CN100493505C - Sustained release formulation with cetirizine and pseudoephedrine hydronate - Google Patents
Sustained release formulation with cetirizine and pseudoephedrine hydronate Download PDFInfo
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- CN100493505C CN100493505C CNB2005101144896A CN200510114489A CN100493505C CN 100493505 C CN100493505 C CN 100493505C CN B2005101144896 A CNB2005101144896 A CN B2005101144896A CN 200510114489 A CN200510114489 A CN 200510114489A CN 100493505 C CN100493505 C CN 100493505C
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- pseudoephedrine
- cetirizine
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Abstract
The invention relates to a slow release preparation of Certirizine and Pseudoephedrine Hydrochloride, wherein optimum formulation being, the pesudoephedrine hydrochloride slow release layer comprises d-pesudoephedrine hydrochloride 120g, HPMC60RT1000 20g, HPMC60RT10000 80g, crystalline cellulose 60g, right amount of 10% polyvinyl pyrrolidon anhydrous alcohol liquid, magnesium stearate 2g, the Certirizine hydrochloride quick release prescription includes Certirizine hydrochloride 5g, crystalline cellulose 80g, lactin 80g, sodium carboxymethylstarch 20g, right amount of 10% polyvinyl pyrrolidon anhydrous alcohol liquid, and magnesium stearate 1g.
Description
Technical field:
The present invention relates to a kind of medical slow releasing preparation, particularly relate to the double-layer sustained release preparation that a kind of cetirizine and pseudoephedrine hydrochloride are made.
Background technology:
Allergic rhinitis is a kind of more common disease, and crowd's sickness rate is about 1-2%, its annual 2-4 10,000,000 Americans and nearly 100,000,000 Chinese physical and mental health of influencing.The clinical symptoms of allergic rhinitis comprises nasal congestion, airflow obstruction, rhinorrhea, sneeze, nose and/the other pain of eye pruritus, nose and/(or) headache, anosmia or obstacle, chronic pharyngitis, nasal cavity or nasal sinuses recurrent infection.When being exposed in the allergen, can cause producing specific IgE antibody is attached on the pillar cells and the basophilic leukocyte receptor, in addition, and then cause that histamine and other inflammatory mediator discharge from the pillar cells and basophil, this has just caused direct or early stage anaphylaxis.Allergic rhinitis is seasonality or chronicity, and the preventive measure of a common line is the oral antihistamines thing and avoid contacting allergen.It is oral that to separate congested agent also be the effective ways that are used for effectively alleviating the nasal congestion of Allergic Rhinitis.
From first antihistaminic exploitation of nineteen thirty-seven so far, kind of H surplus in the of existing 50
1Receptor antagonist is for clinical use.First generation medicine before the eighties comprises diphenhydramine, chlorphenamine, promethazine etc., and receptor-specific is poor, and the nervus centralis activity is stronger, can cause tangible calmness and cholinolytic effect, so be called as the calmness antihistaminic; So far the second filial generation antihistaminic of developing the eighties comprises terfenadine, astemizole, fluorine Lei Tading, cetirizine etc., H
1The receptor-selective height, no sedation, central nervous system's untoward reaction is less, so be called non-sedative antihistamine medicine (NSA).These medicines particularly terfenadine and astemizole can bring out cardiac toxicity, though incidence rate is very low, consequence is serious, mainly can cause various arrhythmia, and wherein the most serious use is a torsade de pointes, claims the lethal arrhythmia again.Therefore in aforementioned four kinds of medicines, the use of terfenadine and astemizole is restricted, and the former stops using and produce in many countries, and the latter stops using in the U.S..Fluorine Lei Tading and cetirizine receive an acclaim because of cardiac toxicity is less, become the antihistaminic of sales volume maximum in the world wide.
Cetirizine is compared with other antihistaminics, and it is to periphery H
1Receptor has stronger selectivity, but the not only effect of the early stage histamine of antagonism allergy, the chemotactic response that also can suppress allergy related inflammation in late period cell clinically is usually used in treating anaphylactic diseases such as all kinds urticaria, allergic rhinitis, pollinosis, anaphylaxis conjunctivitis, asthma.There are not side effect such as tangible calmness and cholinolytic under the common dose.The pharmacological action that it is unique promptly removes and blocks H in early days in anaphylaxis
1Outside the receptor, also the eosinophilic granulocyte to its important function of anaphylaxis later stage has powerful inhibitory action, so the antiallergic drug effect is better than other all antihistaminics.
According to statistics, about 59% crowd suffers from seasonal and property anaphylaxis throughout the year, and wherein 30% with nasal congestion, and common symptom is rhinorrhea, itch, sneeze and hyperemia; Patient is when existing the multiple symptom of allergic rhinitis, and it is more reasonable that antihistaminic and long-acting adrenergic agonist share, and its effect obviously is better than the use of single medicine, has remedied the deficiency that single medicine can not well be controlled certain symptom.Most of patients is better to the drug combination tolerance, and obvious adverse reaction is not found in clinical observation.
Between pseudoephedrine hydrochloride and the second filial generation antihistaminic collaborative, booster action is arranged, can obviously eliminate flu and upper respiratory tract allergic symptom.In the antiallergic agent field, treat with cetirizine hydrochloride/pseudoephedrine hydrochloride compound formulation at present, clinical boundary obtains certainly in the world.This associating operational version every day 2 times, can effectively alleviate the allergic rhinitis symptom, especially obvious than the patient who blocks to having, give the treatment of patient's the best.And the data of announcing according to Pfizer, this product treat anaphylactic disease widely aspect with like product Claritin-D12Hour, Claritin-D24Hour, Allegra-D relatively, curative effect is sure.
But because cetirizine and pseudoephedrine hydrochloride using dosage, rate of release, the difference of aspects such as absorbance, need provide a kind of discharges both, absorption reaches synchronously, so that better play synergistic compound preparation, prior art can effectively not provide such preparation as yet.
Summary of the invention:
The present invention is directed to two kinds of medicines of cetirizine/pseudoephedrine hydrochloride characteristic separately, selected the double-layer sustained release preparation that both are separately discharged targetedly.
Pseudoephedrine hydrochloride is an adrenomimetic, has the upper respiratory tract of contraction blood capillary, eliminates the hyperemia of nasopharynx part mucosa, the effect that alleviates the nasal obstruction symptom.
Cetirizine is an antihistaminic, can further alleviate the nasal obstruction that flu causes, symptoms such as watery nasal discharge, sneeze.
The present invention adopts a kind of technology of novelty.The slow-released part that will contain the immediate release section of 5mg cetirizine hydrochloride and contain the 120mg pseudoephedrine hydrochloride lumps together, keep the cetirizine hydrochloride onset rapidly, in the long half time, the medicine that has improved 4 administrations on the one of pseudoephedrine hydrochloride palpus is for characteristic, make the double-layer sustained release preparation, 2 administrations on the one make both reach the optimum synergistic curative effect.
Prescription of the present invention is formed the process screening and is obtained, and it is composed as follows preferably to fill a prescription:
The prescription of pseudoephedrine hydrochloride slow release layer
The prescription of cetirizine hydrochloride release layer
Slow releasing preparation of the present invention, its preparation method is as follows:
(1) preparation of supplementary material and processing
With crossing 100 mesh sieves behind pseudoephedrine hydrochloride, the cetirizine hydrochloride pulverize separately, standby; Lactose, microcrystalline Cellulose, carboxymethyl starch sodium, cross 80 mesh sieves respectively, standby.HPMC
60R1100000, HPMC
60R110000Cross 100 mesh sieves respectively, standby.
(2) weighing with mix
According to the amount of 2 prescriptions, take by weighing above-mentioned former, adjuvant respectively respectively, former, adjuvant in above-mentioned 2 prescriptions are inserted mix homogeneously in the mixer respectively through the double calculating inventory of checking.
(3) granulate
The system soft material: use 10%PVP anhydrous alcohol solution salt manufacturing acid pseudoephedrine soft material and cetirizine hydrochloride soft material respectively, granulate with 20 mesh sieves respectively, the granule that makes all should lack fine powder, does not neatly have rectangular.
Dry: 2 kinds of wet granulars are respectively at 60 ± 2 ℃, in the baking oven inner drying.
Granulate: use 16 mesh sieve granulate respectively
Add lubricant respectively by inventory separately, mixed respectively evenly after, put into hermetic container, qualified back to be tested tabletting.
(4) measure granule content, it is heavy to calculate sheet
Sampling is measured 2 kinds of granule contents respectively by quality standard, and the theoretical sheet of pseudoephedrine hydrochloride heavily is 382mg
The theoretical sheet of cetirizine hydrochloride heavily is 186mg, and being calculated as follows separately respectively, sheet weighs.
(5) tabletting
Actual separately sheet according to the double-layer tablet of result of calculation gained is heavy, behind the loading of the loading of adjusting ground floor (skin) cetirizine hydrochloride release layer on the bi-layer tablet press respectively and the second layer (internal layer) pseudoephedrine hydrochloride slow release layer, presses double-layer tablet.Put into hermetic container sampling check hardness and friability etc. after finishing.
(6) packing
The inspection of semifinished product: tablet need be checked outward appearance, hardness and pack after the assay was approved by the quality standard requirement.Requirement according to product is packed, and packing back warehouse-in can dispatch from the factory after the assay was approved according to quality standard.
Prescription of the present invention is formed the process screening and is obtained, and its screening process is as follows:
West of the present invention is for every hydrochloric pseudoephedrine of pseudoephedrine release sheet (slow release) 120mg; Cetirizine hydrochloride (rapid release) 5mg.When prescription screening, release layer is a filler with lactose, microcrystalline Cellulose; Carboxymethyl starch sodium is a disintegrating agent; The 10%PVP anhydrous alcohol solution is a binding agent; Magnesium stearate is a lubricant.Slow release layer is a slow-release material with the HPMC (hydroxypropyl emthylcellulose) of multiple different viscosities; Microcrystalline Cellulose is filler and disintegrating agent; The 10%PVP anhydrous alcohol solution is a binding agent; Magnesium stearate is a lubricant.Make pseudoephedrine hydrochloride in the release profiles of considering tablet by reasonable combination, also with the index as the evaluation quality of the pharmaceutical preparations such as the mode of appearance of preparation, hardness, friability to the HPMC of different viscosities.
According to the general rule of tablet and the requirement of slow releasing preparation in the Chinese Pharmacopoeia version in 2000, be that standard is carried out prescription screening to cetirizine hydrochloride with 15 minutes, 30 minutes, 45 minutes accumulation dissolutions; With 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours cumulative release degree was that standard is carried out prescription screening to pseudoephedrine hydrochloride, determined that the prescription that adheres to specification forms, and concrete testing program and result are as follows:
Table 1, pseudoephedrine hydrochloride slow release layer prescription screening (unit: mg)
The result is as follows for table 2, pseudoephedrine hydrochloride release test:
| The prescription release time | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 0.5 hour | 31.8％ | 31.2％ | 26.7％ | 15.9％ | 24.8％ | 20.6％ | 22.5％ |
| 1 hour | 64.8％ | 62.6％ | 53.5％ | 31.6％ | 49.8％ | 40.9％ | 38.2％ |
| 2 hours | 80.3％ | 74.7％ | 71.0％ | 40.0％ | 65.6％ | 59.0％ | 55.4％ |
| 4 hours | 97.2％ | 92.3％ | 84.5％ | 54.1％ | 78.4％ | 77.1％ | 69.3％ |
| 6 hours | ＿ | 96.9％ | 92.7％ | 71.3％ | 91.8％ | 89.8％ | 86.4％ |
| 8 hours | ＿ | ＿ | 99.2％ | 80.2％ | 98.2％ | 95.4％ | 93.4％ |
| 12 hours | ＿ | ＿ | ＿ | 91.0％ | 101.8％ | 101.7％ | 100.1％ |
Table 3, cetirizine hydrochloride release layer prescription screening (unit: mg)
The result is as follows for table 4, cetirizine hydrochloride dissolution test:
| The prescription dissolution time | 1 | 2 | 3 | 4 |
| 15 minutes | 26.1％ | 39.8％ | 45.6％ | 50.7％ |
| 30 minutes | 44.9％ | 58.3％ | 64.9％ | 75.9％ |
| 45 minutes | 60.0％ | 66.0％ | 78.7％ | 93.1％ |
Result of the test shows: the pseudoephedrine hydrochloride slow release layer: slow-release material HPMC
60R1100000, HPMC
60R110000Comprehensive function, share with the disintegrating agent microcrystalline Cellulose again and can obtain satisfied release result.The cetirizine hydrochloride release layer: with the carboxymethyl starch sodium is that disintegrating agent, lactose and microcrystalline Cellulose are that filler has also obtained satisfied result.The quality standard of comprehensive tablet, selecting pseudoephedrine hydrochloride slow release layer prescription 7, cetirizine hydrochloride release layer prescription 4 is the best prescription of double-layer tablet.
The most preferred prescription of the present invention has been carried out stability experiment research, we have carried out preliminary investigation to the west for the pseudoephedrine release tablet stability, the assay method of clinical quality standard (draft) regulation detects sample appearance color and luster, catabolite, release, content project.
The result is as follows:
(1) light durability test:
Get 020811 batch of west and place glass dish for the pseudoephedrine release sheet, placed 10 days under 4500LX ± 100 LX illumination, detect in sampling in 0,5,10 day, testing result sees Table 5:
Table 5 light durability result of the test
(2) thimble test:
Get 020811 batch of west and place glass dish for the pseudoephedrine release sheet, placed 10 days in 60 ℃ calorstat, detect in sampling in 0,5,10 day, testing result sees Table 6:
60 ℃ of thimble test results of table 6
The constant temperature accelerated stability test:
Get the west for the pseudoephedrine release sheet, lot number 020811,020813,020815 pack with plastic-aluminum bubble eye, and constant temperature is placed under 40 ℃ ± 2 relative humiditys 75% (NaCL saturated solution) condition, and respectively at 0,1,2,3, sampling detection in June, testing result sees Table 7
The room temperature examine stability that keeps sample:
Get the west for the pseudoephedrine release sheet, lot number 020811,020813,020815 pack with plastic-aluminum bubble eye, places under the natural conditions in the breadboard sample cabinet, and respectively at 0,3, sampling detection in June, testing result sees Table 8 constant temperature accelerated tests:
The constant temperature accelerated test shows: this product has stability preferably under the condition of 40 ℃ ± 2 relative humiditys 75%, in 6 months of having investigated, each investigates every index of project does not have significant change.
Table 9 is the explanation of the effect of each adjuvant in prescription.
The effect of each adjuvant of table 9. in prescription
| The adjuvant title | Effect in the prescription |
| HPMC 60RT10000 | Slow-release material |
| HPMC 60R1100000 | Slow-release material |
| Microcrystalline Cellulose | Filler and disintegrating agent |
| Lactose | Filler |
| Carboxymethyl starch sodium | Disintegrating agent |
| Polyvidone | Binding agent |
| Magnesium stearate | Lubricant |
Double-layer sustained release preparation of the present invention, be according to two kinds of medicines of cetirizine/pseudoephedrine hydrochloride characteristic such as rate of release separately, the difference of aspects such as absorbance, carry out the prescription that the compatibility screening obtains, both discharge, absorption reaches synchronously, has better played synergism, and the cetirizine hydrochloride onset is rapid keeping, in the time of long half time, the medicine that has improved 4 administrations on the one of pseudoephedrine hydrochloride palpus is for characteristic, 2 administrations on the one make both reach the optimum synergistic curative effect, simultaneously the prepared preparation good stability, few side effects, synergism is strong, and prescription is formed superior, is fit to large-scale production.
The specific embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
The prescription of pseudoephedrine hydrochloride slow release layer
The prescription of cetirizine hydrochloride release layer
Preparation method is as follows:
(1) preparation of supplementary material and processing
With crossing 100 mesh sieves behind pseudoephedrine hydrochloride, the cetirizine hydrochloride pulverize separately, standby; Lactose, microcrystalline Cellulose, carboxymethyl starch sodium, cross 80 mesh sieves respectively, standby.HPMC
60R1100000, HPMC
60R110000Cross 100 mesh sieves respectively, standby.
(2) weighing with mix
According to the amount of 2 prescriptions, take by weighing above-mentioned former, adjuvant respectively respectively, former, adjuvant in above-mentioned 2 prescriptions are inserted mix homogeneously in the mixer respectively through the double calculating inventory of checking.
(3) granulate
The system soft material: use 10%PVP anhydrous alcohol solution salt manufacturing acid pseudoephedrine soft material and cetirizine hydrochloride soft material respectively, granulate with 20 mesh sieves respectively, the granule that makes all should lack fine powder, does not neatly have rectangular.
Dry: 2 kinds of wet granulars are respectively at 60 ± 2 ℃, in the baking oven inner drying.
Granulate: use 16 mesh sieve granulate respectively
Add lubricant respectively by inventory separately, mixed respectively evenly after, put into hermetic container, after the assay was approved tabletting.
(4) measure granule content, it is heavy to calculate sheet
Sampling is measured 2 kinds of granule contents respectively by quality standard, and the theoretical sheet of pseudoephedrine hydrochloride heavily is 382mg
The theoretical sheet of cetirizine hydrochloride heavily is 186mg, and being calculated as follows separately respectively, sheet weighs.
(5) tabletting
Actual separately sheet according to the double-layer tablet of result of calculation gained is heavy, behind the loading of the loading of adjusting ground floor cetirizine hydrochloride release layer on the bi-layer tablet press respectively and second layer pseudoephedrine hydrochloride slow release layer, presses double-layer tablet.Put into hermetic container sampling check hardness and friability etc. after finishing.
(6) packing
The inspection of semifinished product: tablet need be checked outward appearance, hardness and pack after the assay was approved by the quality standard requirement.Requirement according to product is packed, and packing back warehouse-in can dispatch from the factory after the assay was approved according to quality standard.
Claims (1)
1, the slow releasing preparation of a kind of cetirizine and pseudoephedrine hydrochloride is characterized in that,
The prescription of pseudoephedrine hydrochloride slow release layer is
The prescription of cetirizine hydrochloride release layer is
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| CN105232487A (en) * | 2015-11-19 | 2016-01-13 | 哈尔滨圣吉药业股份有限公司 | Double-layer sustained release tablet treating allergic rhinitis and preparation method thereof |
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Non-Patent Citations (4)
| Title |
|---|
| 国产与进口羟丙基甲基纤维素的性质对比. 张静等.辽宁药物与临床，第4卷第1期. 2001 |
| 国产与进口羟丙基甲基纤维素的性质对比. 张静等.辽宁药物与临床，第4卷第1期. 2001 * |
| 西替伪麻缓释片制备工艺及体外释药研究. 孙晔等.药学研究，第28卷第12期. 2004 |
| 西替伪麻缓释片制备工艺及体外释药研究. 孙晔等.药学研究，第28卷第12期. 2004 * |
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