CN104800214A - Roflumilast inhalation aerosol compound and preparation method thereof - Google Patents

Abstract

The invention discloses a compound aerosol for quick-acting treatment of COPD, and a preparation method thereof. The compound aerosol comprises roflumilast and salbutamol. The compound aerosol combines respective characteristics of the long-acting COPD medicine roflumilast and the quick-acting COPD medicine salbutamol, and realizes rapid effectiveness and long lasting time in order to reduce the oral spray frequency of patients and reduce toxic side effects. A propellent changes from CFCs to HFC in order to eliminate destroys to the earth's ozone layer. Lecithin selected in the invention is in favor of realizing immersion and penetration of medicines to lung cells in order to improve the bioavailability and realize quick acting. Mentholum is added into a dispersant, so the patients have refreshing and comfortable feeling after administration, thereby the patients' compliance is improved.

Description

A kind of roflumilast inhalation aerosol compound recipe and preparation method

Technical field

The present invention relates to the formula of the compound preparation of roflumilast and albuterol, dosage form and preparation method thereof, particularly relate to compound recipe roflumilast inhalation aerosol and preparation method thereof, belong to biochemical field of medicaments.

Background technology

Chronic obstructive pulmonary disease (Chronic obstructive pulmonary disseases, COPD) being that one enters chronic and life-threatening respiratory system disease, is one of human health " killer ", and it makes patient respiratory difficulty, LOM, reduces quality of life.COPD patient is after acute attack stage.Clinical symptoms year is alleviated to some extent, but its pulmonary function still worsens in continuation, and due to self-defense and the reduction of immunologic function and the impact of extraneous various harmful factor, frequent recurrent exerbation, and producing various heart and lung diseases gradually, disease generally includes chronic bronchitis and emphysema.According to estimates, the whole world about has 2.1 hundred million people to suffer from this disease, and because present environmental pollution is serious, PM2.5 wreaks havoc throughout the country, and patient COPD continues to increase, and expects the year two thousand twenty, and COPD will become global the third-largest death factors.

Pulmonary administration is always to control respiratory tract local disease for target in history, at present listing to be used for the treatment of asthma, chronic obstructive pulmonary disease (COPD) and bronchitic suction product be mostly such.Now with the alveolar surface in lung, special lung deep, as the systemic administration position of medicine that cannot be oral, cause the attention of height.Because pulmonary administration is non-invasive; there are the potentiality of alternative drug administration by injection; its therapeutic goal is widened in fact, and the new pulmonary delivery system enough little granule or droplet being transported to lung periphery or lung deep is developed rapidly, to meet these new therapeutic goals.

Pulmonary administration is one of three kinds of medications below: propellant (nebulizer), metered dose inhaler (MDI) or aerosol inhalation (DPI), the dosage form that the character of medicine and therapeutic goal thereof may show any pulmonary administration is more suitable.

Metered dose inhaler (metereddoseinhaler, MDI) is the drug-supplying system for oral cavity or nasal cavity, is the aerosolization respiratory tract administration of interval.MDI is that active substance dissolves or is suspended in propellant, and is loaded on being furnished with in the container of proportional valve of sealing pressing.The atomization medicine that after valve starts, ejection is quantitative, sucks in oral cavity or nasal cavity.

Each MDI can have the high spraying secondary to hundreds of, and the medicine that each spraying is generally 10-500 μ g is scattered in 25-100 μ L liquid, and the liquid of ejection, through the Quick-gasifying of propellant, produces equally distributed spraying.The clinical efficacy produced by drug deposition, depend on and suck the amount of granule, its granule should have suitable aerodynamic diameter, is usually less than 5um. and is just deposited in lung tissue (can suction part).

First MDI product is born in the room of testing, Riker room, and in listing in 1956, used was patented novel quantitative valve.At present in most countries, MDI becomes the master of bronchial asthma and chronic obstructive pulmonary disease (COPD) Inhalation in Treating medicine the sixth of the twelve Earthly Branches by dosage form.Since it is produced, MDI technology is in stable development, but along with freon (CFC) is as main propellant progressively the exiting in the application of market of MDI, propellant transfers hydrofluoroalkane (HFC) to, and MDI leans on art development and accelerates.

Although MDI uses very easy, its device is complicated, comprises the integral structure (Fig. 1) of pharmaceutical formulation, container, quantitatively wealthy and actuator.Change its any part formed and all will affect the final function of MDI, this design is consistent with the even particle size that medicine distributes in aerosol for ensureing dosage, meets spray timings and the requirement of storage life of MDI sign.

Albuterol has another name called salbutamol.For a kind of selectivity broxaterol.Act on bronchus beta 2 adrenoreceptor, relaxing smooth muscle, its mechanism is activated adenyl cyclase, promotes that adenosine cyclophosphate generates.Be used for the treatment of the bronchospasm caused by asthmatic bronchitis, bronchial asthma, emphysema.

Roflumilast (Roflumilast) researches and develops successful roflumilast (product under Metrizamide drugmaker of current Yi Shi Switzerland (Nycomed Pharma GmbH)) first by German Anda (Altana) company in 1993.2009, complete III clinical trial phase of roflumilast.Listing in European Union's approval roflumilast on July 6th, 2010 (roflumilast, Daxas), FDA (Food and Drug Adminstration) on March 1 in 2011 (FDA) is in approval listing.

Roflumilast is a kind of selectivity phosphodiesterase 4 (PDE4) inhibitor, belongs to benzamide compound.By Selective depression PDE4, block inflammatory reaction signal transmission, and then suppress the damage as the respiratory tract disease such as COPD and asthma causes lung tissue.Be proved to be able to suppress COPD dependency inflammation with the novel binding mode of one.

The dosage form of current roflumilast Clinical practice is tablet, is first medicine for serious symptom COPD novel therapeutic.The character of its uniqueness, contribute to managing patients with chronic obstructive pulmonary diseases better: when treating most severe chronic obstructive pulmonary disease with bronchodilator drug combination, roflumilast can provide the additional benefit reducing further symptom and disease progression rate, becomes targeting particular phenotype chronic obstructive pulmonary disease thus and namely there is the serious flow limitation relevant to chronic cough and excessive phlegm and first medicine of tool disease progression history patient repeatedly.

The patent documentation of roflumilast compound has IN2004MU00478, WO2005026095, WO2004033430, US6822114.Roflumilast in state-owned compound patent " Fluoroalkyloxy replace benzamides and its preparation method and application " (WO09501338, CN94192659), this patent is in protecting this compound, preparation method and in treatment airway disorders or dermopathic application.

It is active component containing roflumilast that US Patent No. 2005159492 discloses a kind of, is conventional tablet of binding agent and preparation method thereof containing PVP.

As COPD class medicine, optimal dosage form is inhalant.The dosage form of inhalation aerosol is adopted to have apparent benefit.Site of action is accurate, enough effectively increases bioavailability, reduces medicine and enter the blood time and improve effect, can also regulate consumption voluntarily, thus reduce overall consumption, alleviate side effect according to the state of an illness of patient.

Summary of the invention

The object of this invention is to provide a kind of containing roflumilast, albuterol as the inhalation aerosol formula and preparation method thereof of active component, said composition can solve prior art Problems existing, and reaches the harsh conditions sucking formulation requirements.

Specifically, suction aerosol combination of the present invention is by active component roflumilast, albuterol, and these parts of surfactant, cosolvent, process auxiliaries, propellant form

Wherein roflumilast accounts for the 0.01%-1% of composition total weight, preferred 0.1%-0.5%, more preferably 0.1-0.2%.Albuterol accounts for the 0.01%-1% of composition total weight, preferred 0.01%-0.2%, more preferably 0.05-0.1%;

Wherein surfactant comprises: lecithin, soybean phospholipid, oleic acid, span, tween, comprises its single and mixed composition;

Wherein cosolvent comprises: ethanol, propylene glycol, glycerol, comprises their compositions;

Wherein process auxiliaries comprises: Mentholum, mannitol;

Wherein propellant comprises: tetrafluoroethane, chlorodifluoroethane, dichlorodifluoromethane, isceon.

Particle diameter of the present invention is all the values recorded with laser-diffractometer by dry dispersion method, and wherein drop has following particle size distribution profiles:

1) particle of 10% has the particle diameter being less than 2 μm;

2) particle of 50% has the particle diameter being less than 4 μm;

3) particle of 90% has the particle diameter being less than 6 μm;

Inhalation aerosol composition of medicine of the present invention is the sterile pharmaceutical formulation that 5-500 μ g/ presses, and preferred 25-100 μ g/ presses, and more preferably 50 μ g/ press;

Suction aerosol composition of medicine of the present invention take HFA as the aerosol Aluminum Bottle pressurized tank packaging container of propellant;

Suction aerosol composition of medicine of the present invention is the packaged form adopting metered dose inhaler, comprises container, proportional valve, rubber components, actuator and compartment these parts composition.

Suction aerosol composition of medicine of the present invention is the canned amount of design is 200 press/bottle, considers the situations such as leakage, and actual canned amount is 240 press/bottle;

The present invention also aims to provide a kind of containing roflumilast, albuterol as the preparation method of the inhalation aerosol compositions of active component, its feature is contained in following step:

1) crude drug micronization: salbutamol sulfate is crushed to less than 7 μm;

2) weigh: take the roflumilast of formula ratio, albuterol, lecithin, dehydrated alcohol;

3) surfactant dissolves: the dehydrated alcohol first getting formula ratio 2/3, adds the lecithin of formula ratio, and under high-shear homogenizing machine, homogenizing stirs 20min;

4) drug solution preparing: the salbutamol sulfate upper liquid being added formula ratio, stirs 30min under high-shear homogenizing machine; Supplement remaining dehydrated alcohol to full dose, after continuing to stir 20min, open cycle pump, circulation 15min;

5) valve is pricked in fill, and fill propellant tetrafluoroethane, leak detection is weighed;

6) pack: mobility aid (case) is installed

The superiority of the method is:

1, combine the feature of long-acting COPD medicine roflumilast and quick-acting COPD drugs salbutamol, accomplish that onset is rapid, the persistent period is long, thus reduces the number of times of patient's mouth spray, reduces the generation of toxic and side effects.

2, propellant is replaced to HFC by CFCs, eliminate the destruction to earth's ozone layer.

3, the size droplet diameter sprayed, about 1-5 μm, has good pulmonary deposition.

4, the lecithin selected by the present invention is conducive to medicine to the immersion of lung cells and infiltration, thus improves bioavailability, reaches quick-acting objects.

5, in dispersant, add Mentholum, after patient's administration, obtain refrigerant comfortable sensation, improve the compliance of patient.

Accompanying drawing explanation

Fig. 1 embodiment 1 particle size distribution

Fig. 2 embodiment 2 particle size distribution

Detailed description of the invention

Illustrate the present invention below by embodiment, but the present invention is not limited only to these embodiments.

Embodiment 1

1, formula (according to 1000 bottles of calculating):

Roflumilast: 24.4g;

Albuterol: 12.2g;

Lecithin: 4.8g;

Dehydrated alcohol: 1200g;

HFA: add to 18000g.

2, preparation method:

1) crude drug micronization: salbutamol sulfate is crushed to less than 7 μm;

2) weigh: take the roflumilast of formula ratio, albuterol, lecithin, dehydrated alcohol;

3) surfactant dissolves: the dehydrated alcohol first getting formula ratio 2/3, adds the lecithin of formula ratio, and under high-shear homogenizing machine, homogenizing stirs 20min;

4) drug solution preparing: the salbutamol sulfate upper liquid being added formula ratio, stirs 30min under high-shear homogenizing machine; Supplement remaining dehydrated alcohol to full dose, after continuing to stir 20min, open cycle pump, circulation 15min;

5) valve is pricked in fill, and fill propellant tetrafluoroethane, leak detection is weighed;

6) pack: mobility aid (case) is installed.

3, particle size determination

Use Mastersizer3000(MalvernInstruments, Worcs, UK) by determination of laser diffraction droplet size distribution.Dispersed powders is removed with the compressed air of 4bar by measurement by Scirocco3000 aerosol feeder (MalvernInstruments, Worcs, UK).Described granule refractive index and absorbance be respectively 1.52 and 0.1. dispersant refractive index be that all measurement of 1.000. is all carried out three times and repeated for air, measurement result is in table 1 and Fig. 1.

Table 1 embodiment 1 particle size distribution

	10%	50%	90%
				Mean diameter (μm)	1.16	3.05	4.63
Standard deviation (%)	0.03	0.04	0.05

Embodiment 2

1, formula (according to 1000 bottles of calculating):

Roflumilast: 28g;

Albuterol: 14g;

Mentholum: 50g;

Propylene glycol: 350g;

HFA: add to 14000g.

2, preparation method:

See embodiment 1.

3, particle size determination

Particle Size Determination Method is see embodiment 1, and measurement result is in table 2 and Fig. 2.

Table 2 particle size distribution

	10%	50%	90%
				Mean diameter (μm)	1.76	3.58	4.67
Standard deviation (%)	0.02	0.04	0.05

Test example deposition ratio in the effective position measures and stability test

1, deposition ratio in the effective position measures

With the sample prepared by embodiment 1,2, with reference to Chinese Pharmacopoeia version in 2000 two annex XH theeffectivedose algoscopys, use (the artificial larynx of inhalation aerosol active drug quantitative determination instrument, Pharmaceutical National Engineering Research Center), measure the different drug effective region drug deposition amount for inhalation aerosol compositions respectively, and with high performance liquid chromatograph (Waters2695), measure roflumilast content with reference to high-efficient liquid phase technique (Chinese Pharmacopoeia version in 2000 two annex VD), calculate deposition ratio in the effective position.Result shows, and within the scope of content of phospholipid of the present invention, drug effective region deposition significantly improves.The results are shown in Table 3:

Table 3 deposition ratio in the effective position (%)

	Embodiment 1	Embodiment 2
			Deposition ratio in the effective position (%)	48	51

2, stability test:

Compound recipe roflumilast inhalation aerosol sample is pressed commercially available back (adopt aluminium foil and PVC stiff sheet packaging, and adopt damp-prrof packing), temperature 25 DEG C ± 2 DEG C, keep sample under the condition of relative humidity 60% ± 10% placement for a long time.After placement the 1st, 2,3, sample detection respectively, and compare with initial detecting result June.The investigation that keeps sample for a long time of compound recipe roflumilast inhalation aerosol sample the results are shown in Table 4:

Table 4 stability test result

Claims (10)

1. a roflumilast inhalation aerosol compound recipe, by active component roflumilast, albuterol, surfactant, cosolvent, process auxiliaries, propellant form; Wherein roflumilast accounts for the 0.01%-1% of composition total weight, and albuterol accounts for the 0.01%-1% of composition total weight, and wherein this solid roflumilast particle has following particle size distribution profiles:

1) particle of 10% has the particle diameter being less than 2 μm;

2) particle of 50% has the particle diameter being less than 4 μm;

3) particle of 90% has the particle diameter being less than 6 μm.

2. roflumilast inhalation aerosol compound recipe as claimed in claim 1, is characterized in that roflumilast accounts for the 0.1%-0.5% of composition total weight.

3. roflumilast inhalation aerosol compound recipe as claimed in claim 1 or 2, is characterized in that roflumilast accounts for the 0.1-0.2% of composition total weight.

4. roflumilast inhalation aerosol compound recipe as claimed in claim 1, is characterized in that albuterol accounts for the 0.01%-0.2% of composition total weight.

5. the roflumilast inhalation aerosol compound recipe as described in claim 1 or 4, is characterized in that albuterol accounts for the 0.05-0.1% of composition total weight.

6. roflumilast inhalation aerosol compound recipe as claimed in claim 1, is characterized in that surfactant comprises: lecithin, soybean phospholipid, oleic acid, span, tween, comprises its single and mixed composition.

7. roflumilast inhalation aerosol compound recipe as claimed in claim 1, is characterized in that cosolvent is: ethanol, propylene glycol, glycerol, comprises their compositions.

8. roflumilast inhalation aerosol compound recipe as claimed in claim 1, is characterized in that process auxiliaries is: Mentholum, mannitol.

9. roflumilast inhalation aerosol compound recipe as claimed in claim 1, is characterized in that propellant is: tetrafluoroethane, chlorodifluoroethane, dichlorodifluoromethane, isceon.

10. a preparation method for roflumilast inhalation aerosol compound recipe, step is:

1) crude drug micronization: salbutamol sulfate is crushed to less than 7 μm;

2) weigh: take the roflumilast of formula ratio, albuterol, lecithin, dehydrated alcohol;

3) surfactant dissolves: the dehydrated alcohol first getting formula ratio 2/3, adds the lecithin of formula ratio, and under high-shear homogenizing machine, homogenizing stirs 20min;

4) drug solution preparing: the salbutamol sulfate upper liquid being added formula ratio, stirs 30min under high-shear homogenizing machine; Supplement remaining dehydrated alcohol to full dose, after continuing to stir 20min, open cycle pump, circulation 15min;

5) valve is pricked in fill, and fill propellant tetrafluoroethane, leak detection is weighed;

6) pack: mobility aid case is installed.