WO2024104349A1 - 氨溴索口溶膜组合物、其制备方法及应用 - Google Patents

氨溴索口溶膜组合物、其制备方法及应用 Download PDF

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WO2024104349A1
WO2024104349A1 PCT/CN2023/131591 CN2023131591W WO2024104349A1 WO 2024104349 A1 WO2024104349 A1 WO 2024104349A1 CN 2023131591 W CN2023131591 W CN 2023131591W WO 2024104349 A1 WO2024104349 A1 WO 2024104349A1
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ambroxol
composition
mass
film
percentage
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PCT/CN2023/131591
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English (en)
French (fr)
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应述欢
郭桢
付俊
卢鹏程
刘俞利
王婷婷
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上海云晟研新生物科技有限公司
博志研新泰州药物技术有限公司
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Publication of WO2024104349A1 publication Critical patent/WO2024104349A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the invention relates to an ambroxol hydrochloride orally dissolving film composition, a preparation method and application thereof.
  • Ambroxol hydrochloride is the active metabolite of the expectorant bromhexine, which is less toxic than bromhexine and more active than bromhexine.
  • Ambroxol hydrochloride is a mucolytic developed by Boehringer Ingelheim in Germany. The drug was first launched in Germany in the early 1980s, and then in many countries such as France, Italy, Japan, and Spain. It is a new generation of mucolytics that can improve expectoration and promote pulmonary surfactant and airway secretion and ciliary movement. Clinically, it can regulate mucus and viscous secretion, activate ciliary swing, dilute sputum, strengthen mucus outward transport, and facilitate excretion.
  • this drug can be widely used clinically for acute and chronic respiratory diseases accompanied by abnormal respiratory secretions, especially the expectorant treatment of chronic bronchitis, neonatal respiratory distress syndrome, and adjuvant treatment of lung surgery. It has the advantages of low toxicity, definite efficacy, and the ability to produce good synergistic effects when used with antibiotics. It is one of the most commonly used expectorants.
  • the original research company's domestically marketed dosage forms include injections, tablets, sustained-release capsules and oral solutions.
  • the drug has been authorized in the following countries through the approval procedures of various countries: Austria, Belgium, Bulgaria, China, Cyprus, Czech Republic, Denmark, Estonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Moldova, Lithuania, Luxembourg, Malta, Norway, Poland Portugal, Romania, Slovakia, Slovenia, Spain, Sweden and the Netherlands.
  • Ambroxol is very popular among clinicians because of its very significant expectorant effect, and its injection is widely used in nebulization treatment of patients with respiratory diseases (off-label). But in fact, the weakly acidic ambroxol injection itself will irritate the airway after nebulization, causing airway spasm and dyspnea. This adverse effect is more obvious in COPD patients.
  • the injection prepared with normal saline, whether in terms of aerosol particle diameter or excipients (including preservatives contained), may have the risk of lung infection or induce aggravated asthma after nebulization inhalation.
  • oral preparations of ambroxol are all over-the-counter (OTC) drugs. They are one of the best-selling products for respiratory system drugs and are widely used by a wide range of people, especially infants and children.
  • OTC over-the-counter
  • the instructions for oral ambroxol hydrochloride solution also clearly state that infants and young children can take it.
  • OTC over-the-counter
  • Many organizations are concerned about whether it is appropriate for children under 6 years old to use ambroxol as an expectorant, and believe that the benefits of such drugs in this patient population do not outweigh the risks.
  • Ambroxol tablets and sustained-release capsules require drinking water and swallowing to complete the medication process.
  • This dosage form has poor compliance for some elderly people, children, and patients with swallowing difficulties. Its use is restricted under some special conditions (such as lack of drinking water) or has poor effects. Injections have potential safety hazards and poor patient compliance.
  • oral solutions have a good taste, they have the disadvantages of large dosage, difficulty in quantification, poor stability, etc., and have high requirements for production technology and packaging. It is inconvenient to carry, which brings many inconveniences and unsafe factors to patients in taking, carrying and transporting.
  • Ambroxol hydrochloride is slightly soluble in water, and the drug tastes bitter and numb, and the bitterness and numbness are long-lasting and cannot be masked by conventionally adding solubilizers and flavor correctors, resulting in poor compliance of patients, especially not conducive to children's medication.
  • Patent document CN102846581A discloses an ambroxol hydrochloride oral dissolving film, but after experiments, it was found that the ambroxol hydrochloride oral fast dissolving film prepared by the prescription has poor mechanical strength, poor stability, slow disintegration and complex preparation process, which is not conducive to commercial production.
  • the present invention provides an ambroxol hydrochloride oral fast-dissolving film composition, a preparation method and application thereof.
  • the ambroxol hydrochloride oral fast-dissolving film composition provided by the present invention has the advantages of thin thickness, good taste, stable properties, stable mechanical properties, instant dissolution in the oral cavity without drinking water, and fast oral absorption speed. At the same time, it has a simple process, high drug loading, and good uniformity of drug content. The market prospects are good.
  • the invention provides an ambroxol orally dissolving film composition, which comprises an active drug, a film-forming material and a taste-masking agent, wherein the active drug comprises 2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl)benzylamine (also known as ambroxol) or a pharmaceutically acceptable salt thereof, such as the hydrochloride of 2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl)benzylamine (also known as ambroxol hydrochloride) as shown in formula I;
  • the active drug comprises 2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl)benzylamine (also known as ambroxol) or a pharmaceutically acceptable salt thereof, such as the hydrochloride of 2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl)benzylamine (also
  • the ambroxol orodispersible film composition of the present invention may be an ambroxol hydrochloride orodispersible film composition.
  • the ambroxol orodispersible film composition (such as ambroxol hydrochloride orodispersible film composition) of the present invention preferably does not contain a pH regulator.
  • the ambroxol orodispersible film composition (such as ambroxol hydrochloride orodispersible film composition) of the present invention preferably does not contain a free pH regulator.
  • the free pH regulator refers to a pH regulator that does not form a salt with an active drug.
  • the pH adjusting agent includes but is not limited to pharmaceutically acceptable acids known in the art for adjusting pH value, such as organic acids, inorganic acids, organic bases and inorganic bases.
  • the above-mentioned inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • the above-mentioned organic acids include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid (citric acid), benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, formic acid, trifluoroacetic acid, etc.
  • the ambroxol orodispersible film composition (such as ambroxol hydrochloride orodispersible film composition) of the present invention does not contain an alkaline pH regulator, such as a pharmaceutically acceptable base known in the art for adjusting pH.
  • an alkaline pH regulator such as a pharmaceutically acceptable base known in the art for adjusting pH.
  • the mass percentage of the active drug is 1.00% to 40.00%, preferably 5.00% to 30.00%, for example 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, 9.09%, 10.00%, 12.45%, 15.00%, 15.23%, 16.48%, 19.23%, 19.48%, 20.00%, 21.43%, 25.00% or 30.00%, wherein the mass percentage refers to the mass of the active drug in the total amount of the ambroxol oral film composition (such as ambroxol hydrochloride oral film composition) Percentage of mass.
  • the mass percentage refers to the mass of the active drug in the total amount of the ambroxol oral film composition (such as ambroxol hydrochloride oral film composition) Percentage of mass.
  • the taste masking agent is a substance that covers up unpleasant tastes such as bitterness and numbness, which can be selected from cation exchange resins, and the cationic resins are selected from one, two or three of sodium polystyrene sulfonate, potassium polycrilin and polacrilin resin.
  • the particle size D90 of the cation exchange resin is less than 200 ⁇ m.
  • the mass percentage of the taste masking agent is 10.00% to 70.00%, further preferably 15.00% to 60.00%, for example 10.00%, 12.00%, 15.00%, 19.48%, 20.00%, 21.43%, 24.90%, 25.00%, 30.00%, 30.30%, 38.06%, 38.46%, 40.00%, 41.21%, 45.00%, 45.45%, 50.00%, 55.00% or 60.00%, wherein the mass percentage refers to the mass of the taste masking agent as a percentage of the total mass of the ambroxol orodispersible film composition (such as the ambroxol hydrochloride orodispersible film composition).
  • the film-forming material is a drug carrier, selected from one or more of xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hydroxypropyl methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, pullulan, polyvinyl pyrrolidone, polyethylene glycol, polyoxyethylene, acrylic acid copolymer, polylactic acid and silicone rubber.
  • the mass percentage of the film-forming material is 10.00% to 70.00%, preferably 15.00% to 60.00%, for example, 10.00%, 12.00%, 14.29%, 15.00%, 20.00%, 25.00%, 27.47%, 30.00%, 30.30%, 30.45%, 35.00%, 37.34%, 38.46%, 40.00%, 45.00%, 50.00%, 55.00%, 58.44% or 60.00%, wherein the mass percentage refers to the mass of the film-forming material as a percentage of the total mass of the ambroxol oral film-soluble composition (such as ambroxol hydrochloride oral film-soluble composition).
  • the mass percentage refers to the mass of the film-forming material as a percentage of the total mass of the ambroxol oral film-soluble composition (such as ambroxol hydrochloride oral film-soluble composition).
  • the ambroxol oral dissolving film composition (such as ambroxol hydrochloride oral dissolving film composition) of the present invention may further include one or more of a plasticizer, a flavoring agent, a coloring agent and a filler.
  • the ambroxol oral dissolving film composition (such as ambroxol hydrochloride oral dissolving film composition) may contain or not contain a flavoring agent.
  • the plasticizer refers to a substance used to lower the glass transition temperature of the film, increase plasticity and toughness, and improve elongation, which can be selected from one or more of polyethylene glycol, glycerol, propylene glycol, silicone oil, polypropylene glycol and hexylene glycol.
  • the mass percentage of the plasticizer is 0-30.00%, preferably 0-25.00%, for example, 1.00%, 2.00%, 2.60%, 3.00%, 4.00%, 5.00%, 6.00%, 6.06%, 7.00%, 8.00%, 8.67%, 9.00%, 10.00%, 10.15%, 10.99%, 15.00%, 20.00%, 24.90%, 25.00% or 30.00%, wherein the mass percentage refers to the mass of the plasticizer as a percentage of the total mass of the ambroxol oral film-soluble composition (such as ambroxol hydrochloride oral film-soluble composition).
  • the flavoring agent refers to a substance that acts as a flavoring agent, which can be selected from one, two or more of aspartame, sucralose, fructose, sucrose, stevioside, neotame, glycyrrhizin, flavors, spices, saccharin and saccharin sodium.
  • the mass percentage of the flavoring agent is 0-50.00%, preferably 0-45.00%, for example, 1.00%, 1.10%, 1.20%, 1.30%, 1.33%, 1.40%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.00%, 2.10%, 2.20%, 2.30%, 2.40%, 2.50%, 2.60%, 2.70%, 2.80%, 2.90%, 3.00%, 3.05%, 3.50%, 3.85%, 4.00%, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, 9.09%, 10.00%, 12.00%, 15.00%, 20.00%, 25.00%, 30.00%, 35.00%, 40.00%, 42.87%, 45.00% or 50.00%, wherein the mass percentage refers to the mass of the flavoring agent as a percentage of the total mass of the ambroxol orodispersible film composition (such as ambroxol hydrochloride orodispersible film composition).
  • the colorant refers to a substance that can improve the appearance color of the preparation, can be used to identify the concentration of the preparation, distinguish the application method and reduce the patient's aversion to taking the medicine, and is selected from one, two or more of titanium dioxide, pigments and lakes.
  • the mass percentage of the colorant is 0-2.00%, for example, 0, 0.02%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.41%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%, 1.10%, 1.20%, 1.30%, 1.40%, 1.50%, 1.60%, 1.65%, 1.70%, 1.80%, 1.90% or 2.00%, wherein the mass percentage refers to the mass of the colorant as a percentage of the total mass of the ambroxol oral-soluble film composition (such as ambroxol hydrochloride oral-soluble film composition).
  • the filler refers to a solid substance added to a material to improve the material properties, or to increase the volume, weight, and reduce the material cost. It can be selected from one or more of sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose.
  • the mass percentage of the filler is 0-20.00%, for example 0%, 1.00%, 5.00%, 10.00%, 15.00% or 20.00%; the mass percentage refers to the mass of the filler as a percentage of the total mass of the ambroxol orodispersible film composition (such as ambroxol hydrochloride orodispersible film composition).
  • ambroxol orally dissolving film composition (such as ambroxol hydrochloride orally dissolving film composition) is selected from the following formulas 1-1 to 1-5 in terms of mass percentage:
  • Formula 1-1 comprises: 15-22% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 18-52% polyclinic potassium, 18-35% film-forming material, 8-12% plasticizer, and 0.3-7% flavoring agent and/or coloring agent;
  • Formula 1-2 comprises: 15-22% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 18-46% polyclinic potassium, 18-60% film-forming material, 2-22% plasticizer and 0-0.05% flavoring agent and/or coloring agent;
  • Formula 1-3 comprises: 17-21% ambroxol or its pharmaceutically acceptable salt (such as ambroxol hydrochloride), 35-40% polyclonal Potassium lin, 34-41% film-forming material and 2-6% flavoring agent and/or coloring agent;
  • Formula 1-4 comprises: 9-13% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 22-48% sodium polystyrene sulfonate, 30-40% film-forming material, 5-25% plasticizer and 0.2-10% flavoring agent and/or coloring agent;
  • Formulas 1-5 comprise: 18-24% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 20-24% sodium polystyrene sulfonate, 13-15% film-forming material and 40-45% flavoring agent.
  • a pharmaceutically acceptable salt thereof such as ambroxol hydrochloride
  • 20-24% sodium polystyrene sulfonate 20-24% sodium polystyrene sulfonate
  • 13-15% film-forming material and 40-45% flavoring agent.
  • the film-forming material is one, two or more of xanthan gum, polyvinyl alcohol, hydroxypropyl methylcellulose, pullulan, and sodium alginate.
  • the plasticizer is glycerol.
  • the colorant is a lake.
  • ambroxol hydrochloride orally dissolving film composition of the present invention can be any of the following formulas:
  • Formula 2-1 18-22% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 48-52% polyclinic potassium, 14-32% film-forming material, 6-10% plasticizer and 1-3% flavoring agent and/or colorant, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 2-2 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 39-43% polyclinic potassium, 25-29% film-forming material, 9-13% plasticizer, 1.5-6% flavoring agent and/or coloring agent, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 2-3 13-17% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 36-40% polyclinic potassium, 28-32% film-forming material, 8-12% plasticizer, 1-11% flavoring agent and/or colorant, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 2-4 17-21% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 17-21% polyclinic potassium, 58-52% film-forming material and 0.5-4% plasticizer, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 2-5 17-21% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 36-40% polyclinic potassium, 34-41% film-forming material and 2-6% flavoring agent and/or coloring agent, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 2-6 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 38-42% polyclinic potassium, 30-34% film-forming material, 9-13% plasticizer and 0-0.02% flavoring agent and/or coloring agent, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition.
  • Formula 2-7 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 37-41% polyclinic potassium, 29-33% film-forming material, 8-12% plasticizer, 0-6% flavoring agent and/or coloring agent, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition.
  • Formulation 2-8 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 38-42% polyclinic potassium, 30-34% film-forming material, 9-13% plasticizer, 0-0.5% flavoring agent and/or coloring agent, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition.
  • Formula 2-9 13-17% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 43-47% polyclinic potassium, 18-22% film-forming material and 18-22% plasticizer, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 2-10 7-11% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 44-48% sodium polystyrene sulfonate, 26-34% film-forming material, 4-8% plasticizer, 1-15% flavoring agent and/or colorant, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 2-11 10-14% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 21-25% sodium polystyrene sulfonate, 35-39% film-forming material, 23-27% plasticizer and 0-0.5% flavoring agent and/or coloring agent, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 2-12 20-22% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 20-22% sodium polystyrene sulfonate, 12-16% film-forming material, 30-50% flavoring agent and/or coloring agent, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition.
  • a pharmaceutically acceptable salt thereof such as ambroxol hydrochloride
  • sodium polystyrene sulfonate 12-16% film-forming material
  • 30-50% flavoring agent and/or coloring agent wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition.
  • the film-forming material is one, two or more of xanthan gum, polyvinyl alcohol, hydroxypropyl methylcellulose, pullulan, and sodium alginate.
  • the plasticizer is glycerol.
  • the colorant is a lake.
  • ambroxol orally dissolving film composition of the present invention can be any of the following formulas:
  • Formula 3-1 18-22% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 48-52% polyclinic potassium, 11-15% xanthan gum, 4-8% polyvinyl alcohol, 6-10% glycerol and 1-3% aspartame, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 3-2 14-18% ambroxol or its pharmaceutically acceptable salt (such as ambroxol hydrochloride), 39-43% polyclinic potassium, 25-29% polyvinyl alcohol, 9-13% glycerol, 0.5-1.5% stevioside, 0.5-1.5% flavor and 0.5-3% lake, the percentages are It refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 3-3 13-17% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 36-40% polyclinic potassium, 28-32% polyvinyl alcohol, 8-12% glycerol, 1-5% sucralose, 1-5% flavor and 0-0.05% lake, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 3-4 17-21% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 17-21% polyclinic potassium, 58-52% hypromellose and 0.5-4% glycerol, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition;
  • Formula 3-5 17-21% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 36-40% polyclinic potassium, 23-27% polyvinyl alcohol, 11-14% pullulan and 2-6% sucralose, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition;
  • Formula 3-6 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 38-42% polyclinic potassium, 30-34% polyvinyl alcohol, 9-13% glycerol and 0-0.02% lake, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition.
  • Formulation 3-7 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 37-41% polyclinic potassium, 29-33% polyvinyl alcohol, 8-12% glycerol, 1-5% sucralose and 0-0.05% lake, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition.
  • a pharmaceutically acceptable salt thereof such as ambroxol hydrochloride
  • Formula 3-8 14-18% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 38-42% polyclinic potassium, 30-34% polyvinyl alcohol, 9-13% glycerol, 0-0.1% neotame and 0-0.05% lake, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition.
  • Formula 3-9 13-17% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 43-47% polyclinic potassium, 18-22% xanthan gum and 18-22% glycerol, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 3-10 7-11% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 44-48% sodium polystyrene sulfonate, 16-20% sodium alginate, 10-14% polyvinyl alcohol, 4-8% glycerol, 1-5% sucralose, 1-5% stevioside and 1-5% flavor, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 3-11 10-14% ambroxol or a pharmaceutically acceptable salt thereof (such as ambroxol hydrochloride), 21-25% sodium polystyrene sulfonate, 35-39% hydroxypropyl methylcellulose, 23-27% glycerol and 0-0.5% lake, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formulation 3-12 20-22% ambroxol or its pharmaceutically acceptable salt (such as ambroxol hydrochloride), 20-22% polystyrene sulfonate Sodium acetate, 12-16% xanthan gum, 12-16% sucralose, 12-16% stevioside and 12-16% flavors, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition.
  • ambroxol or its pharmaceutically acceptable salt such as ambroxol hydrochloride
  • polystyrene sulfonate Sodium acetate 12-16% xanthan gum, 12-16% sucralose, 12-16% stevioside and 12-16% flavors, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition.
  • ambroxol hydrochloride orally dissolving film composition of the present invention can be any of the following formulas:
  • Formula 1 20.00% ambroxol hydrochloride, 50.00% polyclinic potassium, 13.33% xanthan gum, 6.67% polyvinyl alcohol, 8.67% glycerol and 1.33% aspartame, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition;
  • Formula 2 16.48% ambroxol hydrochloride, 41.21% polyclinic potassium, 27.47% polyvinyl alcohol, 10.99% glycerol, 1.10% stevioside, 1.10% flavor and 1.65% lake, the percentages refer to the percentage of the mass of each component to the total mass of the composition;
  • Formula 3 15.23% ambroxol hydrochloride, 38.06% polyclinic potassium, 30.45% polyvinyl alcohol, 10.15% glycerol, 3.05% sucralose, 3.05% flavor and 0.02% lake, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 4 19.48% ambroxol hydrochloride, 19.48% polyclinic potassium, 58.44% hypromellose and 2.60% glycerol, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition;
  • Formula 5 19.23% ambroxol hydrochloride, 38.46% polyclinic potassium, 25.64% polyvinyl alcohol, 12.82% pullulan and 3.85% sucralose, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition;
  • Formula 6 16.21% ambroxol hydrochloride, 40.53% polyclinic potassium, 32.43% polyvinyl alcohol, 10.81% glycerol and 0.02% lake, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.
  • Formula 7 15.70% ambroxol hydrochloride, 39.26% polyclinic potassium, 31.41% polyvinyl alcohol, 10.47% glycerol, 3.14% sucralose and 0.02% lake, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.
  • Formula 8 16.16% ambroxol hydrochloride, 40.40% polyclinic potassium, 32.32% polyvinyl alcohol, 10.77% glycerol, 0.32% neotame and 0.02% lake, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.
  • Formula 9 15.00% ambroxol hydrochloride, 45.00% polyclinic potassium, 20.00% xanthan gum and 20.00% glycerol, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition;
  • Formula 10 9.09% ambroxol hydrochloride, 45.45% sodium polystyrene sulfonate, 18.18% sodium alginate, 12.12% polyvinyl alcohol, 6.06% glycerol, 3.03% sucralose, 3.03% stevioside and 3.03% flavor, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition;
  • Formula 11 12.45% ambroxol hydrochloride, 24.90% sodium polystyrene sulfonate, 37.34% hydroxypropyl methylcellulose, 24.90% glycerol and 0.41% lake, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition;
  • Formula 12 21.43% ambroxol hydrochloride, 21.43% sodium polystyrene sulfonate, 14.29% xanthan gum, 14.29% sucralose, 14.29% stevioside and 14.29% flavor, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.
  • Formula 13 15.22% ambroxol hydrochloride, 38.06% polyclinic potassium, 30.45% polyvinyl alcohol, 10.15% glycerol, 3.05% sucralose, 3.05% flavor and 0.02% lake, wherein the percentage refers to the percentage of the mass of each component to the total mass of the composition;
  • Formula 14 16.17% ambroxol hydrochloride, 40.40% polyclinic potassium, 32.32% polyvinyl alcohol, 10.77% glycerol, 0.32% neotame and 0.02% lake, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition;
  • Formula 15 9.10% ambroxol hydrochloride, 45.45% sodium polystyrene sulfonate, 18.18% sodium alginate, 12.12% polyvinyl alcohol, 6.06% glycerol, 3.03% sucralose, 3.03% stevioside and 3.03% flavor, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition;
  • Formula 16 21.43% ambroxol hydrochloride, 21.43% sodium polystyrene sulfonate, 14.29% xanthan gum, 14.29% sucralose, 14.29% stevioside and 14.27% flavor, wherein the percentages refer to the percentage of the mass of each component to the total mass of the composition.
  • the mass percentage content of each component in the ambroxol oral film composition (such as ambroxol hydrochloride oral film composition) is 100%.
  • the present invention also provides a method for preparing the ambroxol orally soluble film composition (such as the ambroxol hydrochloride orally soluble film composition), which comprises the following steps:
  • Step 1 Prepare an aqueous solution of the active drug
  • Step 2 Add a taste masking agent to the aqueous solution obtained in step 1, stir, and obtain a sample;
  • Step 3 Centrifuge the sample obtained in step 2, discard part of the supernatant, and make the mass of the remaining lower layer material be 10-15 times that of the active drug to obtain the drug-loaded resin;
  • Step 4 dissolving the film-forming material in water, mixing it with one or more of a flavoring agent, a plasticizer, a colorant and a filler (if any), and stirring evenly to obtain a glue solution;
  • Step 5 transferring the drug-loaded resin obtained in step 3 to the glue obtained in step 4 and stirring them thoroughly to obtain a uniform glue. After stirring, the glue is vacuum-debubbled, coated, dried, and cut to obtain the ambroxol hydrochloride orodispersible film preparation.
  • the active drug solution is preferably prepared under light-proof conditions.
  • the water in step 1 is preferably purified water.
  • step 2 the stirring is preferably carried out in the dark.
  • the stirring time in step 2 is preferably more than 8 hours.
  • the centrifugation is preferably performed in a centrifuge; the centrifuge may be a desktop centrifuge, or the centrifuge may be a low-speed centrifuge.
  • the thickness of the film is 10 ⁇ m to 300 ⁇ m, such as 20 ⁇ m to 100 ⁇ m.
  • the ambroxol orosoluble film composition (such as ambroxol hydrochloride orosoluble film composition) can completely disintegrate within 120 seconds in 900 ml of simulated saliva at 37 ⁇ 1°C, for example, completely disintegrate within 80 seconds.
  • the present invention also provides the use of the ambroxol orodispersible film composition (such as the ambroxol hydrochloride orodispersible film composition) in preparing a drug for treating and/or preventing the indications targeted by ambroxol or its pharmaceutically acceptable salts, such as allergies.
  • the ambroxol orodispersible film composition such as the ambroxol hydrochloride orodispersible film composition
  • the drug is an expectorant or a mucolytic agent.
  • the drug is used for acute or chronic respiratory diseases accompanied by abnormal respiratory secretions, especially for expectorant treatment of chronic bronchitis, neonatal respiratory distress syndrome and auxiliary treatment of lung surgery.
  • the present invention also provides a method for preventing and/or treating a disease or condition, comprising administering the ambroxol orodispersible film composition (such as the ambroxol hydrochloride orodispersible film composition) to a patient in need (such as a human or other mammal).
  • the ambroxol orodispersible film composition such as the ambroxol hydrochloride orodispersible film composition
  • the disease or disorder is selected from allergy, sputum, acute or chronic respiratory diseases with abnormal respiratory secretions, in particular chronic bronchitis, neonatal respiratory distress syndrome and symptoms after lung surgery.
  • ambroxol orodissolving film composition of the present invention particularly the ambroxol hydrochloride orodissolving film composition, has a good dissolution rate, disintegrates quickly in the oral cavity, does not have a sense of grit after dissolution, can improve the taste of the medicine, and increases the compliance of patients.
  • the ambroxol orodissolving film composition of the present invention particularly the ambroxol hydrochloride orodissolving film composition, has a uniform film appearance and good flexibility. Sedimentation does not occur during the film liquid preparation process, and the content uniformity meets the requirements.
  • the reagents and raw materials used in the present invention are commercially available.
  • ambroxol orodispersible film composition (such as ambroxol hydrochloride orodispersible film composition) provided by the present invention has the advantages of thin thickness, good taste, further improved stability, dissolution in the oral cavity without drinking water, fast oral absorption, and good market prospects.
  • ambroxol orally dissolving film composition (such as ambroxol hydrochloride orally dissolving film composition) of the present invention has readily available raw materials, simple process, easy operation, high drug loading, good drug content uniformity, and is suitable for industrial production.
  • A Add the active drug to a certain amount of purified water under light-proof conditions and dissolve it completely.
  • step E Transfer the lower layer material in step 2) to the solution prepared in step 3) and stir thoroughly to obtain a uniform glue solution. After stirring, remove bubbles from the glue solution in a vacuum environment.
  • Comparative Examples 1-3 were prepared in the manner of Examples 3-5 published in CN 102846581A:
  • ambroxol hydrochloride orally soluble films prepared in the above comparative examples 1-3 and in accordance with examples 3-8 were respectively examined for mechanical strength, disintegration time and related substances.
  • ambroxol hydrochloride oral dissolving film was tested using a texture analyzer, and its tensile strength, percent elongation and folding endurance were calculated. The results are shown in Table 3 below (six samples were tested for each embodiment):
  • the maximum force (gf) is the maximum force that the orodispersible film can resist after the yield stage.
  • the average tensile strength is the average of 6 sets of data.
  • the maximum force distance is the distance the orodissolving film is stretched under the maximum force.
  • the average percentage elongation is the average of 6 sets of data.
  • the folding endurance refers to the ability of the orally dissolving film to withstand 180° folding.
  • test method Take 6 pieces of orodissolving films prepared in Examples 1-12 and Comparative Examples 1-3 respectively, and measure the disintegration time of the orodissolving films.
  • the test method is as follows: add 900 ml of pH 6.8 phosphate buffer medium (refer to the preparation method under 8004 buffer of the 2020 edition of the Chinese Pharmacopoeia) in a 1000 ml beaker and heat to 37 ⁇ 0.5°C. Place 6 pieces of orodissolving films in the beaker of the disintegrator at the same time, and record the time for all 6 pieces of orodissolving films in each embodiment and comparative example to disintegrate. Summarize in Table 4 below.
  • the compatibility experiment of raw materials and auxiliary materials was designed according to the mass ratio of ambroxol hydrochloride to citric acid in Comparative Examples 1-3.
  • the raw materials and auxiliary materials were placed at a high temperature of 60° C. for 30 days to detect the compatibility of raw materials and auxiliary materials, and the levels of related substances in Comparative Examples 1-3 and Examples 3-8.
  • the detection method for relevant substances is determined in accordance with high performance liquid chromatography (General Rules 0512 of Part IV of the 2020 Edition of the Chinese Pharmacopoeia).
  • Test solution Take two tablets (7.5 mg specification) or one tablet (15 mg specification) of the product (such as the sample prepared in the above embodiment or comparative example), place it in a 20 mL volumetric flask, add an appropriate amount of methanol, and ultrasonicate for 15 minutes to dissolve the ambroxol hydrochloride. Cool it, and use methanol to make a solution containing about 0.75 mg of ambroxol hydrochloride per 1 mL. Take the supernatant as the test solution.
  • control solution accurately measure an appropriate amount of the test solution and dilute it with methanol to make a solution containing approximately 1.5 ⁇ g per 1 mL.
  • Octylsilane bonded silica gel was used as filler (Agient ZORBAX SB-C8 4.6 mm*150 mm, 3.5 ⁇ m; 10mmol/L diammonium hydrogen phosphate solution (adjusted to pH 7.0 with phosphoric acid)-acetonitrile (50:50) as the mobile phase; the detection wavelength is 248nm; the flow rate is 0.8mL per minute; the column temperature is 30°C; the injection plate temperature is 4°C, the injection volume is 10 ⁇ L, and the running time is 30 minutes.
  • Determination method Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram for 30 minutes.
  • the ambroxol hydrochloride orally soluble film prepared in Examples 1, 3, 6-8 was placed in a stainless steel mesh dish for dissolution curve detection according to the fourth method (paddle-disc method) of the fourth part 0931 dissolution and release determination method of the 2020 edition of the Chinese Pharmacopoeia, using a stirring paddle in method 1 and a dissolution cup according to the second method.
  • the ambroxol hydrochloride orally soluble film was placed in a stainless steel mesh dish for dissolution curve detection.
  • the test conditions are as follows:
  • Test apparatus Tianda Tianfa dissolution apparatus.
  • Test media pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer and pH 6.8 phosphate buffer.
  • a batch of ambroxol hydrochloride orodispersible film was prepared according to Example 3.
  • 6 volunteers were randomly selected to evaluate the palatability of the batch of ambroxol hydrochloride orodispersible film using a comprehensive bitterness value rating method and a multi-factor survey evaluation method.
  • the palatability is evaluated from the aspects of appearance, bitterness, sweetness, numbness, and foreign body sensation in the mouth.
  • Bitterness, numbness, and foreign body sensation in the mouth are the main scoring items, and appearance and sweetness are bonus items.
  • the grades and scoring rules are as follows:
  • the ambroxol hydrochloride orodispersible film provided by the present invention has the advantages of thin thickness, good taste, stable properties, instant dissolution in the oral cavity without drinking water, and fast oral absorption.

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Abstract

本发明提供了一种氨溴索口溶膜组合物、其制备方法及应用。所述氨溴索口溶膜组合物包含活性药物、成膜材料和掩味剂，所述的活性药物为2-氨基-3,5-二溴-N-(反式-4-羟基环己基)苄胺和/或其药学上可接受的盐，例如盐酸氨溴索。本发明提供的氨溴索口溶膜组合物具有厚度薄、口感良好、性质稳定、且无需饮水即可在口腔内即刻溶化、口服吸收速度快的优点。并且，所述氨溴索口溶膜组合物的工艺简单、载药量高、药物含量均匀度好，市场化前景好。

Description

氨溴索口溶膜组合物、其制备方法及应用
本申请要求2022年11月14日向中国国家知识产权局提交的，专利申请号为202211420255.4，发明名称为“盐酸氨溴索口溶膜组合物、其制备方法及应用”在先申请的优先权。该申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及一种盐酸氨溴索口溶膜组合物、其制备方法及应用。
背景技术
盐酸氨溴索(Ambroxol Hydrochloride)是祛痰药溴己新的活性代谢物，毒性低于溴己新，而活性高于溴己新。盐酸氨溴索是由德国勃林格殷格翰公司研发的黏液溶解剂，该药于20世纪80年代初首先在德国上市，随后在法国、意大利、日本、西班牙等许多国家相继上市，是新一代黏痰溶解剂，可以改善排痰，并具有促进肺表面活性物质和气道分泌及纤毛运动的作用。在临床上可以调节黏液与黏浆分泌，活化纤毛摆动，易于稀释痰液，强化黏液向外运输，易于排出，它也可以促进肺表面活性物质合成，以维持肺泡张力，保证肺部功能指标；促进抗生素向组织渗透，以提高浓度，增强杀菌作用；抗氧化，减少炎性介质释放，以减轻炎症反应；与支气管解痉物质协同，以提高解痉药物的疗效。因此，该药在临床上可以广泛用于伴有呼吸道异常分泌的急性、慢性呼吸道疾患，特别是慢性支气管炎的祛痰治疗，新生儿呼吸窘迫症以及肺部手术的辅助治疗，具有毒性低、疗效确切、并能与抗生素并用产生良好的协同效果等优点，为最常用的祛痰药之一。
目前，原研公司在国内上市的剂型有注射剂、片剂、缓释胶囊和口服溶液。该药品已通过各国审批程序在以下国家授权：奥地利、比利时、保加利亚、克罗地亚、塞浦路斯、捷克共和国、丹麦、爱沙尼亚、法国、德国、希腊、匈牙利、冰岛、爱尔兰、意大利、拉脱维亚、立陶宛、卢森堡、马耳他、挪威、波兰葡萄牙、罗马尼亚、斯洛伐克、斯洛文尼亚、西班牙、瑞典和荷兰。
另外，国内已有注射液、口服溶液、糖浆、颗粒剂、普通片、胶囊、缓释片、缓释胶囊、 口崩片、分散片、咀嚼片等仿制药品上市。
氨溴索因具有非常显著的祛痰作用而深受临床医生欢迎，其注射剂被广泛用于呼吸系统疾病患者的雾化治疗(超适应症)。但实际上，弱酸性的氨溴索注射液经雾化后本身也会刺激气道，导致气道痉挛引起呼吸困难，这种不良作用在COPD患者中较明显。另外，生理盐水配置的注射液，无论是在雾化颗粒直径上，还是辅料上(包括含有的防腐剂)，经雾化吸入后都可能有肺部感染或者诱发加重哮喘的风险。但在2019年韩美按照5.2类新药提交的吸入用盐酸氨溴索溶液的上市申请(JXHS1700033)(“儿童用药”的理由获得优先审评)获得国家药品监督管理局批准，针对的也是儿科患者需要大量使用氨溴索但现有剂型无法满足临床需求的痛点。
在我国，氨溴索口服制剂均为非处方药(OTC)，是呼吸系统用药中的畅销品之一，使用人群较广，尤以婴幼儿和儿童居多，而盐酸氨溴索口服溶液的说明书上也明确列明婴幼儿可以服用。但在国际上，对于婴幼儿使用该类产品，争议颇多。不少机构担忧6岁以下儿童使用氨溴索作为祛痰剂是否合适，并认为此类药品在该患者人群的益处并不大于风险。
氨溴索普通片剂和缓释胶囊需要通过饮水并借助吞咽动作完成服药过程，该剂型对于一些老年人、儿童、吞咽有困难的患者依从性差，在一些特殊条件下的使用受到制约(如缺乏饮用水)或效果差。而注射剂存在安全隐患，且患者顺应性差。口服溶液虽口感佳，但口服溶液存在着服用量较大，不易定量，稳定性差等缺点，且对生产工艺和包装有较高要求，携带不方便给患者的服用、携带和运输等带来诸多不便和不安全因素。
盐酸氨溴索在水中微溶，该药口感苦、麻，而次苦味和麻感持久，不能通过常规地加入增溶剂和矫味剂而得到掩蔽，致使患者的服药顺应性差，尤其不利于儿童给药。专利文献CN102846581A公开了盐酸氨溴索口溶膜，但是实验后发现，该处方制备的盐酸氨溴索口腔速溶膜机械强度较差，稳定性不佳、崩解较缓慢且制备工艺复杂，不利于商业化生产。
因此，急需开发一种稳定性好、口感好、患者顺应性好的盐酸氨溴索药物制剂。
发明内容
为了克服现有技术中盐酸氨溴索口腔速溶膜口感不佳、稳定性不佳和/或患者顺应性差等缺陷，本发明提供了一种盐酸氨溴索口溶膜组合物、其制备方法及应用。本发明提供的盐酸氨溴索口溶膜组合物具有厚度薄、口感良好、性质稳定、机械性质稳定、且无需饮水即可在口腔内即刻溶化、口服吸收速度快的优点，同时其工艺简单、载药量高、药物含量均匀度好， 市场化前景好。
本发明提供了一种氨溴索口溶膜组合物，所述组合物包含活性药物、成膜材料和掩味剂，所述的活性药物含有2-氨基-3,5-二溴-N-(反式-4-羟基环己基)苄胺(又称氨溴索)或其药学上可接受的盐，如式I所示的2-氨基-3,5-二溴-N-(反式-4-羟基环己基)苄胺的盐酸盐(又称盐酸氨溴索)；
根据本发明的实施方案，本发明所述的氨溴索口溶膜组合物可以是盐酸氨溴索口溶膜组合物。
根据本发明的实施方案，本发明所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)优选不含pH调节剂。
根据本发明的实施方案，本发明所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)优选不含游离存在的pH调节剂。所述游离存在的pH调节剂是指未与活性药物形成盐的pH调节剂。
根据本发明的实施方案，所述的pH调节剂包括但不限于本领域已知的用于调节pH值的药学上可接受的酸，如有机酸、无机酸、有机碱和无机碱。上述无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等；上述有机酸包括例如乙酸、丙酸、乙醇酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、枸橼酸(柠檬酸)、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸、甲酸、三氟乙酸等。
根据本发明的实施方案，本发明所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)不含有碱性pH调节剂，例如本领域已知的用于调节pH值的药学上可接受的碱。
根据本发明的实施方案，所述的活性药物的质量百分含量为1.00％～40.00％，优选5.00％～30.00％，例如5.00％、6.00％、7.00％、8.00％、9.00％、9.09％、10.00％、12.45％、15.00％、15.23％、16.48％、19.23％、19.48％、20.00％、21.43％、25.00％或30.00％，其中所述的质量百分含量是指活性药物的质量占所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)总 质量的百分比。
根据本发明的实施方案，所述的掩味剂为掩盖苦味和麻味等不良味道的物质，其可以选自阳离子交换树脂，所述的阳离子树脂选自聚苯乙烯磺酸钠、聚克立林钾和波拉克林树脂中的一种、两种或三种。
优选地，所述的阳离子交换树脂的粒径D90小于200μm。
优选地，所述掩味剂的质量百分含量为10.00％～70.00％，进一步优选15.00％～60.00％，例如10.00％、12.00％、15.00％、19.48％、20.00％、21.43％、24.90％、25.00％、30.00％、30.30％、38.06％、38.46％、40.00％、41.21％、45.00％、45.45％、50.00％、55.00％或60.00％，所述的质量百分含量是指掩味剂的质量占氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)总质量的百分比。
根据本发明的实施方案，所述的成膜材料为药物的载体，选自黄原胶、瓜尔胶、果胶、明胶、虫胶、阿拉伯胶、淀粉、糊精、琼脂、海藻酸钠、玉米朊、羟丙甲纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、聚乙烯醇、普鲁兰多糖、聚乙烯吡咯烷酮、聚乙二醇、聚氧乙烯、丙烯酸共聚物、聚乳酸和硅橡胶中的一种或多种。
优选地，所述的成膜材料的质量百分含量为10.00％～70.00％，优选15.00％～60.00％，例如为10.00％、12.00％、14.29％、15.00％、20.00％、25.00％、27.47％、30.00％、30.30％、30.45％、35.00％、37.34％、38.46％、40.00％、45.00％、50.00％、55.00％、58.44％或60.00％，所述的质量百分含量是指成膜材料的质量占氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)总质量的百分比。
根据本发明的实施方案，本发明所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)可以进一步包括增塑剂、矫味剂、着色剂和填充剂中的一种或多种。作为实例，所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)可以包含或不包含矫味剂。
根据本发明的实施方案，所述的增塑剂是指用于降低膜的玻璃转化温度，增加塑性和韧性，提高拉伸率的物质，其可以选自聚乙二醇、甘油、丙二醇、硅油、聚丙二醇和己二醇中的一种或多种。
优选地，所述的增塑剂的质量百分含量为0～30.00％，优选0～25.00％，例如为1.00％、2.00％、2.60％、3.00％、4.00％、5.00％、6.00％、6.06％、7.00％、8.00％、8.67％、9.00％、10.00％、10.15％、10.99％、15.00％、20.00％、24.90％、25.00％或30.00％，所述的质量百分含量是指增塑剂的质量占氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)总质量的百分比。
根据本发明的实施方案，所述矫味剂是指起矫味作用的物质，其可以选自阿司帕坦、三氯蔗糖、果糖、蔗糖、甜菊苷、纽甜、甘草甜素、香精、香料、糖精和糖精钠中的一种，两种或更多种。
优选地，所述的矫味剂的质量百分含量为0～50.00％，优选0～45.00％，例如为1.00％、1.10％、1.20％、1.30％、1.33％、1.40％、1.50％、1.60％、1.70％、1.80％、1.90％、2.00％、2.10％、2.20％、2.30％、2.40％、2.50％、2.60％、2.70％、2.80％、2.90％、3.00％、3.05％、3.50％、3.85％、4.00％、5.00％、6.00％、7.00％、8.00％、9.00％、9.09％、10.00％、12.00％、15.00％、20.00％、25.00％、30.00％、35.00％、40.00％、42.87％、45.00％或50.00％，所述的质量百分含量是指矫味剂的质量占氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)总质量的百分比。
根据本发明的实施方案，所述的着色剂是指能改善制剂的外观颜色，可用来识别制剂的浓度、区分应用方法和减少病人对服药的厌恶感的物质，选自二氧化钛、色素和色淀中的一种，两种或更多种。
优选地，所述的着色剂的质量百分含量为0～2.00％，例如为0、0.02％、0.10％、0.15％、0.20％、0.25％、0.30％、0.41％、0.50％、0.60％、0.70％、0.80％、0.90％、1.00％、1.10％、1.20％、1.30％、1.40％、1.50％、1.60％、1.65％、1.70％、1.80％、1.90％或2.00％，所述的质量百分含量是指着色剂的质量占氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)总质量的百分比。
根据本发明的实施方案，所述的填充剂是指加入物料中可以改善物料性能，或能增容、增重，降低物料成本的固体物质。其可以选自蔗糖、葡萄糖、麦芽糖、乳糖、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种。
优选地，所述的填充剂的质量百分含量为0-20.00％，例如0％、1.00％、5.00％、10.00％、15.00％或20.00％；所述的质量百分含量是指填充剂的质量占氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)总质量的百分比。
根据本发明的实施方案，以质量百分含量计，所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)选自下列配方1-1至1-5：
配方1-1包含：15-22％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、18-52％聚克立林钾、18-35％成膜材料、8-12％增塑剂、0.3-7％的矫味剂和/或着色剂；
配方1-2包含：15-22％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、18-46％聚克立林钾、18-60％成膜材料、2-22％增塑剂及0-0.05％的矫味剂和/或着色剂；
配方1-3包含：17-21％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、35-40％聚克立 林钾、34-41％成膜材料及2-6％的矫味剂和/或着色剂；
配方1-4包含：9-13％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、22-48％聚苯乙烯磺酸钠、30-40％成膜材料、5-25％增塑剂及0.2-10％的矫味剂和/或着色剂；
配方1-5包含：18-24％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、20-24％聚苯乙烯磺酸钠、13-15％成膜材料及40-45％的矫味剂。
根据本发明的实施方案，所述配方1-1至配方1-5中，所述成膜材料为黄原胶、聚乙烯醇、羟丙甲纤维素、普鲁兰多糖、海藻酸钠中的一种，两种或更多种。
根据本发明的实施方案，配方1-1至配方1-5中，所述增塑剂为甘油。
根据本发明的实施方案，配方1-1至配方1-5中，所述着色剂为色淀。
本发明所述的盐酸氨溴索口溶膜组合物，可以为以下任一配方：
配方2-1：18-22％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、48-52％聚克立林钾、14-32％成膜材料、6-10％增塑剂和1-3％的矫味剂和/或着色剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方2-2：14-18％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、39-43％聚克立林钾、25-29％成膜材料、9-13％增塑剂、1.5-6％的矫味剂和/或着色剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方2-3：13-17％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、36-40％聚克立林钾、28-32％成膜材料、8-12％增塑剂、1-11％的矫味剂和/或着色剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方2-4：17-21％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、17-21％聚克立林钾、58-52％成膜材料和0.5-4％增塑剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方2-5：17-21％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、36-40％聚克立林钾、34-41％成膜材料和2-6％的矫味剂和/或着色剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方2-6：14-18％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、38-42％聚克立林钾、30-34％成膜材料、9-13％增塑剂和0-0.02％的矫味剂和/或着色剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
配方2-7：14-18％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、37-41％聚克立林钾、29-33％成膜材料、8-12％增塑剂、0-6％的矫味剂和/或着色剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
配方2-8：14-18％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、38-42％聚克立林钾、30-34％成膜材料、9-13％增塑剂、0-0.5％的矫味剂和/或着色剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
配方2-9：13-17％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、43-47％聚克立林钾、18-22％成膜材料和18-22％增塑剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方2-10：7-11％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、44-48％聚苯乙烯磺酸钠、26-34％成膜材料、4-8％增塑剂、1-15％的矫味剂和/或着色剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方2-11：10-14％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、21-25％聚苯乙烯磺酸钠、35-39％成膜材料、23-27％增塑剂和0-0.5％的矫味剂和/或着色剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方2-12：20-22％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、20-22％聚苯乙烯磺酸钠、12-16％成膜材料、30-50％的矫味剂和/或着色剂，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
根据本发明的实施方案，配方2-1至配方2-12中，成膜材料为黄原胶、聚乙烯醇、羟丙甲纤维素、普鲁兰多糖、海藻酸钠中的一种，两种或更多种。
根据本发明的实施方案，配方2-1至配方2-12中，所述增塑剂为甘油。
根据本发明的实施方案，配方2-1至配方2-12中，所述着色剂为色淀。
本发明所述的氨溴索口溶膜组合物，可以为以下任一配方：
配方3-1：18-22％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、48-52％聚克立林钾、11-15％黄原胶、4-8％聚乙烯醇、6-10％甘油和1-3％阿司帕坦，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方3-2：14-18％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、39-43％聚克立林钾、25-29％聚乙烯醇、9-13％甘油、0.5-1.5％甜菊苷、0.5-1.5％香精和0.5-3％色淀，所述的百分比 是指各组分的质量占所述组合物总质量的百分比；
配方3-3：13-17％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、36-40％聚克立林钾、28-32％聚乙烯醇、8-12％甘油、1-5％三氯蔗糖、1-5％香精和0-0.05％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方3-4：17-21％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、17-21％聚克立林钾、58-52％羟丙甲纤维素和0.5-4％甘油，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方3-5：17-21％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、36-40％聚克立林钾、23-27％聚乙烯醇、11-14％普鲁兰多糖和2-6％三氯蔗糖，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方3-6：14-18％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、38-42％聚克立林钾、30-34％聚乙烯醇、9-13％甘油和0-0.02％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
配方3-7：14-18％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、37-41％聚克立林钾、29-33％聚乙烯醇、8-12％甘油、1-5％三氯蔗糖和0-0.05％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
配方3-8：14-18％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、38-42％聚克立林钾、30-34％聚乙烯醇、9-13％甘油、0-0.1％纽甜和0-0.05％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
配方3-9：13-17％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、43-47％聚克立林钾、18-22％黄原胶和18-22％甘油，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方3-10：7-11％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、44-48％聚苯乙烯磺酸钠、16-20％海藻酸钠、10-14％聚乙烯醇、4-8％甘油、1-5％三氯蔗糖、1-5％甜菊苷和1-5％香精，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方3-11：10-14％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、21-25％聚苯乙烯磺酸钠、35-39％羟丙甲纤维素、23-27％甘油和0-0.5％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方3-12：20-22％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、20-22％聚苯乙烯磺 酸钠、12-16％黄原胶、12-16％三氯蔗糖、12-16％甜菊苷和12-16％香精，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
本发明所述的盐酸氨溴索口溶膜组合物，可以为以下任一配方：
配方一：20.00％盐酸氨溴索、50.00％聚克立林钾、13.33％黄原胶、6.67％聚乙烯醇、8.67％甘油和1.33％阿司帕坦，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方二：16.48％盐酸氨溴索、41.21％聚克立林钾、27.47％聚乙烯醇、10.99％甘油、1.10％甜菊苷、1.10％香精和1.65％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方三：15.23％盐酸氨溴索、38.06％聚克立林钾、30.45％聚乙烯醇、10.15％甘油、3.05％三氯蔗糖、3.05％香精和0.02％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方四：19.48％盐酸氨溴索、19.48％聚克立林钾、58.44％羟丙甲纤维素和2.60％甘油，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方五：19.23％盐酸氨溴索、38.46％聚克立林钾、25.64％聚乙烯醇、12.82％普鲁兰多糖和3.85％三氯蔗糖，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方六：16.21％盐酸氨溴索、40.53％聚克立林钾、32.43％聚乙烯醇、10.81％甘油和0.02％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
配方七：15.70％盐酸氨溴索、39.26％聚克立林钾、31.41％聚乙烯醇、10.47％甘油、3.14％三氯蔗糖和0.02％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
配方八：16.16％盐酸氨溴索、40.40％聚克立林钾、32.32％聚乙烯醇、10.77％甘油、0.32％纽甜和0.02％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
配方九：15.00％盐酸氨溴索、45.00％聚克立林钾、20.00％黄原胶和20.00％甘油，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方十：9.09％盐酸氨溴索、45.45％聚苯乙烯磺酸钠、18.18％海藻酸钠、12.12％聚乙烯醇、6.06％甘油、3.03％三氯蔗糖、3.03％甜菊苷和3.03％香精，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方十一：12.45％盐酸氨溴索、24.90％聚苯乙烯磺酸钠、37.34％羟丙甲纤维素、24.90％甘油和0.41％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方十二：21.43％盐酸氨溴索、21.43％聚苯乙烯磺酸钠、14.29％黄原胶、14.29％三氯蔗糖、14.29％甜菊苷和14.29％香精，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
配方十三：15.22％盐酸氨溴索、38.06％聚克立林钾、30.45％聚乙烯醇、10.15％甘油、3.05％三氯蔗糖、3.05％香精和0.02％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方十四：16.17％盐酸氨溴索、40.40％聚克立林钾、32.32％聚乙烯醇、10.77％甘油、0.32％纽甜和0.02％色淀，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方十五：9.10％盐酸氨溴索、45.45％聚苯乙烯磺酸钠、18.18％海藻酸钠、12.12％聚乙烯醇、6.06％甘油、3.03％三氯蔗糖、3.03％甜菊苷和3.03％香精，所述的百分比是指各组分的质量占所述组合物总质量的百分比；
配方十六：21.43％盐酸氨溴索、21.43％聚苯乙烯磺酸钠、14.29％黄原胶、14.29％三氯蔗糖、14.29％甜菊苷和14.27％香精，所述的百分比是指各组分的质量占所述组合物总质量的百分比。
根据本发明的实施方案，所述氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)中各组分的质量百分比含量为100％。但应当理解，由于数值的舍入可能存在±0.2％的舍入误差。
本发明还提供了所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)的制备方法，其包括以下步骤：
步骤1：制备活性药物的水溶液；
步骤2：向步骤1得到的水溶液中加入掩味剂，搅拌，得到样品；
步骤3：将步骤2得到的样品离心，弃去部分上清液，使剩余下层物料质量为活性药物的10-15倍，得到载药树脂；
步骤4：将成膜材料溶于水后与矫味剂、增塑剂、着色剂和填充剂中的一种或多种(如果存在)混合，搅拌均匀，得到胶液；
步骤5：将步骤3得到的载药树脂转移至步骤4得到的胶液中充分搅拌，得到均一的胶液，搅拌结束后将胶液真空除去气泡、涂布、干燥、裁切得到所述的盐酸氨溴索口溶膜制剂。
根据本发明的实施方案，步骤1中，所述的活性药物溶液优选在避光条件下制备。
根据本发明的实施方案，步骤1中所述的水优选纯化水。
根据本发明的实施方案，步骤2中，所述的搅拌优选避光搅拌。
根据本发明的实施方案，步骤2中所述的搅拌的时间优选8小时以上。
根据本发明的实施方案，步骤3中，所述的离心优选在离心机中进行；所述的离心机可以为台式离心机，所述的离心机可以为低速离心机。
根据本发明的实施方案，所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)中，膜剂的厚度为10μm～300μm，例如20μm～100μm。
根据本发明的实施方案，所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)在900ml 37±1℃的模拟唾液中120s内能够完全崩解，例如在80s内完全崩解。
本发明还提供了所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)在制备治疗和/或预防氨溴索或其药学上可接受的盐所针对的适应症，例如过敏的药物中的应用。
根据本发明的实施方案，所述药物为祛痰药或黏液溶解剂。
根据本发明的实施方案，所述药物用于伴有呼吸道异常分泌的急性或慢性呼吸道疾患，特别是慢性支气管炎的祛痰治疗，新生儿呼吸窘迫症以及肺部手术的辅助治疗。
本发明还提供一种预防和/或治疗疾病或病症的方法，包括向有需要的患者(例如人或其他哺乳动物)给予所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)。
根据本发明的实施方案，所述疾病或病症选自过敏、多痰、伴有呼吸道异常分泌的急性或慢性呼吸道疾患，特别是慢性支气管炎、新生儿呼吸窘迫症以及肺部手术后的症状。
本发明的氨溴索口溶膜组合物，特别是盐酸氨溴索口溶膜组合物具有良好的溶出速率，在口腔中快速崩解，溶解后不会有沙砾感、且能改善药物的味道，增加患者的顺应性。并且，本发明的氨溴索口溶膜组合物，特别是盐酸氨溴索口溶膜组合物的薄膜外观均一、柔韧性好。在膜液配制过程中不会发生沉降，含量均一性符合要求。
本发明所用试剂和原料均市售可得。
有益效果
本发明提供的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)具有厚度薄、口感良好、稳定性得到进一步改进，且无需饮水在口腔内即可溶化、口服吸收速度快的优点，市场化前景好。
并且，本发明氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)的原料易得、工艺简单、操作简便、载药量高、药物含量均匀度好，适合于工业化生产。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1-12
如下表1中实施例1-12中各组分的百分含量，为依据各组分的质量计算的所述组分在干燥后(不含水)的处方中的质量百分含量：
表1


“*”表示所述物质在工艺过程中去除；“/”表示不含有。
以上各实施例配方的制备方法包括：
1)称量配料
按处方量称取原辅料备用。
2)树脂载药
A：在避光条件下将活性药物加入一定量的纯化水中完全溶解。
B：向以上溶液中加入掩味剂，继续避光搅拌8小时以上。
C：将以上样品在低速台式大容量离心机中离心，离心后弃去部分上清液，使剩余下层物料质量为活性药物的10-15倍。
3)胶液配制
D：另将成膜材料溶解在一定量纯化水中，加入矫味剂、增塑剂和着色剂(如果有)，搅拌均匀。
E：将步骤2)中下层物料转移至步骤3)制备的溶液中充分搅拌，得到均一的胶液，搅拌结束后将胶液在真空环境中除去气泡。
4)涂布干燥和裁切
G：将以上胶液，在涂布机进行涂布，干燥后裁切成合适大小得到盐酸氨溴索口溶膜制剂。
对比例1-3
按照CN 102846581A中公布的实施例3-5的方式制备对比例1-3：
表2
“*”表示物质在工艺过程中去除。
性能测试
将以上对比例1-3与按照实施例3-8制备的盐酸氨溴索口溶膜分别进行机械强度、崩解时限和有关物质考察。
测试例1
溶膜机械强度测试方法
使用质构仪对盐酸氨溴索口溶膜进行测试，并计算其抗拉强度、百分伸长率和耐折度，结果如下表3所示(每个实施例取6个样品测试)：
表3


注：上表中“横截面积”为口溶膜的表面积。
最大力(gf)为口溶膜在屈服阶段之后所能抵抗的最大力。
抗拉强度(MPa)＝最大力(gf)÷102÷横截面积(mm2)，百分伸长率＝最大力距离(mm)÷样品高度(mm)×100％。
平均抗拉强度为6组数据的平均值。
最大力距离为最大力下口溶膜伸长的距离。
平均百分伸长率为6组数据的平均值。
耐折度为口溶膜对折180°的承受力。
以上结果表明，按照实施例3-8制备的盐酸氨溴索口溶膜抗拉强度和耐折度高于对比例1-3，更适合于商业化生产、运输、贮存和患者服用。
测试例2
分别取实施例1-12和对比例1-3制备的口溶膜各6片，测定口溶膜崩解时限。测试方法如下：在1000ml烧杯中加入900ml pH6.8磷酸盐缓冲介质(配制方法参考中国药典2020年版8004缓冲液项下)，并加热至37±0.5℃。将6片口溶膜同时置于崩解仪的烧杯中，记录各实施例及对比例6片口溶膜全部崩解的时间。汇总在如下表4中。
表4
结果表明，按实施例1-12制备的盐酸氨溴索口溶膜可在120s内完全崩解。
测试例3
口溶膜有关物质测试
按照对比例1-3中盐酸氨溴索与枸橼酸的质量比设计原辅料相容性实验，在高温60℃条件下放置30天，检测原辅料相容性、对比例1-3和实施例3-8的有关物质水平。
有关物质检测方法按照高效液相色谱法(《中国药典》2020版四部通则0512)测定。
溶剂甲醇
供试品溶液取本品(如上实施例或对比例制备的样品)二片(7.5mg规格)或一片(15mg规格)，置20mL量瓶中，加甲醇适量，超声15分钟，使盐酸氨溴索溶解，放冷，用甲醇制成每1mL约含盐酸氨溴索0.75mg的溶液，取上清液作为供试品溶液。
对照溶液精密量取供试品溶液适量，用甲醇稀释制成每lmL中约含1.5μg的溶液。
色谱条件用辛烷基硅烷键合硅胶为填充剂(Agient ZORBAX SB-C8 4.6mm*150mm， 3.5μm；以10mmol/L磷酸氢二铵溶液(用磷酸调节pH至7.0)-乙腈(50∶50)为流动相；检测波长为248nm；流速为每分钟0.8mL；柱温为30℃；进样盘温度为4℃，进样体积为10μL，运行时间为30分钟。
系统适用性要求供试品溶液色谱图中，主峰与相邻色谱峰之间的分离度应符合要求。
测定法精密量取供试品溶液与对照溶液，分别注入液相色谱仪，记录色谱图至30分钟。
表5杂质校正因子及限度
表6有关物质检测结果

注：*代表参考指导原则中的比例进行，无其他辅料。
结果表明，本发明实施例3-6制备的口溶膜稳定性良好，而对比例1-3中未知杂质含量较高。本申请的口溶膜稳定性优于对比例1-3。
测试例4
口溶膜溶出曲线测试
将实施例1、3、6-8制备的盐酸氨溴索口溶膜按照《中国药典》2020版四部0931溶出度与释放度测定法第四法(桨碟法)，使用方法1搅拌桨、溶出杯按第二法，将盐酸氨溴索口溶膜放置在不锈钢网碟中进行溶出曲线检测，测试条件如下：
试验装置：天大天发溶出仪。
试验介质：pH1.2盐酸溶液、pH4.5醋酸盐缓冲液和pH6.8磷酸盐缓冲液。
实验条件：介质体积为900ml，温度为37±0.5℃；搅拌转速为50rpm，取样时间为5min、10min、15min、30min。
两批次盐酸氨溴索口溶膜溶出结果及溶出曲线试验结果如下表所示：
表7

结果表明，本发明的盐酸氨溴索口溶膜在pH1.2盐酸溶液和pH6.8磷酸盐缓冲液中15min时累计溶出度均在85％以上；在pH4.5醋酸盐缓冲液中，实施例3、6-8批次制剂15min累计溶出度在85％以上，实施例1批次制剂30min时的累计溶出度均在85％以上。
测试例4
口溶膜适口性评价
按照实施例3制备批次盐酸氨溴索口溶膜，参考《儿童用药口感设计与评价的技术指导原则(公开征求意见稿)》和文献《李潘等.志愿者感官试验在药物味觉评价的运用及发展研究[J].中国药学杂志,2017,52(22):1971-1975》，综合采用苦度值等级评价法和多因素调查评价法随机选择6名志愿者对该批次盐酸氨溴索口溶膜进行适口性评价。
根据口溶膜的质量属性，分别从外观、苦味、甜味、麻味、口腔异物感等方面进行适口性评价，其中以苦味、麻味和口腔异物感为主要评分项，外观和甜味为加分项。制定等级及评分规则如下：
表8口溶膜适口性评价表

结果表明，6名志愿者最终适口性评分均在24-30范围内，本发明制备的盐酸氨溴索口溶膜口感良好，接受度良好。
根据上述实验数据可见，本发明提供的盐酸氨溴索口溶膜，具有厚度薄、口感良好、性质稳定、且无需饮水即可在口腔内即刻溶化、口服吸收速度快的优点。
以上对本发明技术方案的实施方式进行了示例性的说明。应当理解，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。

Claims (10)

  1. 一种氨溴索口溶膜组合物，其特征在于：所述组合物包含活性药物、成膜材料和掩味剂，所述的活性药物含有2-氨基-3,5-二溴-N-(反式-4-羟基环己基)苄胺或其药学上可接受的盐，例如下式I所示的2-氨基-3,5-二溴-N-(反式-4-羟基环己基)苄胺的盐酸盐：
    优选地，所述的氨溴索口溶膜组合物是盐酸氨溴索口溶膜组合物；
    优选地，所述的氨溴索口溶膜组合物(如盐酸氨溴索口溶膜组合物)不含pH调节剂；例如，所述的pH调节剂包括但不限于用于调节pH值的药学上可接受的酸。
  2. 如权利要求1所述的组合物，其特征在于：
    所述的活性药物的质量百分含量为1.00％～40.00％，优选5.00％～30.00％，所述的质量百分含量是指活性药物的质量占所述组合物总质量的百分比。
  3. 如权利要求1或2所述的组合物，其特征在于：所述的掩味剂为阳离子交换树脂；所述的阳离子交换树脂优选选自聚苯乙烯磺酸钠、聚克立林钾和波拉克林树脂中的一种、两种或三种；优选地，所述的阳离子交换树脂粒径D90小于200μm；
    和/或，
    所述的掩味剂的质量百分含量为10.00％～70.00％，优选15.00％～60.00％，所述的质量百分含量是指掩味剂的质量占所述组合物总质量的百分比。
  4. 如权利要求1-3任一项所述的组合物，其特征在于：所述的成膜材料选自黄原胶、瓜尔胶、果胶、明胶、虫胶、阿拉伯胶、淀粉、糊精、琼脂、海藻酸钠、玉米朊、羟丙甲纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、聚乙烯醇、普鲁兰多糖、聚乙烯吡咯烷酮、海藻酸钠、聚乙二醇、聚氧乙烯、丙烯酸共聚物、聚乳酸和硅橡胶中的一种或多种；
    和/或，
    所述的成膜材料的质量百分含量为10.00％～70.00％，优选15.00％～60.00％，所述的质量百分含量是指成膜材料的质量占所述组合物总质量的百分比。
  5. 如权利要求1-4任一项所述的组合物，其特征在于：所述的组合物进一步包括增塑剂、矫味剂、着色剂和填充剂中的一种或多种。
  6. 如权利要求5所述的组合物，其特征在于：
    所述的增塑剂选自聚乙二醇、甘油、丙二醇、硅油、聚丙二醇和己二醇中的一种或多种；
    和/或，
    所述的矫味剂选自阿司帕坦、三氯蔗糖、果糖、蔗糖、甜菊苷、纽甜、甘草甜素、香精、香料、糖精和糖精钠中的一种或多种；
    和/或，
    所述的着色剂选自二氧化钛、色素和色淀中的一种或多种；
    和/或，
    所述的填充剂选自蔗糖、葡萄糖、麦芽糖、乳糖、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种。
  7. 如权利要求6所述的组合物，其特征在于：
    所述的增塑剂的质量百分含量为0～30.00％，优选0～25.00％，所述的质量百分含量是指增塑剂的质量占所述组合物总质量的百分比；
    和/或，
    所述的矫味剂的质量百分含量为0～50.00％，优选0～45.00％，所述的质量百分含量是指矫味剂的质量占所述组合物总质量的百分比；
    和/或，
    所述的着色剂的质量百分含量为0～2.00％，所述的质量百分含量是指着色剂的质量占所述组合物总质量的百分比；
    和/或，
    所述的填充剂的质量百分含量为0～20.00％，所述的质量百分含量是指填充剂的质量占 所述组合物总质量的百分比。
  8. 如权利要求1-7任一项所述的组合物，其特征在于：所述的组合物选自以下任一配方：
    配方1-1包含：15-22％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、18-52％聚克立林钾、18-35％成膜材料、8-12％增塑剂、0.3-7％的矫味剂和/或着色剂；
    配方1-2包含：15-22％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、18-46％聚克立林钾、18-60％成膜材料、2-22％增塑剂及0-0.05％的矫味剂和/或着色剂；
    配方1-3包含：17-21％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、35-40％聚克立林钾、34-41％成膜材料及2-6％的矫味剂和/或着色剂；
    配方1-4包含：9-13％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、22-48％聚苯乙烯磺酸钠、30-40％成膜材料、5-25％增塑剂及0.2-10％的矫味剂和/或着色剂；
    配方1-5包含：18-24％氨溴索或其药学上可接受的盐(如盐酸氨溴索)、20-24％聚苯乙烯磺酸钠、13-15％成膜材料及40-45％的矫味剂。
  9. 如权利要求1-8任一项所述的组合物，其特征在于，所述组合物的厚度为10μm-300μm；
    和/或，
    所述组合物在900ml 37±0.5℃的模拟唾液中120s内完全崩解。
  10. 权利要求1-9任一项所述的组合物在制备治疗和/或预防过敏的药物中的应用；
    优选地，所述药物为祛痰药或黏液溶解剂；
    优选地，所述药物用于伴有呼吸道异常分泌的急性或慢性呼吸道疾患，特别是慢性支气管炎的祛痰治疗，新生儿呼吸窘迫症以及肺部手术的辅助治疗。
PCT/CN2023/131591 2022-11-14 2023-11-14 氨溴索口溶膜组合物、其制备方法及应用 WO2024104349A1 (zh)

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