CN106619658B - Medical aerosol preparation and quantitative inhalation aerosol - Google Patents

Medical aerosol preparation and quantitative inhalation aerosol Download PDF

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CN106619658B
CN106619658B CN201611236776.9A CN201611236776A CN106619658B CN 106619658 B CN106619658 B CN 106619658B CN 201611236776 A CN201611236776 A CN 201611236776A CN 106619658 B CN106619658 B CN 106619658B
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舒宏
侯曙光
李丛菊
贺钢民
张静
吴君
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Sichuan Pu Et Pharmaceutical Co ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/124—Aerosols; Foams characterised by the propellant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0065—Inhalators with dosage or measuring devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans

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Abstract

The invention discloses a medical aerosol preparation and a quantitative inhalation aerosol, wherein the preparation comprises active ingredients and a liquefied propellant as a solvent of the active ingredients, the active ingredients comprise mometasone furoate and formoterol fumarate, the liquefied propellant is hydrofluorocarbon, the preparation also comprises ethanol and span 80 which are added into the liquefied propellant, and the weight ratio of the span 80 in the aerosol preparation is 0.01-0.1% w/w; the liquid medicine in the aerosol is the preparation. In the scheme, span 80 is added into the aerosol preparation as a surfactant, so that the span 80 can keep the concentration of the liquid medicine uniform for a long time, and the aim of increasing the stability of the liquid medicine is fulfilled. The limitation on the addition amount of the span 80 aims to ensure that the span 80 has the suspending and lubricating effects and simultaneously the excessive content does not influence the generation of medicinal aerosol and reduce the dosage of fine particles.

Description

Medical aerosol preparation and quantitative inhalation aerosol
Technical Field
The invention relates to the field of medical aerosol products, in particular to a medical aerosol preparation and a quantitative inhalation aerosol.
Background
Currently, pressurized Metered Dose Inhalers (MDIs) are the most effective and accepted means for accurately administering small doses to the human respiratory tract. Therapeutic agents typically delivered by this means include β 2 adrenergic agonist bronchodilators, particularly β 2 agonists and corticosteroids and combinations thereof. Typical MDIs comprise a pressure resistant canister containing a therapeutic agent, most of which is a drug dissolved in a liquefied propellant or micronized particles suspended in a liquefied propellant, and a metering valve is provided on the MDIs for releasing a quantity of the therapeutic agent by actuation of the metering valve.
According to the anatomy and physiological structure of bronchiole and lung, the particle size of the drug or drug-containing droplets is required to be about 5 μm for effective distribution or deposition of the drug at the above-mentioned site. Neither too large (> 10 microns) nor too small (< 1 micron) particle size can deposit the drug at the site, reducing efficacy. Therefore, the particle size of the inhalation aerosol is generally required to be controlled to 10 microns, most of which are below 5 microns. The medicine particles have larger surface energy at 5 microns and are easy to adsorb on the surface of the container, so that the medicine concentration in the liquid medicine is reduced, and the curative effect of the medicine is influenced.
CN1196478 describes the use of an aerosol formulation of a pharmaceutical composition comprising mometasone furoate and formoterol fumarate for the treatment of obstructive or inflammatory airways diseases.
CN101856362 specifically describes that the weight ratio of mometasone furoate to formoterol fumarate is 1:1 to 50:1, the propellant is HFA-227e, simultaneously ethanol is added to adjust the output pressure of the propellant, and oleic acid is added as a surfactant to play roles of dispersing the drug and lubricating a valve.
Since formoterol fumarate is slightly soluble in ethanol, the particle size of the drug aggregates after a long-term standing, resulting in non-uniform concentration of the drug solution, thereby affecting the uniformity of the drug delivery dose. How to solve the above-mentioned problem of uniformity of drug delivery dose is a technical problem to be solved urgently by those skilled in the art.
Disclosure of Invention
The problem that in the prior art, due to the fact that the formoterol fumarate is slightly soluble in ethanol, after the formoterol fumarate is placed for a long time, the particle size of the drug is aggregated, so that the concentration of the drug liquid is uneven, and the uniformity of the delivered dose of the drug is affected is solved. The invention provides a medical aerosol preparation and a quantitative inhalation aerosol, and the medical aerosol preparation can still effectively ensure the dose of micro-fine particles in the medical aerosol preparation after being stored for a certain time, and ensure the uniformity of delivered dose.
In order to solve the problems, the medical aerosol preparation and the quantitative inhalation aerosol provided by the invention solve the problems by the following technical points: a medical aerosol preparation comprises an active ingredient and a liquefied propellant as a solvent of the active ingredient, wherein the active ingredient comprises mometasone furoate and fomesartamine fumarate, the liquefied propellant is hydrofluorocarbon, the medical aerosol preparation further comprises ethanol and span 80 which are added into the liquefied propellant, and the weight ratio of the span 80 in the aerosol preparation is 0.01-0.1% w/w.
In particular, in view of the above-mentioned problem that ethanol affects uniformity of a drug delivery dose, oleic acid is added to an aerosol formulation in the prior art, but the uniformity of the drug delivery dose gradually deteriorates as the time during which the aerosol formulation is left alone increases.
In the scheme, span 80 is added into the aerosol preparation as a surfactant, so that the span 80 can keep the concentration of the liquid medicine uniform for a long time, and the aim of increasing the stability of the liquid medicine is fulfilled. The limitation on the addition amount of the span 80 aims to ensure that the span 80 has the suspending and lubricating effects and simultaneously the excessive content does not influence the generation of medicinal aerosol and reduce the dosage of fine particles.
As a further technical scheme of the medical aerosol preparation, in order to enable effective components in the aerosol preparation to be effectively distributed or deposited on bronchus, bronchiole and lung of a human body, the mometasone furoate and the formoterol fumarate are micro-powder with a median particle size of less than 5 microns obtained by air flow pulverization. In the scheme, because a certain amount of span 80 is added into the aerosol preparation, the active ingredients with the median particle size have larger surface energy, but are still not easy to be adsorbed on the surface of a container.
As an implementation scheme of the liquefied propellant which is beneficial to environmental protection, the hydrofluorocarbon is HFA 134a, HFA227 or a mixture of the two.
Meanwhile, the invention also discloses a medical quantitative inhalation aerosol, which comprises a medical aerosol preparation and a pressurized metered dose inhaler for containing the preparation, wherein the preparation is the medical aerosol preparation provided by any one of the schemes.
The aerosol adopts the aerosol preparation provided by any scheme, and due to the special performance of the aerosol preparation, the aerosol product can keep uniform concentration of liquid medicine for a long time, so that the aim of keeping the stability of the product performance of the aerosol is fulfilled.
As a further technical scheme of the medical quantitative inhalation aerosol, the pressurized metered dose inhaler comprises a containing tank, a metering valve and an actuator, wherein the containing tank is made of magnesium-aluminum alloy, and a part or the whole wall surface inside the containing tank is coated with perfluorocarbon high polymer.
The containing tank is used as a storage container of aerosol preparation, because a natural oxide film on the surface of the common magnesium-aluminum alloy is thin and soft, has poor density and uneven surface, particles in the medicine are easily adsorbed, and magnesium, aluminum elements and the like on the surface layer of the containing tank can infiltrate into the liquid medicine. According to the scheme, the perfluorocarbon high polymer is partially or completely coated on the inner wall of the accommodating tank, so that a layer of compact coating can be formed on the coated part, meanwhile, the surface of the coating is compact and flat, medicine particles are not easy to adsorb, and the contact between an aerosol preparation and the accommodating tank body is avoided.
Preferably, to minimize the effect of magnesium aluminum alloy on the composition of the aerosol formulation, the entire wall of the interior of the containment vessel is lined with a perfluorocarbon polymer.
Preferably, as a specific implementation mode of the perfluorocarbon polymer, the perfluorocarbon polymer is one of the following substances: PTFE, PEP, PFA, and a copolymer of PTFE, PEP, and PFA, which are any two or three of them.
The invention has the following beneficial effects:
in the scheme, span 80 is added into the aerosol preparation as a surfactant, so that the span 80 can keep the concentration of the liquid medicine uniform for a long time, and the aim of increasing the stability of the liquid medicine is fulfilled. The limitation on the addition amount of the span 80 aims to ensure that the span 80 has the suspending and lubricating effects and simultaneously the excessive content does not influence the generation of medicinal aerosol and reduce the dosage of fine particles.
Drawings
FIG. 1 is a schematic diagram of a specific embodiment of a metered dose inhaler according to the present invention.
The reference numerals in fig. 1 are respectively: 1. a containing tank 2, a metering valve 3 and an actuator.
Detailed Description
The invention provides a medical aerosol preparation and a quantitative inhalation aerosol, which are used for solving the following problems: in the prior art, because the fumagillol is slightly soluble in ethanol, the particle size of the medicine can be gathered after the fumarol is placed for a long time, so that the concentration of the medicine liquid is not uniform, and the uniformity of the medicine delivery dosage is influenced. After the medical aerosol preparation is stored for a certain time, the dose of the micro-fine particles in the medical aerosol preparation can still be effectively ensured, and the uniformity of the delivered dose is ensured.
The scheme provided by the invention is that span 80 is added into the aerosol preparation as a surfactant, and the purposes of keeping the concentration of the liquid medicine uniform for a long time and increasing the stability of the liquid medicine can be achieved by limiting the addition amount of the span 80. The present invention will be described in further detail with reference to the following examples, but the apparatus of the present invention is not limited to the following examples:
example 1:
a medical aerosol preparation comprises an active ingredient and a liquefied propellant as a solvent of the active ingredient, wherein the active ingredient comprises mometasone furoate and fomesartamine fumarate, the liquefied propellant is hydrofluorocarbon, the medical aerosol preparation further comprises ethanol and span 80 which are added into the liquefied propellant, and the weight ratio of the span 80 in the aerosol preparation is 0.01-0.1% w/w.
In particular, in view of the above-mentioned problem that ethanol affects uniformity of a drug delivery dose, oleic acid is added to an aerosol formulation in the prior art, but the uniformity of the drug delivery dose gradually deteriorates as the time during which the aerosol formulation is left alone increases.
In the scheme, span 80 is added into the aerosol preparation as a surfactant, so that the span 80 can keep the concentration of the liquid medicine uniform for a long time, and the aim of increasing the stability of the liquid medicine is fulfilled. The limitation on the addition amount of the span 80 aims to ensure that the span 80 has the suspending and lubricating effects and simultaneously the excessive content does not influence the generation of medicinal aerosol and reduce the dosage of fine particles.
In this example, the effect of adding span 80 to an aerosol formulation on drug solution fine particle metering (FPD) and delivery metering uniformity (DCU) was verified using the following comparative experiments.
The following comparative tests included five formulations, with the data on the right hand side of each component in each formulation being the weight ratio of the component in the aerosol formulation, where "to 100%" indicates that the other components of the aerosol formulation are heptafluoropropane, except for the other components at the specified weight ratios.
Prescription 1:
Figure BDA0001195507020000051
prescription 2:
Figure BDA0001195507020000052
Figure BDA0001195507020000061
prescription 3:
Figure BDA0001195507020000062
prescription 4
Figure BDA0001195507020000063
Prescription 5
Figure BDA0001195507020000064
Figure BDA0001195507020000071
The formulations were all contained in canisters coated with PTFE (polytetrafluoroethylene), and aerosol formulations of the formulations were tested for 6 months at 40 ℃ and 75% RH, using a usp apparatus to determine delivered dose uniformity (DCU) and an anderson cascade impactor to determine Fine Particle Dose (FPD).
The results are given in the following table:
Figure BDA0001195507020000072
from the above test results, the indexes of DCU and FPD, etc. after accelerated storage for 6 months at 40 ℃ using span 80 as a surfactant are superior to those of the prescription using oleic acid. DCU and FPD were both good at span 80 concentrations of 0.01% -0.1% w/w. Namely, MMAD is obviously increased after prescription 1 is placed in an accelerated manner, which shows that the particle size of drug particles is increased, the inhalable effective drug dose FDA is obviously reduced, and the effect of oleic acid is reduced after the oleic acid is placed.
Meanwhile, the embodiment also discloses a medical quantitative inhalation aerosol, which comprises a medical aerosol preparation and a pressurized metered dose inhaler for containing the preparation, wherein the preparation is the medical aerosol preparation provided by any one of the schemes.
The aerosol adopts the aerosol preparation provided by any scheme, and due to the special performance of the aerosol preparation, the aerosol product can keep uniform concentration of liquid medicine for a long time, so that the aim of keeping the stability of the product performance of the aerosol is fulfilled.
Example 2:
in this embodiment, as a further technical solution of the above medical aerosol formulation, in order to enable effective components in the aerosol formulation to be effectively distributed or deposited on the bronchi, bronchioles and lungs of the human body, the mometasone furoate and the formoterol fumarate are both fine powders with median particle size of less than 5 μm obtained by jet milling. In the scheme, because a certain amount of span 80 is added into the aerosol preparation, the active ingredients with the median particle size have larger surface energy, but are still not easy to be adsorbed on the surface of a container.
As an implementation scheme of the liquefied propellant which is beneficial to environmental protection, the hydrofluorocarbon is HFA 134a, HFA227 or a mixture of the two.
Example 3:
the present embodiment is further limited based on embodiment 1, and as a further technical solution of the above medical metered dose inhaler, the pressurized metered dose inhaler includes a container 1, a metering valve 2 and an actuator 3, the container 1 is made of magnesium-aluminum alloy, and a part or all of the wall surface inside the container 1 is coated with perfluorocarbon polymer.
The holding tank 1 is used as a storage container of aerosol preparation, because the natural oxide film on the surface of the common magnesium-aluminum alloy is thin and soft, has poor density and uneven surface, particles in the medicine are easily adsorbed, and meanwhile, magnesium, aluminum elements and the like on the surface layer of the holding tank 1 can infiltrate into the liquid medicine. In the scheme, the perfluorocarbon high polymer is partially or completely coated on the inner wall of the accommodating tank 1, so that a dense coating can be formed on the coated part, the surface of the coating is dense and flat, medicine particles are not easy to adsorb, and the contact between the aerosol preparation and the accommodating tank 1 body is avoided.
In this example, the following comparative test was conducted to verify the effect of lining the inner surface of the container 1 with the perfluorocarbon polymer on the components of the aerosol formulation contained therein, and the data on the right side of each component in the following formulation is the weight ratio of the component in the aerosol formulation, wherein "to 100%" indicates that the other components of the aerosol formulation are heptafluoropropane, except for the other components contained in the specific weight ratio. Wherein, the material of the containing tank 1 used for containing the aerosol preparation in the aerosol is magnesium aluminum alloy.
The aerosol containing mometasone furoate, formoterol fumarate micropowder and propellant HFA227e (hydrofluorocarbon) has the following formula:
Figure BDA0001195507020000091
the aerosol with the formula is subjected to an accelerated experiment for 6 months at 40 ℃ and 75% RH, the residual amount of the drug on the inner surface of the accommodating tank 1 is measured, the measuring method comprises the steps of continuously spraying the aerosol until no liquid medicine is sprayed out, freezing the accommodating tank 1 in a dry ice bath, cutting the accommodating tank, taking down the metering valve 2, disassembling, cleaning the inner surface of the accommodating tank 1, measuring the residual amounts of mometasone furoate and formoterol fumarate by using HPLC after constant volume to obtain the following data:
container pot PTFE Non-coating layer
Mometasone furoate (mg/bottle) 0.07 1.86
Formoterol fumarate (mg/bottle) 0.10 0.52
Wherein PTFE shown in the above table indicates that the entire inner surface of the accommodation tank 1 is coated with a teflon coating; the shown uncoated representation means that the aerosol formulation is in direct contact with the inner surface of the containment tank 1, i.e. no coating is provided on the inner surface of the containment tank 1.
The aerosol with the above formula is subjected to an accelerated test for 6 months at 40 ℃ and with the RH being 75%, and the contents of magnesium ions, aluminum ions and formoterol hydrolysate in the liquid medicine are measured to obtain the following data:
Figure BDA0001195507020000101
wherein PTFE shown in the above table indicates that the entire inner surface of the accommodation tank 1 is coated with a teflon coating; the shown uncoated representation means that the aerosol formulation is in direct contact with the inner surface of the containment tank 1, i.e. no coating is provided on the inner surface of the containment tank 1.
Example 4:
this embodiment is further defined on the basis of embodiment 1, and preferably, in order to minimize the influence of magnesium-aluminum alloy on the components of the aerosol preparation, all the wall surfaces inside the holding tank 1 are coated with perfluorocarbon polymers.
Preferably, as a specific implementation mode of the perfluorocarbon polymer, the perfluorocarbon polymer is one of the following substances: PTFE, PEP, PFA, and a copolymer of PTFE, PEP, and PFA, which are any two or three of them.
The foregoing is a more detailed description of the present invention in connection with specific preferred embodiments thereof, and it is not intended that the specific embodiments of the present invention be limited to these descriptions. For those skilled in the art to which the invention pertains, other embodiments that do not depart from the gist of the invention are intended to be within the scope of the invention.

Claims (7)

1. A medical aerosol preparation comprises an active ingredient and a liquefied propellant as a solvent of the active ingredient, wherein the active ingredient comprises mometasone furoate and formoterol fumarate, and is characterized in that the liquefied propellant is hydrofluorocarbon, the medical aerosol preparation also comprises ethanol and span 80 which are added into the liquefied propellant, the weight ratio of the span 80 in the aerosol preparation is 0.01-0.1% w/w, and the medical aerosol preparation contains 0.17 wt% of mometasone furoate, 0.009 wt% of formoterol fumarate and 1.8 wt% of ethanol.
2. A medicinal aerosol formulation as claimed in claim 1, wherein the mometasone furoate and the formoterol fumarate are each a fine powder having a median particle size of less than 5 μm obtained by jet milling.
3. A medicinal aerosol formulation as claimed in claim 1, wherein the hydrofluorocarbon is either HFA 134a, HFA227 or a mixture of both.
4. A metered dose inhalation aerosol formulation for medical use comprising a medicinal aerosol formulation and a pressurised metered dose inhaler for containing the formulation, characterised in that the formulation is a medicinal aerosol formulation as claimed in any one of claims 1 to 3, comprising 0.17% by weight mometasone furoate, 0.009% by weight formoterol fumarate and 1.8% by weight ethanol.
5. The aerosol for metered dose inhalation according to claim 4, wherein the pressurized metered dose inhaler comprises a canister (1), a metering valve (2) and an actuator (3), the canister (1) is made of magnesium aluminum alloy, and a part or the whole of the inner wall of the canister (1) is coated with perfluorocarbon polymer.
6. The medical metered dose inhalation aerosol of claim 5, wherein the entire wall surface of the interior of the canister (1) is coated with the perfluorocarbon polymer.
7. The metered dose inhalation aerosol of claim 5, wherein said perfluorocarbon polymer is one of the following: PTFE, PEP, PFA, and a copolymer of PTFE, PEP, and PFA, which are any two or three of them.
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WO2008102128A2 (en) * 2007-02-19 2008-08-28 Cipla Limited Pharmaceutical combinations of at least two bronchodilators or of a bronchodilator with a corticosteroid
CN101856362A (en) * 2001-08-28 2010-10-13 先灵公司 Pharmaceutical compositions for the treatment of asthma
CN104225739A (en) * 2014-09-30 2014-12-24 四川普锐特医药科技有限责任公司 Medical quantitative inhalation aerosol

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