CN105326805B - The preparation method of ambroxol salbutamol dripping pill - Google Patents

Abstract

The present invention relates to ambroxol salbutamol dripping pills, belong to field of pharmaceutical preparations.PLURONICS F87, meglumine and the mannitol that the dripping pill of the present invention appropriately adds in, the stability and bioavilability of ambroxol hydrochloride and salbutamol sulfate in preparation can be significantly improved, stable quality, significant effect can effectively treat the respiratory diseases such as acute/chronic bronchitis and asthma.

Description

The preparation method of ambroxol salbutamol dripping pill

Technical field

The present invention relates to field of pharmaceutical preparations, and in particular to a kind of ambroxol salbutamol dripping pill and preparation method thereof.

Background technology

Respiratory disease is a kind of common disease, frequently-occurring disease, and major lesions are in trachea-bronchial epithelial cell, lung and thoracic cavity, lesion The lighter's mostly cough, pectoralgia, breathing is impacted, severe one is had difficulty in breathing, anoxic or even respiratory failure and it is lethal.Death in city Rate accounts for the 3rd, and in rural area then account for the first.Should more pay attention to, due to atmosphere pollution, smoking, aging of population and other because Element makes chronic obstructive pulmonary disease both domestic and external (abbreviation chronic obstructive pulmonary disease, including chronic bronchitis, pulmonary emphysema, pulmonary heart disease), bronchus The incidence of the diseases such as asthma, lung cancer, lung's dispersivity interstitial fibrosis and pulmonary infection, the death rate are growing on and on.

According to national urbans in 2006 and the statistical number of the rural area top ten principal disease cause of death, respiratory system disease Sick (not including lung cancer) accounts for the 4th (13.1%) in the Death causes in city, and third position (16.4%) is accounted in rural area.Due to Physical and chemical factor caused by atmosphere pollution, smoking, Industrial Economic Development, biotic factor inhale the factors such as people and population ages aging, Make the incidence of respiratory disease such as lung cancer, bronchial asthma in recent years significantly increase, Chronic Obstructive Pulmonary Disease occupies height not Under (more than 8% in 40 years old or more crowd).Though pulmonary tuberculosis rate is controlled, have again in recent years and increase trend.Lung thrombus bolt Plug disease has constituted important health care problem, and pulmonary hypertension is also of increasing concern in recent years.Between pulmonary Diffuse The disease incidences such as matter fibrosis and immunocompromised pulmonary infection are increased.The major causes of death of AIDS is felt for lung Dye, particularly pneumocystis carinii pneumonia.Since the end of the year 2002, the infectiousness atypia lung that is broken out in China and world wide Scorching (serious acute respiratory syndrome, SARS) epidemic situation, due to mostly occurring in the young and the middle aged, infectiousness is strong, and case fatality rate is high, and lacks Targetedly drug, thus the fear of the masses is caused, while bring about great losses to national economy.Go out at present in multiple countries Existing human avian influenza case fatality rate is more than 60%.And it is also lung that avian influenza virus, which invades main target organ in human body,.This positive explanation is exhaled Desorption system disease is still very big to health of our people harm, prevents arduous task.

Ambroxol hydrochloride (Ambroxol Hydrochloride) is also known as ambroxol hydrochloride, the entitled trans- -4- of chemistry [(2- amino 3,5- dibromo-benzyls) amino] cyclohexanol hydrochloridumi, it be expectorant bromhexine active metabolite (N- demethyls, Cyclohexyl contraposition introduces trans- hydroxyl), toxicity is less than bromhexine, and activity is higher than bromhexine.Ambroxol hydrochloride is by German vigorous Lin Geyinge writing brushes company research and development mucolytic, the medicine in early 1980s first Germany list, then France, The successive listing of many countries such as Italy, Japan, Spain is the glutinous phlegm lytic agent of a new generation, can improve expectoration, and with rush Into pulmonary surfactant and Airway secretion and the effect of ciliary movement.Ambroxol hydrochloride can clinically adjust mucus with sticking Slurry secretion, activates fibre swing, is easy to dilute sputum, strengthens mucus and transports outward, is easy to discharge, it can also promote lung surface Active material synthesizes, and to maintain alveolar tension, ensures lung functions index；Promote antibiotic to tissue infiltration, to improve concentration, Enhance bactericidal effect；It is anti-oxidant, inflammatory mediator release is reduced, with the reaction that reduces inflammation；It is cooperateed with bronchus spasmolysis substance, to carry The effect of high spasmolysis drug.Therefore, which clinically can be widely applied to the acute and chronic breathing with respiratory tract abnormal secretion The auxiliary treatment of the eliminating the phlegm treatment of road illness, particularly chronic bronchitis, transient respiratory distress of the newborn disease and pulmonary surgery, tool It is toxic it is low, it is curative for effect and can with antibiotic and with generate good synergy the advantages that, be most common expectorant it One.In recent years in the emphasis hospital administration ranking of China main cities, it ranks forefront always.

Salbutamol sulfate (Salbutamol Sulfate) also known as albuterol, main component are salbutamols, chemistry Entitled 1- (4- hydroxyl -3- hydroxymethyl phenyls) -2- (tert-butylamine base) ethyl alcohol, is a kind of highly selective exciting bronchial smooth muscle β-adrenoreceptor excitant, bronchial smooth muscle is made to relax, so as to release bronchial muscular spasm.To bronchiectasis Effect is stronger, and weaker to the β1-receptor effect of heart, is current safer, most common antiasthmatic.Suitable for preventing branch gas The bronchial spasm of pipe asthma, asthmatic bronchitis and emphysematic patients, alleviate because bronchial asthma, chronic bronchitis and Symptoms, the advantage such as expiratory dyspnea are rapid-action caused by the airway obstructive diseases such as pulmonary emphysema, can improve patient symptom rapidly, Spasmolysis is relievingd asthma, eliminating the phlegm, and shortcoming is to act on persistently, not functioning only as the effect for alleviating patient's asthma symptoms；Long period application can Beta-receptor is caused to adjust downwards, patient is made to occur losing beta receptor agonist quick or even invalid to treating asthma drug resistance phenomenon.

The dosage forms such as solution and granule containing ambroxol hydrochloride and salbutamol sulfate are had existed in the prior art, But have no the report of dripping pill.

In addition, salbutamol sulfate and ambroxol hydrochloride are active constituent in same minimum preparation unit, it is long-term to protect When depositing, chemical compatible change occurs due to possible between each ingredient, easily generates by-product, therefore meeting reducing effect or increase pair are made With product stability is not ideal enough.

Invention content

In view of the synergistic effect of ambroxol hydrochloride and salbutamol sulfate, the purpose of the present invention is to provide a kind of safety Effectively, stable quality, patient adaptability is strong, significant effect, can effectively treat the respiratory systems such as acute/chronic bronchitis and asthma The ambroxol salbutamol dripping pill of disease.

Under study for action, it has been surprisingly found that, the PLURONICS F87 that is appropriately added in the preparation of preparation, meglumine and Mannitol can significantly improve the stability and bioavilability of ambroxol hydrochloride and salbutamol sulfate in preparation, for medicine The Clinical practice of product is of great significance.

The present invention solve the technical problem technical solution be：

A kind of ambroxol salbutamol dripping pill, is made of the component of following weight：

Salbutamol sulfate：8-10g；

Ambroxol hydrochloride：20-30g；

PLURONICS F87:6-8g；

Meglumine：6-8g；

Mannitol：2-4g；

PEG400：30-40g；

PEG6000:1000-1500g。

Preparation method is：

1) PEG400 and PEG6000 are sufficiently mixed uniformly, form substrate mixture, substrate mixture is placed in heating holds Heating makes melting while stirring in device；

2) salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol is taken to add in base after mixing In matter mixture, continue to heat, until obtaining molten liquid；

3) temperature control system of pill dripping machine is adjusted, the water dropper temperature of pill dripping machine is made to be heated and maintained at 60 DEG C~90 DEG C, The temperature cooling of condensing agent, and keep 30 DEG C~10 DEG C of the upper temp of condensing agent, the state that 10 DEG C~-5 DEG C of bottom temp；

4) molten liquid is poured into the Materials hopper of pill dripping machine, instills and forming is shunk in condensing agent, filtered, detached, wiping Totally to get.

The condensing agent is any one or two or more mixing in atoleine, dimethicone, vegetable oil Object.

Optimizing prescriptions are：(1000 ball)

Salbutamol sulfate：10g；

Ambroxol hydrochloride：20g；

PLURONICS F87:8g；

Meglumine：8g；

Mannitol：4g；

PEG400：40g；

PEG6000:1500g。

It is preferred that preparation method is：

1) PEG400 and PEG6000 are sufficiently mixed uniformly, form substrate mixture, substrate mixture is placed in heating holds Heating makes melting while stirring in device；

2) salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol is taken to add in base after mixing In matter mixture, continue to heat, until obtaining molten liquid；

3) temperature control system of pill dripping machine is adjusted, the water dropper temperature of pill dripping machine is made to be heated and maintained at 80 DEG C, dimethyl The temperature cooling of silicone oil, and keep 10 DEG C of the upper temp of dimethicone, the state of -5 DEG C of bottom temp；

4) molten liquid is poured into the Materials hopper of pill dripping machine, instills and forming is shunk in condensing agent, filtered, detached, wiping Totally to get.

Active component content the beneficial effects of the invention are as follows the ambroxol salbutamol dripping pill dramatically increases；Stability It greatly improves；Therefore stable quality, significant effect can effectively treat the respiratory diseases such as acute/chronic bronchitis and asthma.

Specific embodiment

With reference to specific embodiment, the present invention is further explained.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.Test method without specific conditions in the following example, usually according to conventional strip Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise all percentage, ratio, ratio or number is pressed Weight meter.

Unless otherwise defined, it anticipates known to all professional and scientific terms used in text and one skilled in the art Justice is identical.In addition, any method similar or impartial to described content and material all can be applied in the method for the present invention.Wen Zhong The preferred implement methods and materials are for illustrative purposes only.

Embodiment 1

Prescription：(1000 ball)

Salbutamol sulfate：10g；

Ambroxol hydrochloride：20g；

PLURONICS F87:8g；

Meglumine：8g；

Mannitol：4g；

PEG400：40g；

PEG6000:1500g。

Preparation method：

1) PEG400 and PEG6000 are sufficiently mixed uniformly, form substrate mixture, substrate mixture is placed in heating holds Heating makes melting while stirring in device；

2) salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol is taken to add in base after mixing In matter mixture, continue to heat, until obtaining molten liquid；

3) temperature control system of pill dripping machine is adjusted, the water dropper temperature of pill dripping machine is made to be heated and maintained at 80 DEG C, dimethyl The temperature cooling of silicone oil, and keep 10 DEG C of the upper temp of dimethicone, the state of -5 DEG C of bottom temp；

4) molten liquid is poured into the Materials hopper of pill dripping machine, instills and forming is shunk in dimethicone, filtered, separation, Wiped clean to get.

Embodiment 2

Prescription：(1000 ball)

Salbutamol sulfate：10g；

Ambroxol hydrochloride：30g；

PLURONICS F87:8g；

Meglumine：6g；

Mannitol：2g；

PEG400：30g；

PEG6000:1000g。

Preparation method is：

1) PEG400 and PEG6000 are sufficiently mixed uniformly, form substrate mixture, substrate mixture is placed in heating holds Heating makes melting while stirring in device；

2) salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol is taken to add in base after mixing In matter mixture, continue to heat, until obtaining molten liquid；

3) temperature control system of pill dripping machine is adjusted, the water dropper temperature of pill dripping machine is made to be heated and maintained at 90 DEG C, liquid stone The temperature cooling of wax, and keep 10 DEG C of the upper temp of atoleine, the state of -5 DEG C of bottom temp；

4) molten liquid is poured into the Materials hopper of pill dripping machine, instills and forming is shunk in atoleine, filtered, detached, wiped Wipe totally to get.

Preparation method：

1) supplementary material of recipe quantity is weighed, it is spare to cross 80 mesh sieve respectively；

2) the pre-paying starch after sieving is taken to add in distilled water, binder solution is made；

3) by after sieving salbutamol sulfate, ambroxol hydrochloride, meglumine, PLURONICS F87, mannitol, starch and Sodium carboxymethyl starch is uniformly mixed by equal increments method, adds in above-mentioned binder solution and softwood is made；

4) with after 40 mesh sieve series grains, dry 45min at 60 DEG C crosses 20 mesh sieve whole grain, is fitted into empty dripping pill to obtain the final product.

Embodiment 3

Prescription：(1000 ball)

Salbutamol sulfate：8g；

Ambroxol hydrochloride：30g；

PLURONICS F87:8g；

Meglumine：6g；

Mannitol：4g；

PEG400：30g；

PEG6000:1200g。

Preparation method：

1) PEG400 and PEG6000 are sufficiently mixed uniformly, form substrate mixture, substrate mixture is placed in heating holds Heating makes melting while stirring in device；

2) salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol is taken to add in base after mixing In matter mixture, continue to heat, until obtaining molten liquid；

3) temperature control system of pill dripping machine is adjusted, the water dropper temperature of pill dripping machine is made to be heated and maintained at 90 DEG C, liquid stone The temperature cooling of wax, and keep 10 DEG C of the upper temp of atoleine, the state of -5 DEG C of bottom temp；

4) molten liquid is poured into the Materials hopper of pill dripping machine, instills and forming is shunk in atoleine, filtered, detached, wiped Wipe totally to get.

4 stability test of embodiment

Comparative example 1 is identical with embodiment using preparation method；Prescription is as follows：

Salbutamol sulfate：8g；

Ambroxol hydrochloride：30g；

PEG400：30g；

PEG6000:1200g。

Comparative example 2 is identical with embodiment using preparation method；Prescription is as follows：

Salbutamol sulfate：8g；

Ambroxol hydrochloride：30g；

PLURONICS F87:8g；

PEG400：30g；

PEG6000:1200g。

1. accelerated stability test

Embodiment 1, comparative example 1 and 2 gained ambroxol salbutamol dripping pill of comparative example are put into intensity of illumination 4500lx respectively Under the conditions of 10 days, sampled respectively at the 0th, 5,10 day, every quality index such as detection level, related substance the results are shown in Table 1.

1 ambroxol salbutamol dripping pill influence factor result of the test of table

The result shows that：Ambroxol salbutamol dripping pill prepared by the present invention each component content under intense light conditions becomes without apparent Change, stability is significantly better than comparative example.To find out its cause, it is because the ordinary adjuvants in comparative example can not be preferably to active constituent Support and stabilization are played, and then causes chemical compatible change may occur between each ingredient, easily generates by-product；And by It is more than general state of the art in the content of active constituent, stability is caused more to substantially reduce.

2. accelerated test

By 1 gained ambroxol salbutamol dripping pill of embodiment be placed in 40 DEG C, the constant temperature of RH20%, 6 months in constant humidity cabinet, point It was not sampled in the 0th, 1,2,3,6 month, measures every quality index such as content, related substance, the results are shown in Table 2.

2 ambroxol salbutamol dripping pill accelerated test result of table

The result shows that：Ambroxol salbutamol dripping pill is placed 6 months under conditions of 40 DEG C, RH20%, is compared with 0 month Compared in addition to related substance is increased slightly, other every quality index have no significant change, and stable quality is reliable, meets regulation.

The foregoing is merely illustrative of the preferred embodiments of the present invention, is not limited to the substantial technological content model of the present invention It encloses, substantial technological content of the invention is broadly to be defined in the right of application, any technology that other people complete Entity or method, if with the right of application defined in it is identical, also or a kind of equivalent change, will It is considered as being covered by among the right.

Claims (1)

1. a kind of preparation method of ambroxol salbutamol dripping pill, is made of the component of following weight：

Salbutamol sulfate：8-10g；

Ambroxol hydrochloride：20-30g；

PLURONICS F87:6-8g；

Meglumine：6-8g；

Mannitol：2-4g；

PEG400：30-40g；

PEG6000:1000-1500g

Preparation method is：

1) PEG400 and PEG6000 are sufficiently mixed uniformly, form substrate mixture, substrate mixture is placed in heating container Heating makes melting while stirring；

2) salbutamol sulfate, ambroxol hydrochloride, PLURONICS F87, meglumine, mannitol is taken to add in matrix after mixing to mix It closes in object, continues to heat, until obtaining molten liquid；

3) temperature control system of pill dripping machine is adjusted, the water dropper temperature of pill dripping machine is made to be heated and maintained at 60 DEG C~90 DEG C, condensation The temperature cooling of agent, and keep 30 DEG C~10 DEG C of the upper temp of condensing agent, the state that 10 DEG C~-5 DEG C of bottom temp；

4) molten liquid is poured into the Materials hopper of pill dripping machine, instills and forming is shunk in condensing agent, filtered, separation, wiped clean, To obtain the final product；

The water dropper temperature is heated and maintained at 90 DEG C；

30 DEG C of the upper temp of condensing agent, -5 DEG C of bottom temp；

The condensing agent is any one or two or more mixtures in atoleine, dimethicone, vegetable oil.