on this aspect, nizatidine is also optimum in several typical H2 receptor-selective antagonisies.
Under the oxidation material effect, organize the unsaturated fatty acid in lipid film that oxidative degradation can occur, may cause change and the interior enzyme deactivation of cell membrane of membrane structure, also can further increase the weight of gastric mucosa injury.Therefore in evaluation of tissue, the degree of lipid peroxidation is also one of index of passing judgment on degree of tissue damage.In tissue, the peroxidating of unsaturated lipids is mainly due to some activating oxide such as superoxide anion (O in tissue
2 -) etc. cause, the effect that H2 receptor-selective antagonist has the Scavenger of ROS compound namely has its non-oxidizability, from this result, this point has been described also.In several typical H2 receptor-selective antagonisies, the strongest with the effect of the lipotropism matter oxidation of nizatidine again.
Gastric injury generally not only is embodied on ulcer, the generation of gastroenteritic ulcer is mainly because inflammatory cell infiltration causes, why inflammatory cell can injuring normal cell be to depend on, one, the activating oxide of these inflammatory cells generations (be commonly referred to as Reactiveoxygen species, be called for short ROS); Two, normal structure is eliminated the ability of these activating oxides.Activating oxide comprises superoxide radical (O
2 -), hydrogen peroxide (H
2O
2), hypochlorous acid (HOCl) and hydroxyl radical free radical (OH) etc.(be myeloperoxidase-H by myeloperoxidase (MPO)-hydrogen peroxide-halogenide system
2What O2-halide system) produce is powerful chloride oxidation agent at HOCl, and it is one of powerhouse of cytotoxicity in active oxidation.Estimate different H2 receptor-selective antagonisies to the impact of myeloperoxidase (MPO) (being MPO) level, can reflect the ability of their minimizing activating oxides, i.e. the gastric tissue protective capability.Pharmacodynamic result shows that nizatidine and roxatidine acetate all can significantly reduce the amount (p＜0.01) of MPO, and famotidine and lafutidine reduce the effect of MPO amount very weak (p〉0.05).And nizatidine and roxatidine acetate can be down to MPO amount and the level of not processing through ibuprofen (p〉0.05).The amount of nizatidine processed group MPO is significantly lower than famotidine processed group (p＜0.05), and also significantly lower than lafutidine processed group (p＜0.05), the prompting nizatidine all can more effectively reduce the level of MPO than famotidine and lafutidine.Show that nizatidine is having good performance aspect reduction myeloperoxidase enzyme level.
Superoxide dismutase, catalase and glutathion peroxidase are to participate in activating oxide to comprise superoxide radical (O
2 -) and hydrogen peroxide (H
2O
2) important enzyme of metabolism, by investigating the activity of different these serial enzymes, can estimate different H2 receptor-selective antagonist antioxidative effects, also just reflected the ability of gastric tissue protection.Pharmacodynamic result shows that nizatidine, famotidine and roxatidine acetate all have the effect that recovers well antioxidase SOD and GPx in gastric tissue, wherein nizatidine is suitable with the famotidine effect, and effect is optimum, and both all can make two kinds of enzyme levels return to ibuprofen and process front level.Roxatidine acetate takes second place, and the effect of lafutidine a little less than.The prompting nizatidine can significantly improve multiple important antioxidase level, and effect is remarkable.
Comprehensive above-mentioned pharmacodynamic study result, nizatidine has the most comprehensive, optimal protection effect than the gastric injury that other several typical H2 receptor-selective antagonisies cause ibuprofen.
When being applied to the present invention and having the compound iuprofen of pipe intestinal protection effect; clinical use amount existing according to both; active component comprises ibuprofen or its pharmaceutical salts, nizatidine, and its weight proportion is: ibuprofen or its pharmaceutical salts 15-120 part, nizatidine 1-40 part.
Have in the compound iuprofen of pipe intestinal protection effect ibuprofen or its pharmaceutical salts and adopt on pharmacokinetics effectively ratio to mix in nizatidine, satisfy to take and reach its effective dose.
After the patient takes ibuprofen; especially arthritis is (as rheumatic arthritis; osteoarthritis), the chronic disease such as gout, chronic pain needs the patient of long-term taking ibuprofen; or be to suffer from acute pain, dysmenorrhea or acutely inflamed patient; easily produce the gastrointestinal side effects such as gastritis, heart-burn sense, dyspepsia and gastric duodenal ulcer; can significantly suppress gastrointestinal side effect with addition of nizatidine, reach the purpose of stomach protection.
The diseases such as chronic pain, tenderness, inflammation, swelling, heating, headache or stiff (stiff can being caused by inflammation disease, myalgia, dysmenorrhea, injured, catch a cold, have a back ache pain or the inflammation relevant with shell or dentistry) can be improved, be treated to ibuprofen or its pharmaceutical salts with addition of nizatidine, significantly improve and reduce the generation of the gastrointestinal side effects such as gastritis, heart-burn sense, dyspepsia and gastric duodenal ulcer.
Second technical problem solved by the invention has been to provide the preparation that contains ibuprofen and nizatidine with pipe intestinal protection effect, is used for suppressing the gastrointestinal side effect of ibuprofen.
Concrete, said preparation is peroral dosage form, can adopt a kind of in the common tablet of formulation art, capsule, pill or pellet.Described tablet can make the dosage forms such as conventional tablet, coated tablet, bilayer tablet.
Further, when the inventor finds that ibuprofen and nizatidine compatibility are used, nizatidine is very easily degraded, the stability extreme difference, reason is that ibuprofen is weak acidic drug, and nizatidine is alkalescence, because can causing nizatidine content, acid-base reaction descends after two medicament mixed, and be to select the main points of dosage form and screening preparation process so how to avoid this problem.
In order to overcome this defective, the invention provides a kind of preparation prescription to overcome this technological deficiency, improve the stability of nizatidine in preparation.As:
After one: two kind of active component of method is granulated respectively, then after two kinds of granules are mixed, tabletting or encapsulated.Granulate respectively and can avoid two medicines directly to contact, add other adjuvant to have again later on and intercept the effect that two medicines contact, therefore can obtain stable preparation.
Method two: after two kinds of active component are granulated respectively, then two kinds of granules are pressed into double-layer tablet, the skin of Double-skin can coat an outer coating again, is used for shading or prevents that double-layer tablet from scattering.Be pressed into double-layer tablet and further reduced preparation in the interactional probability of storage process Chinese medicine.
Method three: two kinds of medicines are made respectively micropill, more encapsulated after mixing according to a certain percentage.
Method four: method four: first preparation contains the label of ibuprofen, then by the method for coating, nizatidine is wrapped in skin.Particularly, be the label that first prepares ibuprofen, then at the surface of label bag sealing coat, be used for intercepting the nizatidine interaction of label and outer coating; And then the mode of nizatidine by coating wrapped in outside sealing coat, namely medicated layer, wrap the outer coatings layer at last again, is used for shading or other corresponding effects.
The ibuprofen part for preparing in above-mentioned several method can be both rapid release (namely under suitable leaching condition, in 30min, drug-eluting is more than 75%), can be also slow release.
In preparation of the present invention, the mass ratio of active component is:
In unit formulation, active component comprises the ibuprofen of 100-800mg and the nizatidine of 25-200mg.
Further preferred: in unit formulation, active component comprises the ibuprofen of 200-800mg and the nizatidine of 50-100mg.
To sum up, use the stomach side effect that nizatidine can realize improving ibuprofen, reach the purpose of stomach protective effect.And the present invention has also overcome nizatidine and the application of ibuprofen compatibility causes nizatidine easily to be degraded, and the technological deficiency of poor stability provides feasible solution, effectively uses ibuprofen for clinical safety a kind of new selection is provided.
Describe in detail
1, " nizatidine " is N-(2-(((2-(dimethylamino) methyl)-4-thiazolyl) methyl) sulfur) ethyl)-N'-methyl-2-nitro)-1, the 1-ethylene diamine.
2, " ibuprofen " is Ibuprofen, and it comprises multiple crystal formation and pharmaceutically acceptable salt.There are two kinds of corresponding isomers.What adopt in the present invention is racemic mixture or arbitrary enantiomer.
3, " API " is active pharmaceutical ingredient.As ibuprofen and or the nizatidine that uses in this article.
4, the required amount of its corresponding disease is eliminated, alleviated to the ibuprofen of " treatment effective dose " or a pharmaceutically acceptable salt
5, the nizatidine of " treatment effective dose " is the amount of nizatidine or its pharmaceutically acceptable salt protection gastric mucosa.
6, " solid oral dosage form ", " peroral dosage form ", " unit dosage form ", " dosage form that is used for oral administration " etc. can exchange use mutually, and form can be the drug regimen of tablet, capsule, micropill etc.
7, the present invention " excipient " is the arbitrary composition in the peroral dosage form of non-API.Excipient comprises blocker, disintegrating agent, binding agent, porogen, lubricant, fluidizer, coating, sealing coat composition and other compositions.Excipient is known in this area.Some excipient provide multi-functional, and for example Klucel EF can be used as blocker, and the low viscosity hypromellose can be used as porogen; Some excipient add in peroral dosage form by different modes, and effect is different, for example directly adds the hypromellose powder and can be used as blocker, and hypromellose is dissolved in wetting agent, can be used as binding agent.
8, " wetting agent " for itself does not have viscosity, but the viscosity that can bring out material particles to be made, the liquid that is beneficial to granulate.Wetting agent commonly used has: water, ethanol etc.
9, " binding agent " means and gives viscosity to material inviscid or that viscosity is not enough, thereby makes the adjuvant of the coalescent granulating of material.Normally used binding agent comprises, such as starch slurry, cellulose derivative, hypromellose, hypromellose receive, ethyl cellulose, polyvidone, gelatin, Polyethylene Glycol etc. and and the mixture of these similar components.
10, " disintegrating agent " means it is to impel tablet to be fragmented into rapidly the adjuvant of fine particle in gastro-intestinal Fluid.Comprise dried starch and derivant thereof, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, gas-producing disintegrant etc.
11, " blocker " means and controls the rate of release of medicine in slow, controlled release preparation mainly with macromolecular compound as blocker.Its retardance mode has matrix type, coating membranous type and viscosifying action etc.Matrix type retardance material has: 1. erodible framework material, and commonly used have Animal fat, Cera Flava, Brazil wax, hydrogenated vegetable oil, stearyl alcohol, glyceryl monostearate etc., but the dissolving of retardation water soluble drug, dispose procedure; 2. the hydrophilic gel framework material, have methylcellulose (MC), sodium carboxymethyl cellulose (CMC-Na), hypromellose (HPMC), polyvidone (PVP), carbopol, alginate, chitosan (chitosan) etc.; 3. insoluble framework material, have ethyl cellulose (EC), polymethacrylates (Eu RS, Eu RL), non-toxic polyvinyl chloride, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber etc.
12, " porogen " is the macromolecular material of some hydrophilic small-molecule substances or low-viscosity, as low-substituted hydroxypropyl cellulose (L-HPC), hypromellose (HPMC), polyvidone (PVP), lactose, sodium chloride etc., they can form some hydrophilic and spread the duct in matrix tablet, drug release rate is accelerated.
13, " fluidizer " is for reducing frictional force between granule before tabletting, thereby improves powder fluidity, reduces weight differential.Fluidizer commonly used comprises micropowder silica gel, Pulvis Talci etc.
Frictional force when 14, " lubricant " means the reduction tabletting and release sheet between tablet and die wall, during with the assurance tabletting, stress distribution is even, prevents the excipient such as sliver.The example of lubricant comprises that magnesium stearate, calcium stearate, sodium benzoate, Pulvis Talci Polyethylene Glycol etc. have the excipient of similar functions.
15, " outer coatings layer (over-coating layer) " or " outer coatings (over-coat) " refer to outermost layer coating or the multilamellar outermost coating of unit dosage forms such as the relevant dosage forms such as tablet.The outer coatings layer does not contain API, and suitable outer coatings layer is solvable or cracked rapidly in water, and is used for purpose of the present invention.Exemplary outer coatings layer material is from Tianjin Ai Leyi or block the acquisition of happy Kanggong department.
16, " sealing coat (Isolation layer) " refers in unit dosage forms between the ibuprofen tablet core marker space middle with containing the nizatidine medicated layer.Sealing coat does not contain API.In the present invention, sealing coat is that water miscible material makes, and its Main Function reacts to each other for isolating ibuprofen and nizatidine, can discharge fast simultaneously, does not affect the release of ibuprofen.Exemplary insolated layer materials in the present invention is from Tianjin Ai Leyi or block the acquisition of happy Kanggong department.
17, " medicated layer (Drug-containing layer) " refers in unit dosage forms, between sealing coat and outer coatings layer, contains the API nizatidine for the treatment of effective dose and the suitable marker space of coating material.Exemplary medicated layer coating material in the present invention is from Tianjin Ai Leyi or block the acquisition of happy Kanggong department.
Exemplary peroral dosage form 1 coated tablet
In one embodiment, the ibuprofen label is arranged, label has sealing coat outward, and sealing coat is outward the medicated layer that contains nizatidine, and medicated layer is outward the outer coatings layer.
In one embodiment, the screening of binding agent in the ibuprofen label, the binding agent that is used for compressed cores can select that starch slurry, cellulose derivative, hypromellose, hypromellose are received, ethyl cellulose, polyvidone, gelatin, Polyethylene Glycol etc. and and the mixture of these similar components; The screening of fluidizer adds fluidizer in ibuprofen label pelletizing press sheet process, can adopt micropowder silica gel and Pulvis Talci etc.; The screening of lubricant in the ibuprofen label comprises magnesium stearate, calcium stearate, sodium benzoate, Pulvis Talci Polyethylene Glycol, sodium laurylsulfate (magnesium) etc.; In the ibuprofen label blocker screening is according to physical and chemical properties of drugs and to the requirement of preparation slow release, the screening blocker, comprise the kind of blocker concrete be its viscosity and consumption thereof.In one embodiment, ibuprofen label blocker can adopt: 1. erodable type framework material, and commonly used have Animal fat, Cera Flava, Brazil wax, hydrogenated vegetable oil, stearyl alcohol, a glyceryl monostearate etc.; 2. the hydrophilic gel framework material, have methylcellulose (MC), sodium carboxymethyl cellulose (CMC-Na), hypromellose (HPMC), polyvidone (PVP), carbopol, alginate, chitosan (chitosan) etc.; 3. insoluble framework material, have ethyl cellulose (EC), polymethacrylates (Eu RS, Eu RL), non-toxic polyvinyl chloride, polyethylene, ethylene one acetate ethylene copolymer, silicone rubber etc.
Exemplary peroral dosage form 2 double-layer tablet
In a scheme, peroral dosage form comprises two-layer medicine, and one deck is ibuprofen, and one deck is nizatidine.
In one embodiment, for the ibuprofen layer of slow release, wherein the screening of blocker is according to physical and chemical properties of drugs and to the requirement of preparation slow release, the screening blocker, comprise the kind of blocker concrete be its viscosity and consumption thereof.Ibuprofen label blocker can adopt: 1. erodable type framework material, and commonly used have Animal fat, Cera Flava, Brazil wax, hydrogenated vegetable oil, stearyl alcohol, a glyceryl monostearate etc.; 2. the hydrophilic gel framework material, have methylcellulose (MC), sodium carboxymethyl cellulose (CMC-Na), hypromellose (HPMC), polyvidone (PVP), carbopol, alginate, chitosan (chitosan) etc.; 3. insoluble framework material, have ethyl cellulose (EC), polymethacrylates (Eu RS, Eu RL), non-toxic polyvinyl chloride, polyethylene, ethylene one acetate ethylene copolymer, silicone rubber etc.Can adopt disintegrating agent such as carboxymethyl starch sodium, dried starch and derivant thereof, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, gas-producing disintegrant etc.The screening starch of ibuprofen layer filler, Icing Sugar, dextrin, lactose, amylum pregelatinisatum, microcrystalline Cellulose, inorganic salts, sugar alcohols etc.; Adoptable porogen: as low-substituted hydroxypropyl cellulose (L-HPC), hypromellose (HPMC), polyvidone (PVP), lactose, sodium chloride etc.; According to physical and chemical properties of drugs and to the requirement of preparation slow release, the screening binding agent.Normally used binding agent comprises, such as starch slurry, cellulose derivative, hypromellose, hypromellose receive, ethyl cellulose, polyvidone, gelatin, Polyethylene Glycol etc. and and the mixture of these similar components; The screening of lubricant and fluidizer, available lubricant and fluidizer comprise: micropowder silica gel, Pulvis Talci, fatty acid magnesium, calcium stearate, sodium benzoate, Pulvis Talci Polyethylene Glycol etc.
The screening of nizatidine layer disintegrating agent, can adopt disintegrating agent to increase the stripping of nizatidine, but the disintegrating agent carboxymethyl starch sodium, dried starch and the derivant thereof that adopt in this preparation, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, gas-producing disintegrant etc.Selectable filler comprises: starch, Icing Sugar, dextrin, lactose, amylum pregelatinisatum, microcrystalline Cellulose, inorganic salts, sugar alcohols etc.; Selectable binding agent comprises, such as starch slurry, cellulose derivative, hypromellose, hypromellose receive, ethyl cellulose, polyvidone, gelatin, Polyethylene Glycol etc. and and the mixture of these similar components.Available lubricant and fluidizer comprise: micropowder silica gel, Pulvis Talci, fatty acid magnesium, calcium stearate, sodium benzoate, Pulvis Talci Polyethylene Glycol etc.
Description of drawings
Fig. 1 is that antiperoxidase is the schematic diagram of Scavenger of ROS compound matter.
Wherein: SOD: superoxide dismutase; CAT: catalase; GPX: glutathion peroxidase; GR: glutathion reductase; GSH: glutathion; GSSG: oxidized glutathione; NADP
+: nicotinamide-adenine dinucleotide phosphate; NADPH: NADH phosphoric acid.
Fig. 2 is the photo of gastric mucosa of rat after processing.
The specific embodiment
Below by specific description of embodiments of the present invention the explanation but do not limit the present invention.
The inventor when estimating the stomach protective effect, after having estimated the different H2 receptor-selective of coupling antagonist, the degree that the more alone ibuprofen of the damage of gastric mucosa and ulcer alleviates.And gastric injury generally not only is embodied on ulcer, and the generation that the gastrointestinal tract permeability increases prior to the generation of ulcer, is therefore a pointer of gastrointestinal tract early lesion.Ibuprofen can cause the gastrointestinal tract permeability to increase, and then forms ulcer.Sucrose is as the probe of people and animal gastrointestinal tract permeability, has been used to the labelling of the upper digestive tract side effect that NSAID (non-steroidal anti-inflammatory drug) causes.The permeability of sucrose on the upper digestive tract path of healthy body is very little, and is hydrolyzed at small intestinal.Therefore after oral sucrose, the sucrose that detects in urine is due to the increase of upper digestive tract permeability, percolation ratio by measuring sucrose in urine as the sign of estimating the stomach permeability (referring to Davies etc., 1995, " Sucrose urinary excretion in the rat measured using assay a model of gastroduodenal permeability " Pharmaceutical Research, 12 (11), 1733-1736).
The generation of gastroenteritic ulcer is mainly because inflammatory cell infiltration causes, and why inflammatory cell can injuring normal cell be to depend on, and one, the activating oxide (be commonly referred to as Reactive oxygen species, be called for short ROS) that produces of these inflammatory cells; Two, normal structure is eliminated the ability of these activating oxides.Activating oxide comprises superoxide radical (O
2 -), hydrogen peroxide (H
2O
2), hydroxyl radical free radical (OH) and hypochlorous acid (HOCl) etc.These activating oxides are the damaged tissue cell directly or indirectly, also may cause unsaturated lipids peroxidating in tissue, increases the weight of tissue injury.H2 receptor-selective antagonist antioxidation plays very important effect in gastrointestinal tissue's protective effect, be to estimate the important indicator of its gastrointestinal protection effect therefore estimate the antioxidation of different H2 receptor-selective antagonisies.
In activating oxide, hypochlorous acid is powerful chloride oxidation agent, and it is (to be myeloperoxidase-H by myeloperoxidase (MPO)-hydrogen peroxide-halogenide system
2O
2-halide system) producing, is one of powerhouse of cytotoxicity in active oxidation.Myeloperoxidase (MPO) (being called for short MPO) is the interior a kind of enzyme of azurophilic granule that is present in polymorphonuclear leukocyte, is also one of monocytic constituent simultaneously.Ripe macrophage lacks MPO, but can absorb at an easy rate this enzyme, therefore macrophage can be to produce oxidation material referring to Fantone etc. by this enzyme, 1982, " ROLE OF OXYGEN-DERIVED FREERADICALS AND METABOLITES IN LEUKOCYTE-DEPENDENT INFLAMMATORY REACTIONS ", American Association of Pathologists, 107(3): 397-418).During H2 receptor-selective antagonist can be organized by reduction, the amount of myeloperoxidase (MPO) plays the effect of protective tissue; the effect of different H2 receptor-selective antagonisies can be estimated the level of myeloperoxidase (MPO) by measuring them, and this index is very important in the evaluation oxidation resistance.
The acute inflammatory reaction of gastric mucosa is often followed neutrophil infiltration, and neutrophilic granulocyte can produce a kind of activating oxide superoxide anion (O
2 -), superoxide anion can make the lipid peroxidation on cell membranes in tissue, and this process is to the gastric mucosa injury.Body has the enzyme system of these active oxidation materials of a series of removings, as Fig. 1.Superoxide dismutase can become the lower hydrogen peroxide of toxicity by the catalysis superoxide anion, and hydrogen peroxide can further be degraded to by catalase or glutathion peroxidase water and the oxygen of totally nontoxic.In glutathion peroxidase reduction hydrogen peroxide, the glutathion of reduced form is converted into the glutathion of oxidized form.Therefore superoxide dismutase, catalase and glutathion peroxidase are the important enzymes that participates in activating oxide, by measuring the activity of this serial enzymes, can estimate different H2 receptor-selective antagonist antioxidative effects, these assessment items are very important.
Under the oxidation material effect, organize the unsaturated fatty acid in lipid film that oxidative degradation can occur, may cause change and the interior enzyme deactivation of cell membrane of membrane structure, also can further increase the weight of gastric mucosa injury.Therefore in evaluation of tissue, the degree of lipid peroxidation is also one of index of passing judgment on degree of tissue damage, can reflect the protection effect of H2 receptor-selective antagonist.
It is below the protection test that the present invention adopts the gastrointestinal side effect that above-mentioned evaluation index causes ibuprofen different H2 receptor-selective antagonisies.
The comparison of the rat gastric ulcer protective effect that several H2 receptor-selective of test example 1 antagonist causes ibuprofen
42 of extracting male Wistar rats, weight is at 220-250g, be divided at random 6 groups, give continuously respectively following sample 6 days, medicine all with sodium carboxymethyl cellulose (1%) as disperse medium, the blank group only gives the not disperse medium of pastille (group 1), ibuprofen group (200mg/kg) (group 2), ibuprofen and nizatidine group (two kinds medicine dosage be 200mg/kg and 31.25mg/kg) respectively (group 3), ibuprofen and famotidine group (two kinds of drug doses are 200mg/kg and 4.19mg/kg) (group 4), ibuprofen and lafutidine (two pharmaceutical quantities are 200mg/kg and 2.06mg/kg) (group 5), ibuprofen and roxatidine acetate (two pharmaceutical quantities are 200mg/kg and 15.63mg/kg) (group 6).Successive administration was put to death later on rat in 6 days, got gastric tissue, and is clean with normal saline flushing, with Guth method counting ulcer.Press Guth standard scoring rule as follows: the rotten to the corn note of speckle 1 minute; Rotten to the corn length＜1mm note 2 minutes; 1 ~ 2mm note 3 minutes; 2 ~ 3mm note 4 minutes; Score value * 2 when＞3mm note 5 minutes, width＞1mm.Result such as table 1.Result shows that giving continuously ibuprofen can cause comparatively serious rat gastric ulcer, the clinical using dosage of this dosage conversion adult only belongs to median dose, and successive administration causes rat ulcer incidence rate very high (only to ibuprofen group gastric ulcer incidence rate nearly 90%) after 6 days, and prompting also can be very high for needing long-term, high-dose to take patient's gastric ulcer incidence rate of ibuprofen.In the situation that give to give H2 receptor-selective antagonist in ibuprofen, nizatidine, famotidine and roxatidine acetate all can alleviate the degree of rat gastric ulcer, wherein nizatidine (p＜0.01) and famotidine (p＜0.05) can significantly alleviate gastric ulcer, and be more excellent with nizatidine.This results suggest, nizatidine can avoid the ulcer that ibuprofen causes to produce than other several typical H2 receptor-selective antagonisies better, even are better than famotidine.
The capacity antacid of famotidine is the strongest in existing H2 receptor-selective antagonist up to now, but sees that from the result of this test the protection of the rat gastric ulcer that it causes ibuprofen is not the best.In fact, ibuprofen causes the mechanism of gastrointestinal damage to be still not clear, and comprises ibuprofen, thinks that mainly possible reason is by activating oxide (ROS) at present.The amount that ibuprofen is secreted from bile seldom, can be again circulation further causes the damage of intestinal through liver sausage, do not observe serious damage of intestines in this process of the test, but take the damage of stomach as main yet.And H2 receptor-selective antagonist ibuprofen is caused the protective effect of gastric injury is not to come from its antiacid effect, but it removes the effect of oxygen-derived free radicals.Therefore, removing Scavenging Oxygen Free Radical strong H2 selective antagonist probably is only to have and causes gastric ulcer that the best protection effect is arranged to ibuprofen.
The score of table 1. gastric ulcer
The blank group of * vs. ibuprofen group comparative result p＜0.01
#United H2 receptor-selective antagonist group vs. ibuprofen group comparative result p＜0.05
##United H2 receptor-selective antagonist group vs. ibuprofen group comparative result p＜0.01
The impact of several H2 receptor-selective of test example 2 antagonists on rat gastric tissue permeability changes
Ibuprofen can cause the gastrointestinal tract permeability to increase, and then forms ulcer.It is the inducement of stomach lining inflammation and toxicology performance that research discovery, NSAID (non-steroidal anti-inflammatory drug) cause the gastrointestinal tract epithelial cell permeability to strengthen.The permeability of sucrose on the upper digestive tract path of healthy body is very little, and is hydrolyzed at small intestinal.Therefore after oral sucrose, the sucrose that detects in urine is due to the increase of upper digestive tract permeability.Sucrose in urine can adopt the sucrose in the hydrolysis urine to generate glucose, further adopts the trinder reaction method to measure.The easy not damaged of this method can accurately detect the upper digestive tract permeability changes.
42 of extracting male Wistar rats, weight are divided into 6 groups at random at 220-250g, carry out administration according to the scheme of test example 1 respectively.After last administration 2h, rat is positioned in metabolic cage, every gives the saturated aqueous sucrose solution of 1ml, collects continuously urine 8 hours.As table 2, result shows that the permeability of the rear rat stomach tissue of ibuprofen processing significantly increases (p＜0.01), when giving simultaneously H2 receptor-selective antagonist, nizatidine and famotidine have all significantly reduced the penetrating rate (p＜0.01) of sucrose, and other two groups are not improved this symptom.It is worth mentioning that, the nizatidine group is compared with the famotidine group also has significant difference (p＜0.01).Known to us, the degree that ulcer alleviates is to estimate the index directly perceived of H2 receptor-selective antagonist, evaluation to permeability is to the also not assessment of visualize damage out, and on this aspect, nizatidine is also optimum in several typical H2 receptor-selective antagonisies.
Table 2. gastric mucosa leads to permeability
The blank group of * vs. ibuprofen group comparative result p＜0.01
#United H2 receptor-selective antagonist group vs. ibuprofen group comparative result p＜0.05
##United H2 receptor-selective antagonist group vs. ibuprofen group comparative result p＜0.01
The impact of several H2 receptor-selective of test example 3 antagonists on rat gastric tissue lipid peroxidation (LPO)
Product after organizing unsaturated fatty acid in lipid oxidized is aldehydes, can generate colored compound with thiobarbituricacidα-(thiobarbituric acid, TBA), and generating colored substance as malonaldehyde (MDA) and TBA has absorption maximum at the 530nm place.Therefore can estimate the oxidized degree of lipid by the amount of measuring the oxidation product malonaldehyde.
42 of extracting male Wistar rats, weight are divided into 6 groups at random at 220-250g, carry out administration according to the scheme of test example 1 respectively.Get gastric tissue after administration, clean with normal saline flushing, measure respectively the amount of MDA in tissue in order to the degree of the lipid peroxidation of expression tissue, the results are shown in following table.Result shows, after processing with ibuprofen, in tissue, MDA content significantly increases (p＜0.01) than the blank group, points out obvious lipid peroxidation phenomenon.MDA amount in the nizatidine processed group in tissue more only significantly descends (p＜0.01) with the ibuprofen processed group, and in the group of coupling famotidine, lafutidine and roxatidine processing, MDA descends to some extent, but the difference of comparing with the ibuprofen processed group that there are no significant.In tissue, the peroxidating of unsaturated lipids is mainly because some activating oxide such as superoxide anion (O2-) etc. in tissue cause, the effect that H2 receptor-selective antagonist has the Scavenger of ROS compound, namely have its non-oxidizability, from this result, this point has been described also.In several typical H2 receptor-selective antagonisies, the strongest with the effect of the lipotropism matter oxidation of nizatidine again.
Table 3. gastric mucosa lipid peroxidation
The blank group of * vs. ibuprofen group comparative result p＜0.01
##United H2 receptor-selective antagonist group vs. ibuprofen group comparative result p＜0.01
The comparison of the impact of antioxidase in several H2 receptor-selective of test example 4 antagonists on rat gastric tissue
42 of extracting male Wistar rats, weight are divided into 6 groups at random at 220-250g, carry out administration according to the scheme of test example 1 respectively.Get gastric tissue after administration, clean with normal saline flushing, measure respectively enzyme such as superoxide dismutase (SOD), glutathion peroxidase (GSH-Px) and the catalase (CAT) of several effectively Scavenger of ROS compound matter.SOD can be with ultra-oxygen anion free radical (superoxide radical (O2
-)) change hydrogen peroxide (hydrogenperoxide (H into
2O
2)), to reduce ultra-oxygen anion free radical to the damaging action of tissue.CAT and GSH-Px further hydrogen peroxide are converted into the hydrone of not damaged effect.
Content results such as the table 2 of three kinds of antioxidases in each group gastric tissue.Result shows that the rat stomach tissue SOD value of accepting that ibuprofen processes significantly lowers (p＜0.01) than the blank group.More only give the ibuprofen group and all be improved to some extent and give simultaneously SOD value in the rat stomach tissue of H2 receptor-selective antagonist, wherein with only give the ibuprofen group and compare, nizatidine and famotidine group improve the most remarkable (p＜0.01), and the roxatidine acetate group improves degree comparatively significantly (p＜0.05).And each group of coupling H2 receptor-selective antagonist and blank group there are no significant difference (p〉0.05), prompting SOD level with not with being on close level that ibuprofen is processed, show these several H2 receptor-selective antagonisies recover SOD horizontal aspect effect ideal.
For the CAT enzyme, accepted enzyme level and the blank group there was no significant difference of the rat stomach tissue of ibuprofen, and accepted simultaneously enzyme level and above-mentioned two groups of also there was no significant differences of the rat stomach tissue of ibuprofen and H2 receptor-selective antagonist.Infer that ibuprofen and H2 receptor-selective antagonist all do not affect gastric tissue CAT enzyme level.
For the GSH-Px enzyme, accept the rat stomach of ibuprofen processing and organize this enzyme level significantly to subtract (p＜0.01) than the blank group.More only give the ibuprofen group and all be improved to some extent and give simultaneously this enzyme level in the rat stomach tissue of H2 receptor-selective antagonist, wherein nizatidine, famotidine and roxatidine acetate group improve the most remarkable (p＜0.01).And organize there was no significant difference (p＞0.05) with blank for these three groups, namely in three groups of tissues the GPx level returned to not with being on close level that ibuprofen is processed, this result pointing out equally several H2 receptor-selective antagonisies recover GPx horizontal aspect effect ideal.
To sum up, several H2 receptor-selective antagonisies comparison shows that to the antioxidase effect, nizatidine, famotidine and roxatidine acetate all have the effect that recovers well antioxidase SOD and GPx in gastric tissue, wherein nizatidine is suitable with the famotidine effect, and effect is optimum, roxatidine acetate takes second place, and the effect of lafutidine a little less than.According to the analysis to SOD and GPx effect, nizatidine and famotidine all can be realized in tissue superoxide anion and hydrogen peroxide scavenging action well.
Table 4. antioxidase activity
SOD, CAT, GPx be all with unit of activity/milligram protein refractometer,
* blank is organized vs. ibuprofen group comparative result p＜0.05
The blank group of * vs. ibuprofen group comparative result p＜0.01
#United H2 receptor-selective antagonist group vs. ibuprofen group comparative result p＜0.05
##United H2 receptor-selective antagonist group vs. ibuprofen group comparative result p＜0.01
The comparison of myeloperoxidase (MPO) impact in several H2 receptor-selective of test example 5 antagonists on rat gastric tissue
42 of extracting male Wistar rats, weight are divided into 6 groups at random at 220-250g, carry out administration according to the scheme of test example 1 respectively.Get gastric tissue after administration, clean with normal saline flushing, measure respectively MPO.MPO catalysis Cl-forms hypochlorous acid (HOCl), and HOCl is the cytotoxicity oxidant, also can cause cell injury, and is the strongest to cytotoxicity in several activating oxides.Measurement result shows the amount (p＜0.01) that gives ibuprofen and can significantly improve MPO in gastric tissue, and after giving simultaneously H2 receptor-selective antagonist, nizatidine and roxatidine acetate all can significantly reduce the amount (p＜0.01) of MPO, and famotidine and lafutidine reduce the effect of MPO amount very weak (p〉0.05).And nizatidine and roxatidine acetate can be down to MPO amount and the level of not processing through ibuprofen (p〉0.05).The amount of nizatidine processed group MPO is significantly lower than famotidine processed group (p＜0.05), and also significantly lower than lafutidine processed group (p＜0.05), the prompting nizatidine all can more effectively reduce the level of MPO than famotidine and lafutidine.The results suggest nizatidine can effectively reduce the amount of MPO in tissue, thereby reduces hypochlorous generation, prevents from organizing oxidized damage, and returns on level without ibuprofen.
To sum up; nizatidine is compared with the H2 receptor-selective antagonist of several determined curative effects; has the effect of protecting best gastric tissue not affected by ibuprofen; its reason may be its effect of Scavenger of ROS free radical is relevant very doughtily, show from this result of the test, it brings into play this effect by number of ways; comprise and accelerate Scavenger of ROS compound matter; reduce tissue permeability, reduce and organize lipid peroxidation to occur, finally to reach the gastric tissue protective effect.
Table 5. myeloperoxidase (MPer) (MPO) vigor
Test example 6 nizatidines and famotidine cause the ulcer picture
Take the Wistar rat as animal pattern; give respectively blank (not pastille); ibuprofen; the ibuprofen nizatidine is united group 1; the ibuprofen nizatidine is united group 2; the ibuprofen nizatidine is united group 3, and the ibuprofen famotidine is united group, investigates the protection of the gastrointestinal side effect that various bisfentidines cause ibuprofen.The ibuprofen nizatidine is united group to be increased to group 2 nizatidine consumptions gradually from organizing 1.As a result, it is best to the gastrointestinal protection that the ibuprofen nizatidine is united group, even is better than the ibuprofen famotidine and unites group, during nizatidine causes that to ibuprofen the Mechanism of Protection of gastrointestinal side effect is further being studied.Each is organized gastric ulcer and sees Fig. 2, and the numeral under picture is the ulcer score value according to the standards of grading gained in test example 1.
Test example 7: drug release determination
Measure a kind of method of rate of release and degree, can adopt 2010 editions drug release determination method first methods of Chinese Pharmacopoeia (appendix X D), releasing device is that dissolution the second method turns basket method (appendix X C), release medium is 900mL pH7.2 phosphate buffered solution (50mM), 37 ℃ of release temperatures, 50 rev/mins of rotating speeds, be 1h, 2h, 4h, 6h, 8h and 12h sample time, sample volume 5ml.
Can change in due course dissolve medium or other parameter.Usually, unit dosage forms is joined turn in basket, take out at the appointed time the part medium, and use conventional analytical method to measure API content in medium.Above-mentioned test is used to measure the dissolving characteristic of describing the unit dosage forms of preparation in embodiment.
Test example 8: dissolution determination
Measure a kind of method of dissolution rate and degree, can adopt 2010 editions dissolution method the second methods of Chinese Pharmacopoeia (appendix X C), take phosphate buffer (pH7.2) as dissolution medium, mixing speed (50 rev/mins), 37 ℃ of temperature.Dissolution medium is 900mL pH7.2 phosphate buffered solution (50mM), 37 ℃ of stripping temperature, and 50 rev/mins of rotating speeds, be 0.5h sample time, sample volume 5ml.
Can change in due course dissolve medium or other parameter.Usually, unit dosage forms is joined turn in basket, take out at the appointed time the part medium, and use conventional analytical method to measure API content in medium.Above-mentioned test is used to measure the dissolving characteristic of describing the unit dosage forms of preparation in embodiment.
The quick release of nizatidine and ibuprofen in test example 9 ordinary tablets
The release that the invention human desires provides two kinds of API in a kind of NSAID of making and gastric acid secretion inhibitor occurs about same time greatly, or begins simultaneously the preparation that occurs.As: so that nizatidine and ibuprofen (being about 6.8 to about 7.4 as aqueous solution pH) release fast under condition of neutral pH.Wherein, (rapidly) refers to fast: two kinds of API in 15 minutes, significantly are discharged in solution under the experiment in vitro condition." significantly discharge " refers to API weight about at least 60% dissolved in unit dosage forms.More excellent dissolving at least 75%, more excellent dissolving at least 80%, more solubilized at least 90% can reach 95% sometimes at least.Namely in aqueous environment, two principal agents are discharged into solution rapidly from described dosage form, and at least 75% nizatidine and 75% ibuprofen were released in 15 minutes.
Every tablet of tablet that comprises ibuprofen (100mg) and nizatidine (50mg) is by described determined, and all the other adjuvants and consumption see Table.Use the wet granulation method, preparation ibuprofen/nizatidine tablet
Table 6. ordinary tablet prescription
Tablet is prepared by following process, and described 1-10 is upper table prescription item.
(1) a 1-4(nizatidine, microcrystalline Cellulose, pregelatinized Starch, carboxymethyl starch sodium) 100 orders that sieve, the method that employing equivalent is progressively increased is with its mix homogeneously.
(2) with item 5(HPMC 5% aqueous solution) in the mixture in step (1) of progressively increasing, soft material processed
(3) soft material in step (2) is granulated by 20 eye mesh screens.
(4) dry under 60 ℃ in drying baker with making granule in step (3), until water content is lower than 3% the time, drying stops.
(5) dry granule is crossed 20 eye mesh screen granulate.
(6) a 6-8(ibuprofen, microcrystalline Cellulose, carboxymethyl starch sodium) 100 orders that sieve, the method that employing equivalent is progressively increased is with its mix homogeneously.
(7) with item 9(HPMC 5% aqueous solution) in the mixture in step (6) of progressively increasing, soft material processed.
(8) soft material in step (7) is granulated by 20 eye mesh screens.
(9) dry under 60 ℃ in drying baker with making granule in step (8), until water content is lower than 3% the time, drying stops.
(10) dry granule is crossed 20 eye mesh screens arrangements.
(11) with step (5) and step (10) difference gained granule mix homogeneously.
(12) with item 10(magnesium stearate) join step (11) gained granule, mix homogeneously.
(13) said preparation is pressed into tablet.
After deliberation, the inventor finds to adopt ibuprofen, the nizatidine of 3-20%, 10-60% microcrystalline Cellulose, 3-20% pregelatinized Starch, 2-10% carboxymethyl starch sodium, 2-10% hydroxypropyl cellulose, the 2-10% magnesium stearate of the component of following weight proportioning: 20-80%, all can realize reducing the ibuprofen gastrointestinal side effect, and improve the effect of nizatidine stability.
Wherein, microcrystalline Cellulose, hydroxypropyl cellulose are binding agent, refer to give the excipient of the composition adhesion properties of pharmaceutical composition, can also use other adjuvants with similar effect, as sucrose, glucose, dextrose, lactose, cellulose derivative, cellulose powder, silicified microcrystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose etc.
Magnesium stearate used is lubricant, it is the excipient that the adhesion of the device (as the tablet machine drift) of production dosage form is added for reducing solid preparation, spendable adjuvant with similar effect also is as aluminium stearate, PEG4000-8000, Pulvis Talci, sodium benzoate, glyceryl mono fatty acid, glycerol two behenates, palmitic acid stearic acid ester of glycerol, Polyethylene Glycol, cotmar or castor bean wet goods.
Microcrystalline Cellulose used also has the effect of diluent, and spendable adjuvant with similar effect also is as lactose, Icing Sugar, starch, dextrin, precipitated calcium carbonate, calcium phosphate, kaolin etc.
Table 7. ordinary tablet ibuprofen release and nizatidine dissolution
| Time point (minute) | Ibuprofen (pH of buffer 6.8) | %RSD | Nizatidine (pH of buffer 7.2) | %RSD |
| 5 | 88.4 | 3.6 | 80.8 | 2.0 |
| 15 | 92.1 | 3.2 | 84.8 | 1.7 |
| 30 | 96.6 | 2.1 | 89.5 | 2.5 |
| 45 | 98.0 | 1.7 | 91.3 | 1.1 |
| 60 | 98.8 | 1.5 | 91.7 | 1.4 |
| Endless 1 | 99.2 | 1.3 | 92.5 | 1.8 |
| Endless 2 | 99.5 | 1.2 | 93.6 | 2.0 |
Endless 1:15 minute@250RPM
Endless 2 :@250RPM spends the night
Test example 10: the preparation of ibuprofen/nizatidine unit dosage forms
This embodiment describes how to prepare concrete ibuprofen/nizatidine unit dosage forms, and this dosage form is coated tablet.
A. prepare the ibuprofen label
Table 8. coated tablet ibuprofen label prescription
| Project | Material | The mg/ sheet | Function |
| 1 | Ibuprofen | 300 | |
| 2 | Hypromellose 1 | 10 | Slow-release material |
| 3 | |
10 | |
| 4 | Lactose | 5 | Porogen |
| 5 | Hypromellose 3(mg) | 5 | Binding agent |
| 6 | Magnesium stearate | 3.5 | Lubricant |
| 7 | Pulvis Talci | 3.5 | Lubricant |
1, label: the 1-4 item is crossed 100 order aperture sieve, according to the recipe quantity mix homogeneously, add suitable amount of adhesive wet granulation (20 order), 50 ℃ of oven dry.
2, adopt moisture test apparatus (Sh10A) to measure granule water content, moisture＜3%.
3, granulate (20 order), add lubricant, fluidizer, adopts AR I type Repose angle gauge to measure mobility of particle after mixing, guarantees that be between 30 ° ~ 45 ° angle of repose.
4, adopt single punch tablet machine (Shanghai micromachine factory, model: JY7124) tabletting.
5, sealing coat: according to the explanation of manufacturer, insolated layer materials applies by spraying.For example the insolated layer materials concentrate is put into 70% distilled water, making solid content is 5%, and follows stirring, to form dispersion.The ibuprofen label is placed in temperature and maintains 35 ~ 40 ℃.Insolated layer materials uses lance ejection in coating pan, until the coating weightening finish reaches expected value.(can be expected in the coating process about 70% insolated layer materials with this label of coating, follow about 30% loss).
6, medicated layer: by a certain percentage nizatidine is added in coating solution, will contain the nizatidine coating solution in any suitable mode and be sprayed at the tablet that has sealing coat, until add the nizatidine of desired amt.
7, outer coatings layer: according to product description preparation coating solution, coating solution is sprayed on 6 gained tablets in any appropriate manner, until the coating weightening finish reaches expected value.
Framework material screening in test example 11 ibuprofen labels
According to physical and chemical properties of drugs and to the requirement of preparation slow release, the screening framework material, comprise the kind of framework material concrete be its viscosity, also have the consumption of framework material, obtaining following several more excellent prescription Core formulation 5, Core formulation 7 and Core formulation 8 through screening.
Select full-bodied hypromellose as framework material, wherein hypromellose 1 and hypromellose 2 viscosity＞4000cps, be framework material.Hypromellose 3 viscosity are lower, are porogen.In each prescription, the consumption of adjuvant sees the following form.
Table 9. ibuprofen tablet core crab material screening prescription
| Prescription 5 | Prescription 7 | Prescription 8 | |
| Ibuprofen (mg) | 300 | 300 | 300 |
| Hypromellose 1(mg) | 10 | 20 | - |
| Hypromellose 2(mg) | - | - | 40 |
| Microcrystalline Cellulose (mg) | 10 | 10 | 10 |
| Lactose (mg) | 5 | 5 | 5 |
| Hypromellose 3(mg) | 5 | 5 | 5 |
| Binding agent (concentration: g/100ml) | 2.5% | 2.5% | 2.5% |
| Magnesium stearate (mg) | 3.5 | 3.5 | 3.5 |
| Pulvis Talci (mg) | 3.5 | 3.5 | 3.5 |
[0159]Table 10. is according to the investigation of release, and in each prescription, ibuprofen release percentage rate is as follows
| Time | Label 5 (%) | Label 7 (%) | Label 8 (%) |
| 2 hours | 22.03±8.52 | 11.42±5.01 | 16.46±10.35 |
| 4 hours | 39.57±5.30 | 24.31±9.46 | 30.30±8.62 |
| 6 hours | 55.10±6.77 | 38.98±6.74 | 45.10±7.77 |
| 8 hours | 61.59±4.93 | 55.65±7.19 | 60.17±5.91 |
| 12 hours | 82.54±4.36 | 65.36±8.54 | 75.54±5.36 |
Table 10 result shows, adopts hypromellose 2 as blocker, and during every consumption 20mg, ibuprofen discharges too slowly, and ibuprofen discharges comparatively fast during with 10mg, is not easy to control release.And during with hypromellose 1, rate of release is very suitable, therefore adopt it as blocker.Release satisfied 2 hours: 10 ~ 30%, 4 hours: 30 ~ 45%, 6 hours: 45 ~ 55%, 8 hours: 55 ~ 65%, 12 hours:＞75%.
The screening of binding agent in test example 12 ibuprofen labels
According to physical and chemical properties of drugs and to the requirement of preparation slow release, the screening binding agent mainly comprises kind and the concentration of binding agent obtaining following several more excellent prescription Core formulation 9, Core formulation 16 and Core formulation 21 through screening, sees Table 11.
Table 11. ibuprofen tablet core binder screening prescription
| Prescription 11 | Prescription 12 | Prescription 5 | |
| Ibuprofen (mg) | 300 | 300 | 300 |
| Hypromellose 1(mg) | 10 | 10 | 10 |
| Microcrystalline Cellulose (mg) | 10 | 10 | 10 |
| Lactose (mg) | 5 | 5 | 5 |
| Hypromellose 3(mg) | 5 | 5 | 5 |
| Binding agent 1(concentration) | 5% | 8% | - |
| Binding agent 2 | - | - | 2.5% |
| Magnesium stearate (mg) | 3.5 | 3.5 | 3.5 |
| Pulvis Talci (mg) | 3.5 | 3.5 | 3.5 |
According to the investigation method of release, in each prescription, ibuprofen discharges percentage rate such as following table:
Table 12. is according to the investigation of release, and in each prescription, ibuprofen release percentage rate is as follows
| Time | Label 11 (%) | Label 12 (%) | Label 5 (%) |
| 2 hours | 22.49±8.50 | 27.54±8.22 | 22.03±7.52 |
| 4 hours | 41.62±7.11 | 51.53±9.09 | 39.57±5.30 |
| 6 hours | 48.11±8.32 | 69.21± | 55.10±6.77 |
| 8 hours | 54.07±7.49 | 86.81±10.03 | 61.59±4.93 |
| 12 hours | 67.28±10.63 | 86.39±7.46 | 82.54±4.36 |
Table 12 result shows, adopt concentration be 2.5% binding agent 2 as the binding agent in pelletization, the ibuprofen release is optimum.Release satisfied 2 hours: 10 ~ 30%, 4 hours: 30 ~ 45%, 6 hours: 45 ~ 55%, 8 hours: 55 ~ 65%, 12 hours:＞75%
The screening of porogen in test example 13 ibuprofen labels
According to physical and chemical properties of drugs and to the requirement of preparation slow release, the screening porogen mainly comprises kind and the consumption of porogen obtaining following several more excellent prescription Core formulation 5, Core formulation 16 and Core formulation 18 through screening, sees Table 13.
Table 13. ibuprofen label porogen screening prescription
| Prescription 5 | Prescription 16 | Prescription 18 | |
| Ibuprofen (mg) | 300 | 300 | 300 |
| Hypromellose 1(mg) | 10 | 10 | 10 |
| Microcrystalline Cellulose (mg) | 10 | 10 | 10 |
| Lactose (mg) | 5 | 5 | - |
| Hypromellose 3(mg) | 5 | - | 5 |
| Sodium chloride (mg) | - | 5 | - |
| Binding agent (concentration: g/100ml) | 2.5% | 2.5% | 2.5% |
| Magnesium stearate (mg) | 3.5 | 3.5 | 3.5 |
| Pulvis Talci (mg) | 3.5 | 3.5 | 3.5 |
[0174]Table 14. is according to the investigation of release, and in each prescription, ibuprofen discharges percentage rate
| Time | Label 21 (%) | Label (%) | Label (%) |
| 2 hours | 22.03±7.52 | 34.54±7.93 | 17.77±10.61 |
| 4 hours | 39.57±7.52 | 60.07±7.99 | 29.03±9.97 |
| 6 hours | 55.10±7.52 | 78.50±5.82 | 42.54±11.53 |
| 8 hours | 61.59±7.52 | 90.09±5.44 | 66.29±12.57 |
| 12 hours | 82.54±7.52 | 95.08±3.21 | 78.71±11.20 |
Result shows that doing porogen with sodium chloride can make ibuprofen release too fast, and alone hypromellose is effective not as good as associating lactose and hypromellose.
The screening of sealing coat in test example 14 ibuprofen/nizatidine unit dosage forms
According to physical and chemical properties of drugs and to the requirement of preparation, carry out the screening of sealing coat.The method of bag sealing coat is as follows, and the coating temperature is controlled at 40 degree, and the coating pan rotating speed is 30 rev/mins, carries out coating, generally speaking increases weight 4% to get final product.Coating 1 and coating solution 2 are the molten material of rapid release harmonization of the stomach duodenum, after their difference coatings, by investigating the release conditions of ibuprofen in label, in order to understand the impact that sealing coat discharges ibuprofen.Ibuprofen discharges before and after coating the results are shown in following table.
The screening of table 15. sealing coat coating solution
| Sample time | Release (%) before coating | Coating solution 1 release (%) | |
| 2 hours | 22.03±7.52 | 19.64±8.01 | 20.91±10.49 |
| 4 hours | 39.57±5.30 | 38.39±6.47 | 38.81±7.35 |
| 6 hours | 55.10±6.77 | 57.88±7.93 | 51.09±8.41 |
| 8 hours | 61.59±4.93 | 64.41±5.09 | 60.77±6.22 |
| 12 hours | 82.54±4.36 | 88.92±5.28 | 80.25±6.36 |
Shown by table 15 result, in this case study on implementation, coating solution 1 is as sealing coat, can appreciable impact label release, compare p＞0.05 with not containing the sealing coat label, compare with coating solution 2, the relative standard difference is less, therefore select coating solution 1 more excellent as insolated layer materials.
Test example 15 contains the screening of nizatidine coatings (being medicated layer) coating solution kind
Spray medicated layer according to embodiment outside sealing coat, particularly, the nizatidine after sieving is dissolved in different coating solutions, the coating temperature is controlled at 50 degree, and rotating speed is 30 rev/mins, carries out coating, and weightening finish gets final product to 14%.Investigate two kinds of coating solutions to the impact that ibuprofen in label discharges, investigated respectively again the stripping of nizatidine in two kinds of coating solutions.
The release conditions of ibuprofen in label before and after table 16. bag medicated layer
| Release | Release (%) before coating | Coating solution 6(%) | Coating solution 7(%) |
| 2 hours | 22.03±7.52 | 15.21±7.80 | 14.05±5.37 |
| 4 hours | 39.57±5.30 | 30.11±8.32 | 34.20±6.25 |
| 6 hours | 55.10±6.77 | 50.46±5.69 | 47.88±8.76 |
| 8 hours | 61.59±4.93 | 66.37±5.92 | 60.77±7.64 |
| 12 hours | 82.54±4.36 | 89.16±5.01 | 77.20±6.73 |
Upper table result shows, adopts coating solution 6 as the medicated layer material, do not change ibuprofen label release (with comparing release there was no significant difference p＞0.05 before bag), and the uniformity of coating solution 7 coatings is too large not as good as coating solution 6(RSD).
Nizatidine dissolution after table 17. bag medicated layer
| Medicated layer 1(%) | Medicated layer 2(%) | |
| 30min | 91.03±5.06 | 80.25±4.26 |
Result shows, as medicated layer, is sprayed at the ibuprofen tablet wicking surface that contains sealing coat after coating solution 6 and coating solution 7 mix with nizatidine, and the nizatidine stripping meets the demands, dissolution 30 minutes＞75%.
To sum up, selecting coating solution 6 is excellent as the medicated layer material.
The screening of test example 16 outer coatings layers
Adopt the coating solution of sealing coat, the coating temperature is controlled at 40 degree, and rotating speed is 30 rev/mins, carries out coating, and weightening finish 2% gets final product.The change of ibuprofen release before and after same investigation bag outer coatings layer the results are shown in following table:
The screening of table 18. outer coatings layer coating solution
| Release | Before coating (%) | Coating solution 9(%) | Coating solution 10(%) |
| 2 hours | 22.03±7.52 | 13.76±11.33 | 13.09±8.19 |
| 4 hours | 39.57±5.30 | 30.10±8.46 | 33.44±7.31 |
| 6 hours | 55.10±6.77 | 48.99±7.02 | 45.67±6.25 |
| 8 hours | 61.59±4.93 | 59.39±5.38 | 61.64±6.31 |
| 12 hours | 82.54±4.36 | 85.94±5.25 | 80.04±5.98 |
Also investigate the change of nizatidine dissolution before and after bag outer coatings layer, the results are shown in following table:
Table 19. nizatidine dissolution
| | Coating solution | 10 | Coating solution 9 |
| 30min | 86.33±5.10 | 64.9±5.28 |
[0198]Upper table result demonstration, coating solution 10 is very little on the impact of ibuprofen release as outsourcing layer, compares there was no significant difference p＞0.05 with the uncoated tablets core.Coating solution 9 is larger on the release impact of ibuprofen, and the dissolution fluid of nizatidine is had certain impact.To sum up, select coating solution 10.
Test example 17: the preparation of ibuprofen/nizatidine double-layer tablet
This embodiment describes how to prepare concrete ibuprofen/nizatidine unit dosage forms, and this dosage form is for covering the bilayer tablet of outer coatings layer outward.Two-layer middle ingredient such as following table:
The ibuprofen layer
Table 20. double-layer tablet ibuprofen layer prescription
| Project | Material | Consumption (mg) | Purposes |
| 1 | Ibuprofen | 300 | |
| 2 | HPMC 1 | 10 | Blocker |
| 3 | |
10 | |
| 4 | Lactose | 5 | Porogen |
| 5 | Carboxymethyl cellulose 3 | 5 | Porogen |
| 6 | Binding agent | 2.5(concentration: g/100ml) | Binding agent |
| 7 | Magnesium stearate | 3.5 | Lubricant |
| 8 | Pulvis Talci | 3.5 | Lubricant |
The nizatidine layer
Table 21. double-layer tablet nizatidine layer prescription
| Project | Material | Consumption (mg) | Purposes |
| 1 | Nizatidine (mg) | 75 | |
| 2 | Carboxymethyl starch sodium (mg) | 8.5 | Disintegrating agent |
| 3 | Microcrystalline Cellulose | 75 | |
| 4 | Lactose (mg) | 3 | Filler |
| 5 | Binding agent (concentration: g/100ml) | 5% | Binding agent |
| 6 | Magnesium stearate (mg) | 3.5 | Lubricant |
| 7 | Pulvis Talci (mg) | 3.5 | Lubricant |
1, ibuprofen and excipient thereof are crossed respectively 100 mesh sieves, mixing, add binding agent, wet granulation, oven dry arranges, and adds lubricant, fluidizer, mixing.
2, the nizatidine layer is crossed respectively 100 mesh sieves, mixing with ibuprofen and excipient thereof, adds binding agent, wet granulation, and oven dry arranges, and adds lubricant, fluidizer, mixing.
Adopt bi-layer tablet press or other various preparation ways to prepare double-layer tablet.
The different proportionings of test example 18 ibuprofen and nizatidine
Table 22. ibuprofen and nizatidine proportioning form
After measured, when unit formulation contains the ibuprofen of 100-400mg and 25-200mg nizatidine, all realize the stomach protective effect.
The incompatibility of test example 19 ibuprofen and nizatidine
The pressure degraded (forced degradation) of emergent experiment (stress assay) is used for estimating the stability of pharmaceutical composition.
1, the pressure degradation condition is intended to accelerate the hot conditions of chemical degradation process, or high temperature and high humidity.Force to continue for some time under degradation condition, be used for prediction and store the effect of longer time under milder (for example, room temperature) condition.It is found that, under " forcing degraded " condition, ibuprofen and nizatidine raw mix are that pharmacy is inconsistent., be degraded separately 60 ℃ of relative humidity storages that store 2 weeks or 40 ℃ and 75% 1 month when nizatidine, stability result sees Table 1.
Under table 23 stressed condition, nizatidine/ibuprofen stability
| API | Storage condition | Nizatidine content * |
| Nizatidine | 60 ℃, 2 weeks | 98% |
| Nizatidine+ibuprofen | 60 ℃, 2 weeks | 77% |
| Nizatidine+ibuprofen | 40 ℃/75%RH, 1 month | 56% |
* nizatidine content is measured by analytical HPLC, and represents with the percent of target content.
2, similarly, shown in table 24, under stressed condition, comprise in tablet formulation in the tablet of ibuprofen.This tablet contains ibuprofen 300mg, and nizatidine 46.88mg and relevant excipient, this tablet formulation are preparation after test example 16 coatings.Observe under hot conditions, nizatidine is degraded in a large number; Under the strong illumination condition, nizatidine is slightly degraded; Room temperature keeps in Dark Place, and nizatidine is degraded hardly in 4 months.
Under table 24. stressed condition in tablet, the stability of nizatidine
| API | Storage condition | Nizatidine content * |
| Ibuprofen (300mg+) nizatidine (46.88mg) | Initial | 100% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | 60 ℃, 10 days | 78.42% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | 40 ℃/75%RH, 1 month | 66.71% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | Be under 4500 ± 500lx in illumination, 5 days | 97.21% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | Be under 4500 ± 500lx in illumination, 10 days | 97.06% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | In room temperature, RH65%, under the lucifuge condition, 10 days | 98.34% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | In room temperature, RH65%, under the lucifuge condition, 1 month | 98.41% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | In room temperature, RH65%, under the lucifuge condition, 4 months | 98.29% |
Under test example 20 stressed conditions in tablet, the stability of nizatidine in bilayer tablet
As table 25, ibuprofen and nizatidine under stressed condition, the stability of nizatidine, this tablet formulation is test example 17 preparations.Compare with coated tablet, under the same conditions, in double-layer tablet, nizatidine stability improves, degraded to some extent under hot conditions, explanation hardly under illumination and room temperature lucifuge condition; Keep in Dark Place at room temperature and can preserve 4 months at least.
Under table 25. stressed condition in bilayer tablet, the stability of nizatidine.
| API | Storage condition | Nizatidine content * |
| Ibuprofen (300mg+) nizatidine (46.88mg) | Initial | 100% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | 60 ℃, 10 days | 96.25% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | 40 ℃/75%RH, 1 month | 95.82% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | Be under 4500 ± 500lx in illumination, 5 days | 99.49% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | Be under 4500 ± 500lx in illumination, 10 days | 99.36% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | In room temperature, RH65%, under the lucifuge condition, 10 days | 99.01% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | In room temperature, RH65%, under the lucifuge condition, 1 month | 98.78% |
| Ibuprofen (300mg+) nizatidine (46.88mg) | In room temperature, RH65%, under the lucifuge condition, 4 months | 98.57% |
Claims (9)
1. have the compound iuprofen of pipe intestinal protection effect, it is characterized in that: active component comprises ibuprofen or its pharmaceutical salts, nizatidine, and its weight proportion is:
Ibuprofen or its pharmaceutical salts 15-120 part, nizatidine 1-40 part.
2. the compound iuprofen with pipe intestinal protection effect according to claim 1, it is characterized in that: in described anti-inflammatory agent unit formulation, active component comprises the ibuprofen of 100-800mg and the nizatidine of 25-200mg.
3. the compound iuprofen with pipe intestinal protection effect according to claim 2, it is characterized in that: in described anti-inflammatory agent unit formulation, active component comprises the ibuprofen of 200-800mg and the nizatidine of 50-100mg.
4. the described compound iuprofen with pipe intestinal protection effect of according to claim 1-3 any one is characterized in that: described anti-inflammatory agent is take ibuprofen or its pharmaceutical salts and nizatidine as active component, the preparation that adds pharmaceutically acceptable adjuvant to make.
5. the compound iuprofen with pipe intestinal protection effect according to claim 4, it is characterized in that: described preparation is oral formulations.
6. the compound iuprofen with pipe intestinal protection effect according to claim 5 is characterized in that: described oral formulations is a kind of in tablet, capsule, pill or pellet.
7. the compound iuprofen with pipe intestinal protection effect according to claim 5, it is characterized in that: described oral formulations is after two kinds of active component are granulated respectively, then after two kinds of granules are mixed, tabletting or encapsulated; Or
Described oral formulations be be two kinds of active component are granulated respectively after, then two kinds of granules are pressed into double-layer tablet, one deck contains ibuprofen, one deck contains nizatidine; Or
Described oral formulations is after two kinds of active component are made micropill respectively, then two kinds of micropills are encapsulated; Or
Described oral formulations is coated preparation, and ibuprofen is made label, and in bag, coatings forms sealing coat, then nizatidine is wrapped in outside sealing coat, wraps at last the outer coatings layer.
8. the compound iuprofen with pipe intestinal protection effect according to claim 7, is characterized in that: described double-layer tablet is adopted Cotton seeds.
9. claim 1-8 any one is described has the compound iuprofen of pipe intestinal protection effect for the preparation of the purposes in treatment rheumatic arthritis, osteoarthritis, dysmenorrhea, acute and chronic pain or acutely inflamed medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106466307A (en) * | 2015-08-18 | 2017-03-01 | 北京蓝丹医药科技有限公司 | Ibuprofen and glycine betaine pharmaceutical composition and preparation method thereof |
| CN106466308A (en) * | 2015-08-19 | 2017-03-01 | 北京蓝丹医药科技有限公司 | Naproxen and glycine betaine pharmaceutical composition and preparation method thereof |
| WO2020167262A1 (en) * | 2019-02-12 | 2020-08-20 | Pisak Mehmet Nevzat | Immediate release formulations of gel forming polymers |
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| US20080020040A1 (en) * | 2006-07-18 | 2008-01-24 | Horizon Therapeutics, Inc. | Unit dose form for administration of ibuprofen |
| CN101257800A (en) * | 2005-07-18 | 2008-09-03 | 好利用医疗公司 | Medicaments containing famotidine and ibuprofen and administration of same |
| US20090233970A1 (en) * | 2008-03-11 | 2009-09-17 | Nickell Robert P | Combined nsaid and acid blocker formulation and method |
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| CN101257800A (en) * | 2005-07-18 | 2008-09-03 | 好利用医疗公司 | Medicaments containing famotidine and ibuprofen and administration of same |
| US20080020040A1 (en) * | 2006-07-18 | 2008-01-24 | Horizon Therapeutics, Inc. | Unit dose form for administration of ibuprofen |
| US20090233970A1 (en) * | 2008-03-11 | 2009-09-17 | Nickell Robert P | Combined nsaid and acid blocker formulation and method |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106466307A (en) * | 2015-08-18 | 2017-03-01 | 北京蓝丹医药科技有限公司 | Ibuprofen and glycine betaine pharmaceutical composition and preparation method thereof |
| CN106466308A (en) * | 2015-08-19 | 2017-03-01 | 北京蓝丹医药科技有限公司 | Naproxen and glycine betaine pharmaceutical composition and preparation method thereof |
| WO2020167262A1 (en) * | 2019-02-12 | 2020-08-20 | Pisak Mehmet Nevzat | Immediate release formulations of gel forming polymers |
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