Oral arginine ibuprofen liquid preparation
Technical field
The invention belongs to technical field of medicine, relate to a kind of oral liquid of antipyretic-antalgic anti-inflammatory agent arginine Ibuprofen.
Background technology
Ibuprofen is non-steroidal antiinflammatory, an analgesic commonly used clinically, has become the pillar product of antipyretic analgesic in many countries.Be applicable to: fever, headache that (1) flu, upper respiratory tract infection or acute pharyngitis cause.(2) alleviating pain, as headache, toothache, extremities aching pain, neuralgia, migraine, dysmenorrhea, gout, obstetrics or hand orthosis postoperative pain, and the musculoskeletal pain behind the soft tissue motional injury etc., also can alleviate the pain of non-rheumatic inflammations such as synovitis, tendinitis.(3) arthritis is used for the remission of rheumatic arthritis, acute and chronic rheumatoid arthritis and osteoarthritis.Research report to Motrin is a lot of both at home and abroad, have preparation capable of permeating skin, compound tablet, solid dispersion, suspensoid, slow releasing preparation, suppository, slurry agent, gel, speed to collapse the report of agent, microemulsion formulation etc., its liquid suspension is quite extensive in countries use such as Europe, the United States.Compare with countries such as Europe, the United States, the drug effect of ibuprofen is not fully used in China, is mainly used in antiinflammatory, analgesia, and is also not extensive in application analgesic, aspect bringing down a fever.This and its water solublity is low, and the exploitation and the application of also rare quick-acting water soluble preparation have some relations.For increasing its water solublity, all be added with a large amount of alcohol (containing the alcohol amount reaches more than 30%) in the oral liquid of the report prescription or times over the alkaline matter of ibuprofen, this is unfavorable for that the patient accepts, and is unfavorable for that especially the child takes medicine.For increasing the water solublity of ibuprofen, make in its water soluble preparation and needn't contain a large amount of alcohol and alkaline matter, we have developed ibuprofen soluble derivative-arginine Ibuprofen, because arginine Ibuprofen is soluble in water, so be easy to be prepared into water soluble preparation, and needn't contain alcohol and alkaline matter hydrotropy in the preparation.The existing at home and abroad report of ibuprofen syrup and using, but the arginine Ibuprofen oral liquid do not appear in the newspapers and application as yet, and said preparation is compared to have with the ibuprofen oral liquid of bibliographical information and is not contained alcohol and NaHCO
3Deng the characteristics of alkaline matter, absorb rapidly, rapid-action, little to GI irritation.
Advantage such as that solid orally ingestible such as tablet, capsule etc. have is easy to carry, be easy to take.But concerning child or elderly patients etc. swallowed the inconvenient special population of solid preparation (account for patient's sum 1/4), the liquid oral medicament was more welcome.In liquid preparation, medicine is dispersed in the medium with molecule or graininess in addition, and dispersion is big, absorbs soon, can bring into play drug effect more rapidly, is beneficial to the performance of analgesic, the function of bringing down a fever that needs quick acting especially; The said preparation taking convenience, be easy to divided dose, can reduce medicine zest, improve bioavailability of medicament, be specially adapted to child and gerontal patient.
Summary of the invention
The objective of the invention is arginine Ibuprofen is made oral liquid, said preparation has taking convenience, is easy to divided dose, is specially adapted to child or elderly patients etc. is swallowed the inconvenient special population of solid preparation, do not contain alcohol and NaHCO
3Deng the characteristics of alkaline matter, absorb rapidly, rapid-action, little to GI irritation.
Arginine Ibuprofen oral liquid of the present invention is for containing arginine Ibuprofen that drug effect dosage is arranged and the suitable pharmaceutic adjuvant pharmaceutical solutions of making soluble in water.Wherein the consumption of arginine Ibuprofen is that every 1ml liquid preparation contains 5mg~100mg, and preferred every 1ml contains arginine Ibuprofen 35mg~85mg.Pharmaceutic adjuvant comprises: the one or more combination in sweeting agent, mucilage, aromatic, antiseptic, stabilizing agent, the coloring agent.
Contain at least a sweeting agent and at least a antiseptic in the oral arginine ibuprofen liquid preparation of the present invention.
Sweeting agent can be glucide, acesulfame potassium, aspartame, alitame, sucralose, Radix Glycyrrhizae and ammonium glycyrrhizinate, glycyrrhizic acid one potassium and tripotassium, the steviol glycosides of sucrose, glycerol, Sorbitol, lactose, maltose, mannitol, fructose and the high sugariness of low sugariness, the one or more combination in the Momordica-Glycosides.
Antiseptic can be the one or more combination in p-Hydroxybenzoate (nipalgin) class, potassium sorbate, the sodium benzoate, and its percentage by weight is 0.01%-2.5%.
Can also contain mucilage, aromatic, coloring agent and stabilizing agent in the oral arginine ibuprofen liquid preparation of the present invention.
Mucilage can be the one or more combination in sodium carboxymethyl cellulose, methylcellulose, Hydroxypropylcelliloxe, sodium alginate, arabic gum, tragakanta, agar, gelatin, pectin, xanthan gum, dextrin, the carbomer; Aromatic can be the one or more combination in natural or the synthetic essence, for example Herba Menthae, Fructus Mali pumilae, Fructus Citri tangerinae, Fructus Musae, Fructus Citri Limoniae, Fructus Citri sinensis, Fructus Pruni pseudocerasi, Fructus Chaenomelis, hami melon essence, and its percentage by weight is 0.01%-5%; Coloring agent can be the food coloring that is complementary with flavouring agent; Stabilizing agent can be the one or more combination in EDTA sodium, sodium sulfite, sodium sulfite, the sodium pyrosulfite.
Oral arginine ibuprofen liquid preparation of the present invention, if it of the high sugariness of its sweeting agent is the liquid preparation that following component is arranged:
Arginine Ibuprofen 1-10%
High-intensity sweeteners 1-10%
Mucilage 1-10%
Antiseptic 0.01-2.5%
Essence 0.01-5%
Coloring agent 0-0.1%
Water adds to 100%
Oral arginine ibuprofen liquid preparation of the present invention, if the sugar of the low sugariness of its sweeting agent it be the liquid preparation that following component is arranged:
Arginine Ibuprofen 1-10%
Low intensity sweeteners 40-85%
Antiseptic 0.01-2.5%
Essence 0.01-5%
Coloring agent 0-0.1%
Water adds to 100%
Oral arginine ibuprofen liquid preparation of the present invention, if the mixing sweetener of low sugariness of its sweeting agent and high sugariness it be the liquid preparation that following component is arranged:
Arginine Ibuprofen 1-10%
Low intensity sweeteners 20-40%
High-intensity sweeteners 0.5-5%
Mucilage 0-5%
Antiseptic 0.01-2.5%
Essence 0.01-5%
Coloring agent 0-0.1%
Water adds to 100%
Oral arginine ibuprofen liquid preparation of the present invention has following characteristics:
1. the arginine ibuprofen liquid preparation Chinese medicine is dispersed in the medium with molecularity, and dispersion is big, absorbs soon, can bring into play drug effect rapidly, helps improving bioavailability of medicament.Rapid-action, these characteristics are crucial for the quick-acting patients analgesic, quickly easing pain of needs, have satisfied clinical different needs.
2. the said preparation taking convenience is easy to divided dose, is specially adapted to child or elderly patients etc. and swallows the inconvenient special population of solid preparation.
3. arginine ibuprofen liquid preparation can reduce the GI irritation effect that the oral back of ibuprofen solid drugs causes owing to local concentration is too high; Do not contain alcohol and NaHC0
3Little Deng alkaline matter to GI irritation.
4. arginine itself is the nutrition of human body, and is without any side effects.Liver there is protective effect, can prevents and correct owing to taking the hepatotoxicity that ibuprofen causes for a long time.
The specific embodiment
Following embodiment is used for the present invention is described and it is not construed as limiting.
Embodiment 1
Every 1000ml arginine Ibuprofen syrup takes by weighing material by following prescription:
Arginine Ibuprofen 37g
Sodium benzoate 2g
Water 100ml
Essence 0.5g
Simple syrup adds to 1000ml
The supplementary material that takes by weighing is prepared arginine Ibuprofen syrup of the present invention according to the following steps:
Get arginine Ibuprofen 37g and sodium benzoate 2g, add essence 0.5ml after adding the 100ml dissolved in distilled water, add simple syrup to 1000ml, mixing, promptly.
Embodiment 2
Every 1000ml arginine Ibuprofen syrup takes by weighing material by following prescription:
Arginine Ibuprofen 37g
Sucrose 595g
Sodium benzoate 2g
Essence 0.5g
Food coloring 0.2g
Water adds to 1000ml
The supplementary material that takes by weighing is prepared arginine Ibuprofen syrup of the present invention according to the following steps:
1. after getting arginine Ibuprofen, sodium benzoate and adding an amount of dissolving of water, with food coloring, dissolving;
2. getting sucrose 595g adds hot water and makes simple syrup in right amount;
3. with stirring in 1 adding 2, add essence again, add water to 1000ml, stir, promptly.
Embodiment 3
Every 1000ml arginine Ibuprofen oral administration solution takes by weighing material by following prescription:
Arginine Ibuprofen 37g
Agar 5g
Aspartame 15g
Methyl parahydroxybenzoate 0.4g
Ethylparaben 0.1g
Essence 1.5g
Food coloring 0.2g
Water adds to 1000ml
The supplementary material that takes by weighing is prepared arginine Ibuprofen oral administration solution of the present invention according to the following steps:
1. getting arginine Ibuprofen, aspartame adds water 100ml dissolving back and adds the food coloring dissolving;
2. get agar, methyl parahydroxybenzoate, ethylparaben and add water 800ml, heating makes abundant dissolving, filters while hot;
3. with stirring in 1 adding 2, add essence again, add water to 1000ml, stir, promptly.
Embodiment 4
Every 1000ml arginine Ibuprofen oral administration solution takes by weighing material by following prescription:
Arginine Ibuprofen 37g
Carbomer 1.5g
Aspartame 15g
Sodium benzoate 5g
Essence 1.5g
Food coloring 0.2g
Water adds to 1000ml
The supplementary material that takes by weighing is prepared arginine Ibuprofen oral administration solution of the present invention according to the following steps:
4. getting arginine Ibuprofen, aspartame, sodium benzoate adds water 100ml dissolving back and adds the food coloring dissolving;
5. get carbomer and add water 800ml, heating makes abundant swelling;
6. with stirring in 1 adding 2, add essence again, add water to 1000ml, stir, promptly.
Embodiment 5
Every 1000ml arginine Ibuprofen oral administration solution takes by weighing material by following prescription:
Arginine Ibuprofen 37g
Fructose 250g
Pectin 25g
Aspartame 5g
Sodium benzoate 5g
Sodium sulfite 1g
Essence 1g
Food coloring 0.2g
Water adds to 1000ml
The supplementary material that takes by weighing is prepared arginine Ibuprofen oral administration solution of the present invention according to the following steps:
1. getting arginine Ibuprofen, aspartame, sodium benzoate, fructose adds water 300ml dissolving back and adds the food coloring dissolving;
2. get pectin and add water 400ml, heating makes abundant dissolving;
3. with stirring in 1 adding 2, add essence again, add water to 1000ml, stir, promptly.
Arginine Ibuprofen syrup human body pharmacokinetics and bioequivalence Journal of Sex Research with embodiment 1 preparation
The reagent trial target: the arginine Ibuprofen syrup, pharmaceutical college of Medical University Of Tianjin, every bottle (10ml) contains 370mg arginine Ibuprofen (being equivalent to ibuprofen 200mg), lot number: 990612, content is 107% of labelled amount; Reference substance: ibuprofen tablet, Li Hua pharmaceutical factory in Tianjin produces, and every contains ibuprofen 100mg, lot number: 9801189, content is 95% of labelled amount.
18 healthy male subjects of EXPERIMENTAL DESIGN are divided into two groups at random, respectively at morning empty stomach oral syrup 20ml (being equivalent to the 400mg ibuprofen) and 4 of comparison films (400mg ibuprofen).Carry out the test second time after one week, intersect and take isodose syrup and comparison film.Syrup and comparison film are all taken with 200ml warm water.The edible unified meal of the back 2h that takes medicine.Each experimenter respectively adopts venous blood 3ml at take medicine preceding, take medicine back 0.25,0.5,1.0,1.5,2.0,3.0,4.0,6.0,8.0 and 10.0h, and centrifugalize goes out serum, places-20 ℃ refrigerator to preserve to be measured.
Chromatographic condition DiamonsilC
18(5 μ m, 4.6mm * 200mm); Mobile phase: methanol-water (0.05%H
3PO
4) (70: 30); Flow velocity: 1.0mL.min
-1Wavelength: 235nm; Interior mark: naproxen (10 μ g.mL
-1) methanol solution.
The serum processing method is got serum (blank serum, pastille serum or the back serum of taking medicine) 0.25mL, adds mark liquid and 0.45mL trifluoroacetic acid aqueous solution in the 0.05mL, shakes 30 seconds, and centrifugal 5 minutes of 1200rpm, supernatant are used for HPLC and analyze, and sample size is 10 μ L.
Date processing is obtained its average and standard deviation by the blood drug level data of 18 experimenter's different times.(Tpeak and Cmax are calculated by measured value, AUC, ke and t to calculate every experimenter's main pharmacokinetic parameter
1/2Calculate with the 3P97 program).Intersect the lower area of blood concentration-time curve (AUC) of taking syrup and comparison film according to every experimenter and calculate every experimenter's relative bioavailability.
Fr=AUC
Syrup/ AUC
Comparison film* 100%
According to the relevant bioequivalence test direction of FDA principle with WHO, adopt the two-way one-side t check of new drug statistical system (NDST4.1) of establishments such as professor Sun Ruiyuan to carry out statistical analysis to AUC and Cmax, adopt non parametric method (Wilcoxon) to carry out statistical analysis Tpeak.
The serum pharmaceutical concentration-time curve was seen Fig. 1 after 18 healthy male subjects of pharmacokinetic parameter were once taken syrup and comparison film, and pharmacokinetic parameters sees Table 1.
The pharmacokinetic parameters of table 1 single oral dose arginine Ibuprofen syrup and ibuprofen tablet
Intersect the lower area of blood concentration-time curve (AUC) of taking syrup and comparison film by every experimenter and calculate every experimenter's relative bioavailability.The result shows that syrup is 98.50 ± 7.30% with respect to the relative bioavailability of comparison film.
AUC data and Cmax data to two kinds of preparations are carried out variance analysis and the check of two-way one-side t, and the result shows the AUC equivalence of two kinds of preparations.The statistical results show trial target of Cmax is tired higher.
To the Tpeak data of two preparations with direct nonparametric statistics analytical method---the Wilcoxon method is carried out statistical analysis, μ (5.222)>μ as a result
0.05(1.96), promptly P<0.05 shows that both peak time difference is more remarkable.
Process is with waiting molar dose cross matching under the same conditions to prove, the degree of absorption of arginine Ibuprofen syrup and ibuprofen tablet (AUC) is suitable, has bioequivalence.But the arginine Ibuprofen syrup absorbs rapidly, and peak time fast 2 hours than ibuprofen tablet makes the patient occur drug effect as early as possible after helping taking medicine, but peak concentration is still in the treatment safety range.
Description of drawings:
Blood drug level-the time graph (C-t) of Figure 118 position experimenter's oral arginine ibuprofen syrup and ibuprofen tablet.