WO2022073459A1 - 吸入制剂及其制备方法和应用 - Google Patents

吸入制剂及其制备方法和应用 Download PDF

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WO2022073459A1
WO2022073459A1 PCT/CN2021/122210 CN2021122210W WO2022073459A1 WO 2022073459 A1 WO2022073459 A1 WO 2022073459A1 CN 2021122210 W CN2021122210 W CN 2021122210W WO 2022073459 A1 WO2022073459 A1 WO 2022073459A1
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potassium
inhalation
preparation
mmol
inhalation preparation
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PCT/CN2021/122210
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English (en)
French (fr)
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刘志
刘欣
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刘志
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Priority to JP2023521825A priority Critical patent/JP2023544638A/ja
Priority to US18/248,056 priority patent/US20230372389A1/en
Publication of WO2022073459A1 publication Critical patent/WO2022073459A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to an inhalation preparation and its preparation method and application.
  • the content of potassium in the human body (the atomic number of potassium is 19, the relative atomic weight is 39.1) is second only to calcium and phosphorus, and it is twice as high as that of sodium (relative atomic weight 23). i.e. 3.6 to 3.8 mol).
  • About 98% of the potassium ions in the human body exist in the intracellular fluid, which is the main cation in the intracellular fluid.
  • the sodium ion mainly exists outside the cell, and its concentration outside the cell is about 10 times higher than that in the cell. Plasma sodium concentration is much higher than potassium concentration (serum potassium concentration ranges from 3.5 to 5 mmol/L, while serum sodium is 140 mmol/L), but muscle tissue and milk potassium concentration is several times higher than sodium.
  • the high concentration of sodium ions outside the cell is also a way of storing energy. It is the same as the hydrogen ions outside the cell membrane, like the water stored in a reservoir, and the high water level has potential energy.
  • sodium ions also regulate blood volume and blood pressure, so it is needed by the human body, which is why people need to add sodium chloride to their daily diet. But the most important role of extracellular sodium ions in animals is to generate nerve impulses.
  • Potassium plays an important role in maintaining the normal function of the heart and plays an important role in the metabolism of cells; potassium contributes to the normal operation of nerve conduction function, and it works together with sodium to regulate the pH of fluids in the body; potassium deficiency or excess potassium in the human body can Affect health.
  • potassium ions are supplemented by oral or intravenous administration, and potassium ions enter the circulatory system to increase the concentration of potassium ions in body fluids as one of the means to lower blood pressure.
  • the basis of this therapy is that potassium ions enter the circulatory system to increase the potassium ion concentration of body fluids.
  • potassium supplementation is a treatment method of total control, divided supply, and observation while treatment.
  • potassium supplements orally with a single dose of 3-7.5g, generally no more than 15g per day (calculated by potassium chloride, molecular weight 74.55, about 200mmoml).
  • concentration of the oral solution is 1.268% (weight percent as potassium chloride), but the total amount of potassium chloride required is the same for oral solids and liquids.
  • the potassium content in each liter of infusion should not exceed 40 mmol (equivalent to 3 g of potassium chloride). -1.5g/h) or less.
  • the total amount of intravenous potassium supplementation should not be too much, and potassium supplementation should be based on the level of serum potassium, a single potassium supplementation of 4.5 to 6g, generally not more than 15g per day (calculated as potassium chloride).
  • both oral and intravenous potassium supplements have safety and efficacy concerns.
  • intravenous infusion of potassium supplementation it is usually due to the high concentration of the drug solution, the fast infusion speed, and the thinness of the human vein, which will stimulate the intima of the vein and cause pain.
  • potassium supplementation is administered intravenously, due to the rapid infusion rate and the damage to the patient's renal function, special attention should be paid to whether the patient has hyperkalemia. Once this symptom occurs, it should be dealt with in time.
  • Oral potassium chloride can irritate the stomach. It causes stomach pain, so it is generally necessary to take it after meals. Potassium that is absorbed orally or entered into the body intravenously is also excreted through the kidneys to maintain relative balance in the body.
  • saline or seawater is used to cleanse nasal or respiratory mucosa. But whether it is normal saline or water from natural sources, the concentration of sodium salts is much higher than that of potassium salts. Almost all liquid water on Earth contains significantly more sodium than potassium. Whether it is river, lake or sea water, sodium is much more than potassium. For example, the concentration of sodium in seawater is 47 times that of potassium (sodium 470mmol/L (mM), potassium 10mM), and the salt content of river water varies with rivers, but generally the concentration of sodium is 10 times that of potassium (sodium is about 0.4mM, Potassium approximately 0.04 mM).
  • the present invention provides an inhalation preparation and its preparation method and application.
  • the inhalation preparation can be administered through the oral cavity or the respiratory tract, and can effectively supplement potassium in the oral cavity or respiratory tract mucosa at a low dose, and at the same time can change the local sodium-potassium balance of the oral cavity or respiratory tract mucosa, bringing about beneficial physiological effects.
  • the present invention provides an inhalation formulation comprising two forms:
  • a liquid inhalation formulation comprising potassium salt and water, and the molar concentration of potassium is 0.001 to 27,410 mmol/L; or
  • a dry powder inhalation preparation which includes a potassium salt and a pharmaceutical carrier, the content of the potassium salt is 0.01% to 100%, and the percentage is the mass percentage of the potassium salt in the dry powder inhalation preparation.
  • the potassium salt can be the potassium salt conventionally used in the field, preferably including potassium chloride, potassium acetate, potassium gluconate, potassium aspartate, potassium amino acid compound, potassium carbonate, hydrogen carbonate Potassium, potassium citrate, potassium dihydrogen citrate, potassium hydrogen citrate, potassium tartrate, potassium hydrogen tartrate, potassium hydrogen tartrate, potassium hydroxide, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, potassium sulfate, One or more of potassium hydrogen sulfate, potassium nitrate, potassium alginate and potassium sorbate; more preferably potassium chloride, potassium acetate, potassium carbonate, potassium hydrogen carbonate, potassium tartrate, potassium hydrogen tartrate, tartrate Potassium Hydrogenate, Potassium Citrate or Potassium Hydrogen Citrate.
  • the molar concentration of potassium in the liquid inhalation preparation may be 0.001-10,000 mmol/L, preferably 0.001-4,700 mmol/L, preferably 3-3,500 mmol/L, more preferably 10-2,000 mmol/L mmol/L, more preferably 20-1,500 mmol/L, still more preferably 50-1,000 mmol/L, even more preferably 75-700 mmol/L.
  • the molar concentration of potassium in the liquid inhalation formulation is, for example, 25.5 mmol/L, 154 mmol/L, 537 mmol/L or 1,221 mmol/L.
  • the molar concentration of potassium in the liquid inhalation preparation is preferably 0.001-2,500 mmol/L, preferably 0.001-1,500 mmol/L, more preferably 3-1,000 mmol/L, still more preferably 20-400 mmol/L, even more preferably 50-200 mmol/L.
  • the potassium salt is potassium chloride
  • the molar concentration of the potassium chloride can be 0.001 to 4,700 mmol/L, such as 25.5 mmol/L, 154 mmol/L, 537 mmol/L L or 1,221 mmol/L.
  • the potassium salt in the liquid inhalation preparation, is potassium acetate, and the molar concentration of the potassium acetate may be 0.001-27,410 mmol/L, for example, 10,000 mmol/L.
  • the pH of the liquid inhalation formulation may be 3.0-9.0, preferably 4.0-8.0, more preferably 5.0-7.0, and still more preferably 5.5-6.5.
  • the liquid inhalation formulation may further comprise pharmaceutically acceptable additives conventional in the art.
  • the additives preferably include one or more of diluents, acidity regulators, isotonicity regulators and preservatives.
  • the diluent can be a conventional diluent in the field, preferably selected from ethanol, isopropanol, propylene glycol, glycerol, mannitol, lactose, gelatin, starch, pregelatinized starch, dextrin, cyclodextrin , sucrose, taurine, amino acids, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, magnesium oxide, calcium carbonate, hydroxypropyl methylcellulose, povidone, starch syrup, syrup, sodium carboxymethyl starch and One or more of the crospovidones.
  • the acidity regulator also known as pH control agent, can be a conventional pharmaceutical additive used in the field to adjust or maintain pH value.
  • the acidity regulator can be acid, alkali, neutralizing agent or buffer, preferably selected from meglumine, boric acid, anhydrous sodium acetate, sodium acetate trihydrate, crystalline sodium acetate, tromethamine, acetic acid, Amino acid, hydrochloric acid, phosphoric acid, ammonium chloride, sodium citrate, dilute ammonia solution, calcium acetate, anhydrous disodium hydrogen phosphate, anhydrous sodium carbonate, potassium hydrogen carbonate, ammonium acetate, acetic acid, tartaric acid, methanesulfonic acid and succinic acid one or more of the acids.
  • the content of the acidity regulator may be 0.05%-20%, and the percentage is by weight.
  • the isotonicity regulator can be a conventional non-sodium salt osmotic pressure regulator in the art, preferably selected from one or more of glucose, sucrose, glycerol and xylitol.
  • the content of the isotonicity modifier may be 0.01%-20%, and the percentage is by weight.
  • the preservatives can be conventional pharmaceutical preservatives in the field, preferably phenol substitutes (such as biphenol, cresol or xylenol), cationic surfactants, halogens, oxidants (such as hydrogen peroxide) or permanganate), aniline dyes, acridine dyes, heavy metal salts, alcohols or aldehydes.
  • the preservative may also be a food preservative, such as benzoic acid, sodium benzoate, sorbic acid, potassium sorbate or calcium propionate.
  • the content of the preservative can be 0.01%-20%, and the percentage is by weight.
  • the liquid inhalation preparation is preferably an aqueous potassium chloride solution, an aqueous potassium acetate solution, an aqueous potassium carbonate solution, an aqueous solution of potassium bicarbonate, an aqueous solution of potassium tartrate, an aqueous solution of potassium hydrogen tartrate, an aqueous solution of potassium citrate or an aqueous solution of potassium hydrogen citrate .
  • the content of the potassium salt in the dry powder inhalation preparation is preferably 1%-90%, more preferably 1%-50%, more preferably 1%-20%.
  • the pharmaceutical carrier of the dry powder inhalation preparation can be selected from mannitol, lactose, gelatin, starch, amino acid, pregelatinized starch, dextrin, cyclodextrin, sucrose, microcrystalline cellulose, calcium sulfate, hydrogen phosphate
  • mannitol lactose
  • gelatin starch
  • amino acid pregelatinized starch
  • dextrin dextrin
  • cyclodextrin sucrose
  • microcrystalline cellulose calcium sulfate
  • hydrogen phosphate One or more of calcium, magnesium oxide, calcium carbonate, hydroxypropyl methylcellulose (HPMC), povidone (PVP), starch syrup, syrup, sodium carboxymethyl starch, and crospovidone.
  • HPMC hydroxypropyl methylcellulose
  • PVP povidone
  • starch syrup syrup
  • sodium carboxymethyl starch sodium carboxymethyl starch
  • crospovidone crospovidone
  • the dry powder inhaler preferably includes potassium chloride and lactose.
  • the content of the potassium chloride is preferably 2% to 10%, more preferably 2% to 6%; for example, 2.2%, 5.7% or 9.3%, and the percentage is that the potassium chloride accounts for The mass percentage of the dry powder inhalation formulation.
  • the dry powder inhalation preparation when the content of the potassium salt in the dry powder inhalation preparation is 100%, the dry powder inhalation preparation is pure potassium salt, such as pure potassium chloride.
  • the average particle size of the dry powder inhalation preparation may be 0.05-1,000 ⁇ m, preferably 0.1-500 ⁇ m, more preferably 0.2-250 ⁇ m, such as 74 ⁇ m; or 0.2-5 ⁇ m, preferably 0.5- 2 ⁇ m, such as 1 ⁇ m or 4 ⁇ m; or 5-10 ⁇ m, such as 7 ⁇ m; or 10-20 ⁇ m, such as 15 ⁇ m.
  • Particles with an average particle size of 10-20 ⁇ m can be deposited on the nasal mucosa, particles with an average particle size of 5-10 ⁇ m can enter the upper respiratory tract, and particles with an average particle size of less than 2 ⁇ m can directly enter the lungs through the mucosa.
  • the present invention also provides a method for preparing the inhalation formulation, which comprises mixing the components uniformly.
  • the preparation method includes mixing the components uniformly to form a solution.
  • the preparation method includes mixing the components uniformly to form a solid mixture with a specific particle size or potassium salt particles with a specific particle size.
  • a preferred preparation method of the dry powder inhalation preparation includes: first dissolving potassium salt in water, then mixing the obtained potassium salt aqueous solution with a drug carrier, and drying to powder.
  • the preparation method of the dry powder inhalation preparation comprises: first dissolving potassium chloride in water, then adding the obtained potassium chloride aqueous solution to lactose by spraying, drying and preparing pink.
  • the present invention also provides a method of administration comprising applying the inhalation formulation to the oral cavity or respiratory tract.
  • the respiratory tract includes the nasal cavity, pharynx, larynx, trachea, bronchi, and branches of the bronchi at all levels within the lungs.
  • the section of the airway from the nose to the throat is called the upper airway.
  • This section of the trachea, bronchi, and bronchial branches of the lungs is the lower respiratory tract.
  • the application mode of the liquid inhalation formulation may include spraying, dripping or washing; preferably spraying.
  • the spraying can be carried out by a conventional spraying device in the art, such as a push-type manual spraying device, an electric spraying device, a pneumatic spraying device, a mechanical spraying device or an ultrasonic atomizer.
  • the spray device may be metered or non-metered.
  • Nebulizers disperse liquid inhalation formulations into fine mist droplets that are sprayed in an aerosol form to suspend them in a gas.
  • the average particle size of the aerosol may be 0.05-1,000 ⁇ m, preferably 0.1-500 ⁇ m, more preferably 0.2-250 ⁇ m, such as 74 ⁇ m; or 0.2-4 ⁇ m, such as 1 ⁇ m; or 5-10 ⁇ m, such as 7 ⁇ m; Or 10 to 20 ⁇ m, such as 15 ⁇ m. Aerosols with an average particle size of 10-20 ⁇ m can be deposited on the nasal mucosa, aerosols with an average particle size of 5-10 ⁇ m can enter the upper respiratory tract, and aerosols with an average particle size of less than 2 ⁇ m can directly enter the lungs through the mucosa.
  • the single dose of the liquid inhalation preparation may be 0.01-0.5 mmol.
  • the single dose of the liquid inhalation preparation is preferably 0.74-37.3 mg, or 0.74-140 mg, calculated as potassium chloride.
  • the application mode of the dry powder inhalation formulation may be direct inhalation or a dry powder inhalation device.
  • the dry powder inhalation device may be conventional in the art, preferably a metered dose pressure inhalation device or a dry powder atomization inhalation device.
  • the single dose of the dry powder inhalation preparation is preferably 0.01-0.5 mmol.
  • the potassium salt is potassium chloride
  • the single dose of the dry powder inhalation preparation is preferably 0.74-37.3 mg, or 0.74-140 mg.
  • potassium salts Due to the high safe dose of potassium salts, continuous liquid atomization or dry powder spraying can also be used in the environment, and the human body continuously obtains potassium ions supplementation by breathing.
  • the upper limit should not exceed oral or intravenous potassium supplementation, with a single dose of ⁇ 3 g and no more than 15 g per day (as potassium chloride). Multiple doses may be used.
  • the present invention also provides the application of the inhalation preparation in preparing a medicine for treating hypertension.
  • the invention also provides the application of the inhalation preparation in the preparation of sedative drugs.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the present invention is administered through the oral cavity or respiratory tract by means of inhalation, and provides a low dose of potassium ions.
  • the potassium ions can enter the blood system through the mucosa, and the dose and blood drug concentration are far less than other existing routes of administration (oral or intravenous injection) Under the circumstance, increase the local potassium ion concentration of the oral or respiratory mucosa, especially increase the local potassium ion/sodium ion ratio of the oral or respiratory mucosa, thereby reducing the resistance of the cell membrane to transmit potassium ions, reducing energy consumption, and effectively replenishing potassium effect.
  • the unexpected point of the present invention is to use a small amount of potassium ions to act on the oral cavity or respiratory tract mucosa, change the local sodium-potassium balance of the mucosa, activate the specific cells of the mucosal layer, and thus have unexpected beneficial physiological effects (such as lowering blood pressure and sedative effect, etc.).
  • FIG. 1 is a blood pressure record of a subject in Effect Example 5.
  • FIG. 1 is a blood pressure record of a subject in Effect Example 5.
  • FIG. 2 shows the blood pressure records of the subjects in Effect Example 6.
  • FIG. 3 is a blood pressure record of a subject in Effect Example 7.
  • FIG. 3 is a blood pressure record of a subject in Effect Example 7.
  • FIG. 4 is a blood pressure record of a subject in Effect Example 8.
  • FIG. 4 is a blood pressure record of a subject in Effect Example 8.
  • KCl molecular weight is 74.55
  • 200mL purified water molar concentration is 154mmol/L, or 1.15% w/v
  • KCl 8g was dissolved in 200mL of purified water (molar concentration was 537mmol/L, or 4.0% w/v) to form a clear solution, i.e., a liquid inhalation preparation; then it was dispensed into a 50mL pump-type manual nebulizer.
  • KCl 2.3 g was dissolved in 200 mL of purified water (molar concentration was 154 mmol/L, or 1.15% w/v) to form a clear solution, i.e., a liquid inhalation preparation; then it was placed in a commercially available ultrasonic nebulizer.
  • the ultrasonic nebulizer When it needs to be used, turn on the ultrasonic nebulizer near the nasal cavity and oral cavity, which can continuously generate droplets with a particle size of less than 100 ⁇ m, and the generated droplets are inhaled into the respiratory tract.
  • the ultrasonic nebulizer can nebulize 6 mL of liquid every 30 minutes, which is equivalent to 69 mg KCl (0.9 mmol). About 23 mg of KCl (0.30 mmol KCl) were inhaled for about 10 minutes per inhalation. The inhaler does not experience any discomfort.
  • KCl molecular weight 74.55
  • 200mL purified water molar concentration is 25.5mmol/L, or 0.19% w/v
  • KCl 18.2 g was dissolved in 200 mL of purified water (1,221 mmol/L, or 9.1% w/v molar concentration) to form a clear solution, a liquid inhalation formulation; then dispensed into a 50 mL pump-type manual nebulizer.
  • 70g KCl is dissolved in 200mL purified water (molar concentration is about 4700mmol/L, or 35% w/v) to form a clear solution, i.e. liquid inhalation preparation;
  • the above solution is added to a commercially available ultrasonic atomizer to form a potassium ion-rich mist.
  • the ultrasonic nebulizer can nebulize 6 mL of liquid every 30 minutes, which is equivalent to 2.1 g of KCl (28 mmol).
  • About 140 mg of KCl (1.88 mmol KCl) was inhaled for about 2 minutes per inhalation.
  • the inhaler does not experience any discomfort. When inhaled through the nose or mouth, there is basically no discomfort caused by the high concentration of electrolytes (high osmotic pressure) in the solution in the droplets.
  • KCl molecular weight is 74.55
  • purified water molar concentration is 154mmol/L, or 1.15%w/v
  • the nozzle of the push-type spray plastic bottle is aimed at the left and right nostrils, respectively, and press the spray when taking a deep breath.
  • the amount of each inhalation is about 0.2mL of liquid, containing 2.3mg KCl (0.03mmol KCl).
  • both nostrils are used, about 4.6 mg of KCl (0.06 mmol KCl) will be inhaled in a single dose.
  • 100g potassium acetate (molecular weight is 98.14) is dissolved in 100mL purified water (molar concentration is about 10000mmol/L) to form a clear solution, that is, a liquid inhalation preparation;
  • the nozzle of the push-type spray plastic bottle is aimed at the left and right nostrils, respectively, and press the spray when taking a deep breath.
  • the amount of each inhalation is about 0.2mL liquid, containing 200mg KCl (2.04mmol KCl).
  • about 400mg KCl (4.08mmol KCl) will be inhaled in a single dose. Due to the high salt concentration and osmotic pressure of the solution, the user experiences a slight dizziness, which basically disappears after a period of time.
  • 269g potassium acetate (molecular weight is 98.14) is dissolved in 100mL purified water (molar concentration is 27410mmol/L) to form a clear solution, that is, a liquid inhalation preparation; and then packaged in a 50mL press-type atomizing plastic bottle or an ultrasonic atomizer. This solution forms a good aerosol.
  • the following effect examples are real examples of using the inhalation formulation of the present invention.
  • the subjects were all patients with hypertension for many years, aged between 40 and 70 years old, who had been taking antihypertensive drugs for a long time but their blood pressure control was not ideal.
  • nasal sprays of the present invention or inhalation formulations of the present invention are received.
  • Example 1 A man was found to have high blood pressure (95/145mmHg) in 2015, when he was 52 years old. He started oral antihypertensive drugs, but his blood pressure was not well controlled, and he often experienced dizziness and poor sleep quality.
  • the liquid inhalation formulation of Example 1 was used according to the administration method of Example 1, once in the morning and once in the evening. The amount of each inhalation is about 0.2mL of liquid, containing 2.3mg KCl (0.03mmol KCl). When both nostrils are used, about 4.6 mg of KCl (0.06 mmol KCl) will be inhaled in a single dose. After one week of nasal spray, subjective symptoms improved and blood pressure decreased, so oral antihypertensive drugs were discontinued.
  • Blood pressure was controlled by nasal spray or inhalation only (over 5 years so far) at subsequent time, and this person's blood pressure was effectively controlled (blood pressure below 85/135mmHg) without any other antihypertensive drugs. There were no adverse effects during this period.
  • Example 1 A man, 57 years old. Anxiety and irritability due to poor sleep.
  • the liquid inhalation formulation was used according to the dosing method of Example 1, twice at 7 am and 10 am. Symptoms of anxiety and irritability disappeared by noon. It has been used several times in similar situations since then, with the same sedative effect.
  • a man with high blood pressure (95/145mmHg) was 52 years old.
  • the powder formulation is inhaled according to the administration method of Example 7, and is used once in the morning and once in the evening (the administration interval is one to three days), and each inhalation is about ten minutes. After each use, the person's blood pressure can be significantly reduced, generally to 85/125mmHg. There were no adverse effects during this period.
  • Example 3 A man, 63 years old at the time, had a history of hypertension for ten years. He relied on oral antihypertensive drugs to control his condition, but sometimes it still reached 95/155mmHg.
  • the liquid inhalation formulation in Example 3 was used, once in the morning and once in the evening (with an interval of one to three days), and each inhalation was about ten minutes.
  • the ultrasonic nebulizer can nebulize 6 mL of liquid every 30 minutes, which is equivalent to 69 mg KCl (0.9 mmol). About 23 mg of KCl (0.30 mmol KCl) was inhaled for about 10 minutes per inhalation.
  • the person's blood pressure can be significantly reduced, generally down to 85/135mmHg.
  • this person has been using a liquid inhalation formulation as an effective means of assisting blood pressure control in addition to oral medication. There were no adverse effects during this period.
  • Example 11 According to the liquid inhalation preparation and use method of Example 11, use it once a day in the morning and evening, and use it continuously for 70 days.
  • the subjects measured and reported their blood pressure with a sphygmomanometer every day.
  • the blood pressure records are shown in Figure 1.
  • the subjects' systolic and diastolic blood pressure decreased during use.
  • the slight increase in blood pressure on day 6 was due to the subjects playing mahjong for too long on that day.
  • the subject did not have any other side effects except occasional slight nasal discomfort.
  • Example 11 use it once a day in the morning and evening, and use it continuously for 70 days.
  • the nasal spray was used continuously for 45 days, the patient stopped taking the oral medication for 3 days, and then changed to taking the medication every other day due to the improvement of blood pressure.
  • the subjects measured and reported their blood pressure with a sphygmomanometer every day.
  • the blood pressure records are shown in Figure 2. As can be seen in Figure 2, the subjects' systolic and diastolic blood pressure decreased during use. During the whole period of use, the subject did not have any other side effects except occasional slight nasal discomfort.
  • Example 11 According to the liquid inhalation preparation and using method of Example 11, use it once in the morning and evening, and use it continuously for 35 days. From the 4th day of the nasal spray, the subjects stopped taking the oral medication by themselves for 4 days. The subjects measured and reported their blood pressure with a sphygmomanometer every day. The blood pressure records are shown in Figure 3. As can be seen from Figure 3, the subjects' systolic and diastolic blood pressure decreased during use. During the entire period of use, the subject did not have any other side effects other than occasional slight nasal discomfort.
  • Example 11 use it once a day in the morning and evening, and use it continuously for 60 days. From the 25th day of the nasal spray, the subjects stopped taking the oral drug for 1 day, and the blood pressure rebounded on that day. Subsequent use of amlodipine besylate tablets along with nasal spray. The subjects measured and reported their blood pressure with a sphygmomanometer every day. The blood pressure records are shown in Figure 4. As can be seen in Figure 4, the subjects' systolic and diastolic blood pressure decreased during use. During the entire period of use, the subject did not have any other side effects other than occasional slight nasal discomfort.

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Abstract

一种吸入制剂及其制备方法和应用。吸入制剂包括两种形式：(1)液体吸入制剂，其包含钾盐和水；或(2)干粉吸入制剂，其包括钾盐和药物载体。吸入制剂可以通过口腔或呼吸道给药，在低剂量的情况下有效补充钾，同时可以改变口腔或呼吸道黏膜的局部钠钾平衡，带来有益生理效果。

Description

吸入制剂及其制备方法和应用
本申请要求申请日为2020/10/9的中国专利申请202011073726X的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种吸入制剂及其制备方法和应用。
背景技术
人体内的钾元素(钾的原子序数为19，相对原子量为39.1)的含量仅次于钙和磷，较钠(相对原子量23)的含量高两倍，正常人体内约含钾140～150g(即3.6到3.8mol)。人体内约98％的钾离子存在于细胞内液，是细胞内液的主要阳离子，钾离子在细胞内的浓度比细胞外要高约30倍(约为100-150mmol/L)。而钠离子主要存在于细胞外，其在细胞外的浓度比细胞内要高约10倍。血浆的钠浓度远较钾的浓度高(血清钾的浓度范围为3.5～5mmol/L，而血清钠为140mmol/L)，但肌肉组织与奶的钾浓度则数倍于钠。这种细胞内外钾离子和钠离子浓度的巨大差异产生了跨细胞膜的电位差。要保持细胞外钠高钾低、细胞内钾高钠低的状况，细胞必须不断地将细胞内的钠离子“泵”出去，将细胞外的钾离子“泵”进来。
由于这种跨膜离子运输都是逆着离子的浓度梯度的(即要将离子从浓度低的地方转移到浓度高的地方)，这些过程是需要能量的。平均来讲，细胞消耗的能量中，约有20％用在维持细胞内外钾钠离子浓度不平衡上，而神经细胞用于此目的的能量能够占到神经细胞总能量消耗的60％。即使坐在那里什么也不做，身体里面的细胞也得持续不断地泵进钾，泵出钠。动物的细胞都有一个跨膜电位差，细胞外为正，细胞内为负，幅度大约为-60mV到-150mV。这与许多离子，例如钾离子、氯离子的细胞内外浓度不平衡有关，但是主要是由细胞外带正电的钠离子形成的。细胞外高浓度的钠离子也是储存能量的一种方式，它和细胞膜外的氢离子一样，像水库里蓄的水，高水位的水就具有势能。在人 体里面，钠离子还调节血液的体积和血压，因此是人体所需要的，这也是人每日的饮食中需要加氯化钠的原因。但是细胞外钠离子对于动物最重要的作用还是产生神经脉冲。钾对维护心脏的正常功能有重要作用，在细胞的新陈代谢中起重要作用；钾有助于神经传导功能的正常运行，它与钠共同作用可调节体内液体的酸碱度；人体缺钾或钾过量都对健康有影响。
目前通过口服或静脉给药补充钾离子，钾离子进入循环系统，增加体液中钾离子浓度，作为降血压的手段之一。该疗法的基础是钾离子进入循环系统提升体液的钾离子浓度，考虑到正常成人体液总量约占体重的60％，这需要相对大量的钾离子补充和吸收来达到的。目前补钾是采取总量控制，分次补给，边治疗边观察的治疗方法。能口服者可口服钾剂补钾，单次剂量为3～7.5g，每天一般不超过15g(以氯化钾计，分子量74.55，约200mmoml)。口服溶液的浓度为1.268％(以氯化钾计，重量百分比)，但需要的氯化钾总量口服固体和液体是一样的。静脉补充钾速度存在限制，每升输液中含钾量不宜超过40mmol(相当于氯化钾3g)，溶液应缓慢滴注，输入钾量应控制在10～20mmol/h(相当于氯化钾0.75-1.5g/h)以下。静脉补充钾总量不宜过多，要根据血钾的水平来补钾，单次补钾4.5～6g，每天一般不超过15g(以氯化钾计)。
然而，无论口服和静脉补钾都有安全和有效性的问题。比如，在采用静脉滴注补钾的时候，通常都会因为药液的浓度过高、滴注速度过快以及人的静脉较细等原因，而对静脉内膜造成出现刺激，从而引起疼痛。如果静脉滴注补钾的时候，由于滴注速度较快，以及对患者的肾功能出现损害，就要特别关注患者是否出现高钾血症。一旦出现这种征兆，就要及时进行处理。口服氯化钾，会刺激胃。导致胃痛，所以，一般需要在饭后服用。口服吸收或静脉进入身体内的钾，也要通过肾脏排出体外，以维持体内的相对平衡。
在相关的领域中，用生理盐水或海水被用来清洗鼻腔或呼吸道黏膜。但无论是生理盐水或天然来源的水，都是含钠盐浓度远远高出钾盐。地球上几乎所有的液态水中所含的钠都大大多于钾。无论是河水、湖水还是海水，所含的钠都大大多于钾。例如海水中钠的浓度就是钾的47倍(钠470mmol/L(mM)，钾10mM)，河水中含盐量随河流不同，但大体上钠的浓度是钾的10倍(钠大约0.4mM，钾大约0.04mM)。虽然地壳中钾和钠 的含量其实差不多：钠为2.8％，而钾为2.6％。因此，在用于鼻腔清洗的天然海水、人工配制的生理盐水或其他盐溶液(如乳酸林格氏液等)中钠离子浓度都远远高于钾离子，这种方式并不能在鼻腔或呼吸道黏膜中提高钾/钠离子比值(参考文献：科学网https://blog.csdn.net/cf2SudS8x8F0v/article/details/84038809“细胞内钾多钠少——原初生物的第三大遗迹”，作者朱钦仕)。
发明内容
本发明为了克服上述口服和静脉补钾的缺陷，从而提供了一种吸入制剂及其制备方法和应用。该吸入制剂可以通过口腔或呼吸道给药，在低剂量的情况下有效在口腔或呼吸道黏膜补充钾，同时可以改变口腔或呼吸道黏膜的局部钠钾平衡，带来有益生理效果。
为了实现上述目的，本发明采用以下技术方案：
本发明提供了一种吸入制剂，其包括两种形式：
(1)液体吸入制剂，其包含钾盐和水，钾的摩尔浓度为0.001～27,410mmol/L；或
(2)干粉吸入制剂，其包括钾盐和药物载体，所述钾盐的含量为0.01％～100％，所述百分比为所述钾盐占所述干粉吸入制剂的质量百分比。
本发明中，所述的钾盐可为本领域常规使用的钾盐，较佳地包括氯化钾、醋酸钾、葡糖酸钾、门冬氨酸钾、氨基酸复合钾、碳酸钾、碳酸氢钾、柠檬酸钾、柠檬酸二氢钾、柠檬酸氢钾、酒石酸钾、酒石酸氢钾、酒石二酸氢钾、氢氧化钾、磷酸钾、磷酸氢钾、磷酸二氢钾、硫酸钾、硫酸氢钾、硝酸钾、海藻酸钾和山梨酸钾中的一种或多种；更佳地包括氯化钾、醋酸钾、碳酸钾、碳酸氢钾、酒石酸钾、酒石酸氢钾、酒石二酸氢钾、柠檬酸钾或柠檬酸氢钾。
本发明中，所述液体吸入制剂中钾的摩尔浓度可为0.001～10,000mmol/L，优选为0.001～4,700mmol/L，较佳地为3～3,500mmol/L，更佳地为10～2,000mmol/L，更佳地为20～1,500mmol/L，进一步更佳地为50～1,000mmol/L，甚至更佳地为75～700mmol/L。所述液体吸入制剂中钾的摩尔浓度例如为25.5mmol/L、154mmol/L、537mmol/L或1,221mmol/L。
本发明中，所述液体吸入制剂中钾的摩尔浓度优选为0.001～2,500mmol/L，较佳地为0.001～1,500mmol/L，更佳地为3～1,000mmol/L，较进一步更佳地为20～400mmol/L，甚至更佳地为50～200mmol/L。
本发明中，所述液体吸入制剂中，所述钾盐为氯化钾，所述氯化钾的摩尔浓度可为0.001～4,700mmol/L，例如为25.5mmol/L、154mmol/L、537mmol/L或1,221mmol/L。
本发明中，所述液体吸入制剂中，所述钾盐为醋酸钾，所述醋酸钾的摩尔浓度可为0.001～27,410mmol/L，例如为10,000mmol/L。
本发明中，所述液体吸入制剂的pH可为3.0～9.0，较佳地为4.0～8.0，更佳地为5.0～7.0，进一步更佳地为5.5～6.5。
本发明中，所述液体吸入制剂还可包含本领域常规的药学上可接受的附加剂。所述附加剂较佳地包括稀释剂、酸度调节剂、等渗调节剂和防腐剂中的一种或多种。
其中，所述稀释剂可为本领域常规的稀释剂，较佳地选自乙醇、异丙醇、丙二醇、甘油、甘露醇、乳糖、明胶、淀粉、预胶化淀粉、糊精、环糊精、蔗糖、牛磺酸，氨基酸，微晶纤维素、硫酸钙、磷酸氢钙、氧化镁、碳酸钙、羟丙基甲基纤维素、聚维酮、淀粉浆、糖浆、羧甲基淀粉钠和交联聚维酮中的一种或多种。
所述酸度调节剂，又称pH控制剂，可为本领域常规的用来调整或保持pH值的药物添加剂。所述酸度调节剂可为酸、碱、中和剂或缓冲剂，较佳地选自葡甲胺、硼酸、无水醋酸钠、三水醋酸钠、结晶醋酸钠、氨丁三醇、醋酸、氨基酸、盐酸、磷酸、氯化铵、枸橼酸钠、稀氨溶液、醋酸钙、无水磷酸氢二钠、无水碳酸钠、碳酸氢钾、醋酸铵、乙酸、酒石酸、甲磺酸和琥珀酸中的一种或多种。所述酸度调节剂的含量可为0.05％-20％，所述百分比为重量百分比。
其中，所述等渗调节剂可为本领域常规的非钠盐渗透压调节剂，较佳地选自葡萄糖、蔗糖、甘油和木糖醇中的一种或多种。所述等渗调节剂的含量可为0.01％-20％，所述百分比为重量百分比。
其中，所述防腐剂可为本领域常规的药用防腐剂，较佳地为苯酚取代物(如联苯酚、甲酚或二甲苯酚)、阳离子表面活性物质、卤素、氧化剂(如过氧化氢或高锰酸盐)、苯 胺染料、吖啶染料、重金属盐、醇或醛类。所述防腐剂还可为食品防腐剂，例如苯甲酸、苯甲酸钠、山梨酸、山梨酸钾或丙酸钙。所述防腐剂的含量可为0.01％-20％，所述百分比为重量百分比。
本发明中，所述液体吸入制剂较佳地为氯化钾水溶液、醋酸钾水溶液、碳酸钾水溶液、碳酸氢钾水溶液、酒石酸钾水溶液、酒石酸氢钾水溶液、柠檬酸钾水溶液或柠檬酸氢钾水溶液。
本发明中，所述干粉吸入制剂中所述钾盐的含量较佳地为1％～90％，更佳地为1％～50％，更佳地为1％～20％。
本发明中，所述干粉吸入制剂的药物载体可选自甘露醇、乳糖、明胶、淀粉、氨基酸、预胶化淀粉、糊精、环糊精、蔗糖、微晶纤维素、硫酸钙、磷酸氢钙、氧化镁、碳酸钙、羟丙基甲基纤维素(HPMC)、聚维酮(PVP)、淀粉浆、糖浆、羧甲基淀粉钠和交联聚维酮中的一种或多种。
本发明中，所述干粉吸入剂较佳地包括氯化钾和乳糖。其中，所述氯化钾的含量较佳地为2％～10％，更佳地为2％～6％；例如为2.2％、5.7％或9.3％，所述百分比为所述氯化钾占所述干粉吸入制剂的质量百分比。
本发明中，当所述干粉吸入制剂中所述钾盐的含量为100％时，所述干粉吸入制剂为纯钾盐，例如纯氯化钾。
本发明中，所述干粉吸入制剂的平均粒径可为0.05～1,000μm，较佳地为0.1～500μm，更佳地为0.2～250μm，例如74μm；或者0.2～5μm，较佳地为0.5～2μm，例如1μm或4μm；或者5～10μm，例如7μm；或者10～20μm，例如15μm。平均粒径为10～20μm的颗粒可沉积在鼻粘膜上，平均粒径5～10μm的颗粒能够进入上呼吸道，而平均粒径小于2μm的颗粒可通过粘膜直接进入肺部。
本发明还提供了所述吸入制剂的制备方法，其包括将各组分混合均匀即可。
当所述吸入制剂为液体吸入制剂时，所述制备方法包括将各组分混合均匀形成溶液即可。
当所述吸入制剂为干粉吸入制剂时，所述制备方法包括将各组分混合均匀形成具有 特定颗粒度的固体混合物或者特定颗粒度的钾盐颗粒即可。
本发明中，所述干粉吸入制剂的一较佳的制备方法包括：先将钾盐溶解在水中，然后将所得的钾盐水溶液与药物载体混合，干燥后制粉。
在本发明一较佳的实施方案中，所述干粉吸入制剂的制备方法包括：先将氯化钾溶解在水中，然后将所得的氯化钾水溶液用喷雾的方式加到乳糖中，干燥后制粉。
本发明还提供了一种给药方法，其包括将所述吸入制剂施加至口腔或呼吸道。所述呼吸道包括鼻腔、咽、喉、气管、支气管和肺内的各级支气管的分支。呼吸道从鼻到喉这一段称为上呼吸道。气管、支气管及肺部的各级支气管分支这一段为下呼吸道。
本发明中，所述液体吸入制剂的施加方式可包括喷雾、滴加或洗涤；较佳地为喷雾。
其中，所述喷雾可采用本领域常规的喷雾装置进行，例如按压式手动雾化器、电动喷雾装置、气动喷雾装置、机械喷雾装置或超声雾化器。所述喷雾装置可为定量或非定量。喷雾装置可将液体吸入制剂分散成细小的雾滴，以气雾状喷岀，使其悬浮在气体中。
所述气雾的平均粒径可为0.05～1,000μm，较佳地为0.1～500μm，更佳地为0.2～250μm，例如74μm；或者0.2～4μm，例如1μm；或者5～10μm，例如7μm；或者10～20μm，例如15μm。平均粒径为10～20μm的气雾可沉积在鼻粘膜上，平均粒径5～10μm的气雾能够进入上呼吸道，而平均粒径小于2μm的气雾可通过粘膜直接进入肺部。
本发明中，以钾离子计，所述液体吸入制剂的单次剂量可为0.01～0.5mmol。当所述钾盐为氯化钾时，以氯化钾计，所述液体吸入制剂的单次剂量较佳地为0.74～37.3mg，或者为0.74～140mg。
本发明中，所述干粉吸入制剂的施加方式可为直接吸入或采用干粉吸入装置。其中，所述干粉吸入装置可为本领域常规，较佳地为定量压力吸入装置或干粉雾化吸入装置。
本发明中，以钾离子计，所述干粉吸入制剂的单次剂量较佳地为0.01～0.5mmol。当所述钾盐为氯化钾时，以氯化钾计，所述干粉吸入制剂的单次剂量较佳地为0.74～37.3mg，或者为0.74～140mg。
由于钾盐有很高的安全剂量，也可以采用持续液体雾化或干粉喷雾于环境中，人体采用呼吸的方式连续性地获得钾离子的补充。其上限应该不超过口服或静脉补钾，单次 剂量为～3g，每天不超过15g(以氯化钾计)。可以采用多次给药。
本发明还提供了所述吸入制剂在制备治疗高血压的药物中的应用。
本发明还提供了所述吸入制剂在制备镇静药物中的应用。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明通过吸入的方式经口腔或呼吸道给药，提供低剂量的钾离子，钾离子可以通过黏膜进入血液系统，在剂量和血药浓度远远小于现有其他途径给药(口服或静脉注射)的情况下，增加口腔或呼吸道黏膜的局部钾离子浓度，尤其是提高口腔或呼吸道黏膜的局部钾离子/钠离子的比值，从而减少细胞膜传输钾离子的阻力，降低能量消耗，起到有效补钾的作用。本发明的意外之处是用少量的钾离子作用于口腔或呼吸道黏膜，改变黏膜局部的钠钾平衡，激活黏膜层的特定细胞，从而起到意想不到的有益生理效果(比如降血压和起到镇静作用等)。
附图说明
图1为效果实施例5中受试者的血压记录。
图2为效果实施例6中受试者的血压记录。
图3为效果实施例7中受试者的血压记录。
图4为效果实施例8中受试者的血压记录。
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
2.3g KCl(分子量为74.55)溶解于200mL纯净水中(摩尔浓度为154mmol/L，或1.15％w/v)，形成清澈的溶液，即液体吸入制剂；然后分装在50mL泵式手动雾化器中。
在需要使用时，用喷头对准左鼻孔，按住右鼻孔。在左鼻孔吸气的同时，按下活塞，使产生的雾滴吸入鼻腔。上述操作可以对右鼻孔使用。每一次被吸入的量约0.2mL液体，含2.3mg KCl(0.03mmol KCl)。左右鼻孔都使用的情况下，单次会有约4.6mg KCl(0.06mmol KCl)被吸入。吸入者没有任何不适感。或者，在需要使用时，将液体吸入制剂喷入口腔和舌面，略有苦味，但没有其他不适感。
实施例2
8g KCl溶解于200mL纯净水中(摩尔浓度为537mmol/L，或4.0％w/v)，形成清澈的溶液，即液体吸入制剂；然后分装在50mL泵式手动雾化器中。
在需要使用时，用喷头对准左鼻孔，按住右鼻孔。在左鼻孔吸气的同时，按下活塞，使产生的雾滴吸入鼻腔。上述操作可以对右鼻孔使用。每一次被吸入的量约0.2mL液体，含8mg KCl(0.11mmol KCl)。左右鼻孔都使用的情况下，单次会有约16mg KCl(0.22mmol KCl)被吸入。由于溶液的浓度和渗透压都较高，使用者有轻微的头晕，这种感觉在10分钟左右后基本消失。
实施例3
2.3g KCl溶解于200mL纯净水中(摩尔浓度为154mmol/L，或1.15％w/v)，形成清澈的溶液，即液体吸入制剂；然后装在市售的超声雾化器中。
在需要使用时，将超声雾化器鼻腔和口腔附近，开启超声雾化器，可以连续产生粒径小于100μm的雾滴，所产生的雾滴被吸入呼吸道。超声雾化器每30分钟可雾化6mL液体，相当于69mgKCl(0.9mmol)。每次吸入约10分钟，有约23mg KCl(0.30mmol KCl)被吸入。吸入者没有任何不适感。
实施例4
0.38g KCl(分子量为74.55)溶解于200mL纯净水中(摩尔浓度为25.5mmol/L，或0.19％w/v)，形成清澈的溶液，即液体吸入制剂；然后分装在50mL泵式手动雾化器中。
在需要使用时，用喷头对准左鼻孔，按住右鼻孔。在左鼻孔吸气的同时，按下活塞， 使产生的雾滴吸入鼻腔。上述操作可以对右鼻孔使用。每一次被吸入的量约0.2mL液体，含0.38mg KCl(0.005mmol KCl)。左右鼻孔都使用的情况下，单次会有约0.76mg KCl(0.01mmol KCl)被吸入。吸入者没有任何不适感。
或者，在需要使用时，将液体吸入制剂喷入口腔和舌面，略有苦味，但没有其他不适感。
实施例5
18.2g KCl溶解于200mL纯净水中(摩尔浓度为1,221mmol/L，或9.1％w/v)，形成清澈的溶液，即液体吸入制剂；然后分装在50mL泵式手动雾化器中。
在需要使用时，用喷头对准左鼻孔，按住右鼻孔。在左鼻孔吸气的同时，按下活塞，使产生的雾滴吸入鼻腔。上述操作可以对右鼻孔使用。每一次被吸入的量约0.2mL液体，含18.6mg KCl(0.25mmol KCl)。左右鼻孔都使用的情况下，单次会有约37.3mg KCl(0.5mmol KCl)被吸入。由于溶液的浓度和渗透压都较高，使用者有轻微的头晕，这种感觉在约30分钟左右后基本消失。
实施例6
70g KCl溶解于200mL纯净水中(摩尔浓度约为4700mmol/L，或35％w/v)，形成清澈的溶液，即液体吸入制剂；然后分装在50mL泵式手动雾化器中。
在需要使用时，用喷头对准左鼻孔，按住右鼻孔。在左鼻孔吸气的同时，按下活塞，使产生的雾滴吸入鼻腔。上述操作可以对右鼻孔使用。每一次被吸入的量约0.2mL液体，含70mg KCl(0.94mmol KCl)。左右鼻孔都使用的情况下，单次会有约140mg KCl(1.88mmol KCl)被吸入。由于溶液的浓度和渗透压都很高，使用者有轻度的头晕，这种感觉在约60分钟左右后基本消失。
上述溶液加入市售的超声雾化器中，可以形成富含钾离子的雾。超声雾化器每30分钟可雾化6mL液体，相当于2.1gKCl(28mmol)。每次吸入约2分钟，有约140mg KCl(1.88mmol KCl)被吸入。吸入者没有任何不适感。用鼻子或口腔吸入时，基本没有因为雾滴中溶液含高浓度电解质(高渗透压)而引起的不适感。
实施例7
取2g KCl固体，在碾磨中磨碎，过200目筛子，粒径小于74μm，即得干粉吸入制剂。
在需要使用时，取0.01g细粉，放在干净的白纸上并置于左鼻孔的下方，按住右鼻孔，用力吸气，上述粉末可以部分被吸进鼻腔。左右鼻孔都使用的情况下，单次会有约10mg KCl(0.134mmol KCl)被吸入。吸入者没有任何不适感。
实施例8
取2.3g KCl固体，在碾磨中磨碎，过200目筛子，粒径小于74μm；取用100g药用乳糖，在碾磨中磨碎，过200目筛子，粒径小于74μm。把得到的KCl粉末溶解于20mL纯净水中，形成清澈的溶液；把得到的KCl溶液用喷雾的方式加到乳糖中。干燥后，再碾磨成细粉，过200目筛子，粒径小于74μm，即得干粉吸入制剂，其中KCl的含量约为2.2％。
在需要使用时，取0.2g细粉，放在干净的白纸上并置于左鼻孔的下方，按住右鼻孔，用力吸气，上述粉末可以被吸进鼻腔。每一次被吸入的量约0.2g固体粉末，含4.4mg KCl(0.06mmol KCl)。左右鼻孔都使用的情况下，单次会有约8.8mg KCl(0.12mmol KCl)被吸入。吸入者没有任何不适感。
实施例9
取6g KCl固体，在碾磨中磨碎，过200目筛子，粒径小于74μm；取用100g药用乳糖，在碾磨中磨碎，过200目筛子，粒径小于74μm。把得到的KCl粉末溶解于20mL纯净水中，形成清澈的溶液；把得到的KCl溶液用喷雾的方式加到乳糖中。干燥后，再碾磨成细粉，过200目筛子，粒径小于74μm，即得干粉吸入制剂，其中KCl的含量约为5.7％。
在需要使用时，取0.2g细粉，放在干净的白纸上并置于左鼻孔的下方，按住右鼻孔，用力吸气，上述粉末可以被吸进鼻腔。每一次被吸入的量约0.2g固体粉末，含11.4mg KCl(0.153mmol KCl)。左右鼻孔都使用的情况下，单次会有约22.8mg KCl(0.306mmol KCl)被吸入。由于盐的含量较高，在吸入后于鼻腔黏膜处吸收水分溶解，所形成溶液的盐浓度和渗透压都较高，使用者有轻微的头晕，这种感觉在一个小时后基本消失。
实施例10
取10.3g KCl固体，在碾磨中磨碎，过200目筛子，粒径小于74μm；取用100g药用乳糖，在碾磨中磨碎，过200目筛子，粒径小于74μm。把得到的KCl粉末溶解于50mL纯净水中，形成清澈的溶液；把得到的KCl溶液用喷雾的方式加到乳糖中。干燥后，再碾磨成细粉，过200目筛子，粒径小于74μm，即得干粉吸入制剂，其中KCl的含量约为9.3％。
在需要使用时，取0.2g细粉，放在干净的白纸上并置于左鼻孔的下方，按住右鼻孔，用力吸气，上述粉末可以被吸进鼻腔。每一次被吸入的量约0.2g固体粉末，含18.6mg KCl(0.25mmol KCl)。左右鼻孔都使用的情况下，单次会有约37.3mg KCl(0.50mmol KCl)被吸入。由于钾盐的含量较高，在鼻腔黏膜处吸收水分溶解，所形成溶液的盐浓度和渗透压都较高，使用者有轻微的头晕，这种感觉在一个小时后基本消失。
实施例11
5.74g KCl(分子量为74.55)溶解于500mL纯净水中(摩尔浓度为154mmol/L，或1.15％w/v)，形成清澈的溶液，即液体吸入制剂；然后分装在50mL按压式雾化塑料瓶中。使用时，按压式喷雾塑料瓶喷嘴分别对准左右鼻孔，在深吸气时按压喷雾。每一次被吸入的量约0.2mL液体，含2.3mg KCl(0.03mmol KCl)。左右鼻孔都使用的情况下，单次会有约4.6mg KCl(0.06mmol KCl)被吸入。
实施例12
100g醋酸钾(分子量为98.14)溶解于100mL纯净水中(摩尔浓度约为10000mmol/L)，形成清澈的溶液，即液体吸入制剂；然后分装在50mL按压式雾化塑料瓶中。使用时，按压式喷雾塑料瓶喷嘴分别对准左右鼻孔，在深吸气时按压喷雾。每一次被吸入的量约0.2mL液体，含200mg KCl(2.04mmol KCl)。左右鼻孔都使用的情况下，单次会有约400mg KCl(4.08mmol KCl)被吸入。由于溶液的盐浓度和渗透压都较高，使用者有轻微的头晕，这种感觉在一段后基本消失。
实施例13
269g醋酸钾(分子量为98.14)溶解于100mL纯净水中(摩尔浓度为27410mmol/L)， 形成清澈的溶液，即液体吸入制剂；然后分装在50mL按压式雾化塑料瓶或超声雾化器中。此溶液可以形成很好的气雾。
以下效果实施例为使用本发明的吸入制剂的真实案例。受试者均为患有多年高血压的患者，年龄在40～70岁之间，长期服用降压药但控制血压的情况不理想。在知情和自愿的基础上，接受了本发明的鼻喷或鼻吸本发明的吸入制剂。
效果实施例1
某男，在2015年发现有高血压(95/145mmHg)，时年52岁。开始口服降压药，但血压控制不好，时常有头晕现象，睡眠质量差。按照实施例1的给药方法使用实施例1中的液体吸入制剂，早晚各用一次。每一次被吸入的量约0.2mL液体，含2.3mg KCl(0.03mmol KCl)。左右鼻孔都使用的情况下，单次会有约4.6mg KCl(0.06mmol KCl)被吸入。在用鼻喷剂一周后主观症状变好并有血压降低，因此停止口服降压药。在后续的时间只以来鼻喷剂或吸入剂控制血压(迄今超过5年)，此人的血压在不使用任何其他降压药的情况下都得到有效控制(血压85/135mmHg以下)。期间没有任何不良效果。
效果实施例2
某男，年57岁。由于睡眠不好引起焦虑和烦躁。按照实施例1的给药方法使用液体吸入制剂，早上7点和10点共用两次。焦虑和烦躁的症状在中午的时候就消失。其后在多次类似情况下使用，都有同样的镇静效果。
效果实施例3
某男，有高血压(95/145mmHg)，时年52岁。按照实施例7的给药方法吸入粉末制剂，早晚各用一次(用药间隔为一到三天)，每次吸入约十分钟。每次使用后，此人的血压可显著减低，一般可降至85/125mmHg。期间没有任何不良效果。
效果实施例4
某男，时年63岁，有十年的高血压病史，依赖口服降压药控制病情，但有时仍会达到在95/155mmHg。按照实施例3(超声雾化器)的给药方法使用实施例3中的液体吸入制剂，早晚各用一次(间隔为一到三天)，每次吸入约十分钟。超声雾化器每30分钟可雾化6mL液体，相当于69mgKCl(0.9mmol)。每次吸入约10分钟，有约23mg KCl (0.30mmol KCl)被吸入。每次使用10-20分钟后，此人的血压可显著减低，一般可降至85/135mmHg。迄今有一年，此人一直以液体吸入制剂作为在口服药之外辅助控制血压的有效手段。期间没有任何不良效果。
效果实施例5
张某，59岁，高血压25年，在使用鼻喷剂前每天服用倍他乐克半片，氨氯地平2粒，罗珍胶囊4颗。该患者使用鼻喷剂作为口服降压药的补充血压控制手段。
按照实施例11的液体吸入制剂及使用方法，每日早晚各用一次，持续使用70天。受试者每日用血压计测量血压并报告，血压记录如图1所示。由图1可见，在使用期间，受试者的收缩压和舒张压都有所降低。其中，第6天血压略微升高是由于受试者当天玩麻将太久。整个使用期间，受试者除了偶尔有鼻腔轻微不适之外没有任何其它副作用。
效果实施例6
张某，43岁，9年高血压病史，在使用鼻喷剂前每天服用厄贝沙坦氢氯噻嗪片160mg、12.5mg。该患者使用鼻喷剂作为口服降压药的补充血压控制手段。
按照实施例11的液体吸入制剂及使用方法，每日早晚各用一次，持续使用70天。鼻喷剂连续使用45天时，患者自行停用口服药3天，其后由于血压变好，改为隔天吃药。受试者每日用血压计测量血压并报告，血压记录如图2所示。由图2可见，在使用期间，受试者的收缩压和舒张压都有所降低。整个使用期间，受试者除了偶尔有鼻腔轻微不适之外没有任何其它副作用。
效果实施例7
孙某，60岁，20年高血压病史，在使用鼻喷剂前每天服用厄贝沙坦氢氯噻嗪片160mg、12.5mg。该患者使用鼻喷剂作为口服降压药的补充血压控制手段。
按照实施例11的液体吸入制剂及使用方法，每日早晚各用一次，持续使用35天。鼻喷第4天起，受试者自行停用口服药4天。受试者每日用血压计测量血压并报告，血压记录如图3所示。由图3可见，在使用期间，受试者的收缩压和舒张压都有所降低。整个使用期间，受试者除了偶尔有鼻腔轻微不适之外没有任何其它副作用。
效果实施例8
李某，59岁，15年高血压病史，期间断续用药。在使用鼻喷剂前每天服用苯磺酸氨氯地平片，每天一次，每次一片。该患者使用鼻喷剂作为口服降压药的补充血压控制手段。
按照实施例11的液体吸入制剂及使用方法，每日早晚各用一次，持续使用60天。鼻喷第25天起，受试者自行停用口服药1天，当天血压有回弹情况。后续在使用鼻喷剂时又同时服用苯磺酸氨氯地平片。受试者每日用血压计测量血压并报告，血压记录如图4所示。由图4可见，在使用期间，受试者的收缩压和舒张压都有所降低。整个使用期间，受试者除了偶尔有鼻腔轻微不适之外没有任何其它副作用。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (13)

  1. 一种吸入制剂，其包括两种形式：
    (1)液体吸入制剂，其包含钾盐和水，钾的摩尔浓度为0.001～27,410mmol/L；或
    (2)干粉吸入制剂，其包括钾盐和药物载体，所述钾盐的含量为0.01％～100％，百分比为所述钾盐占所述干粉吸入制剂的质量百分比。
  2. 根据权利要求1所述的吸入制剂，其特征在于，所述的钾盐包括氯化钾、醋酸钾、葡糖酸钾、门冬氨酸钾、氨基酸复合钾、碳酸钾、碳酸氢钾、柠檬酸钾、柠檬酸二氢钾、柠檬酸氢钾、酒石酸钾、酒石酸氢钾、酒石二酸氢钾、氢氧化钾、磷酸钾、磷酸氢钾、磷酸二氢钾、硫酸钾、硫酸氢钾、硝酸钾、海藻酸钾和山梨酸钾中的一种或多种；较佳地包括氯化钾、醋酸钾、碳酸钾、碳酸氢钾、酒石酸钾、酒石酸氢钾、酒石二酸氢钾、柠檬酸钾或柠檬酸氢钾。
  3. 根据权利要求1或2所述的吸入制剂，其特征在于，所述液体吸入制剂中钾的摩尔浓度为0.001～10,000mmol/L，优选为0.001～4,700mmol/L，较佳地为3～3,500mmol/L，更佳地为10～2,000mmol/L，更佳地为20～1,500mmol/L，进一步更佳地为50～1,000mmol/L，甚至更佳地为75～700mmol/L；所述液体吸入制剂中钾的摩尔浓度例如为25.5mmol/L、154mmol/L、537mmol/L或1,221mmol/L；
    或者，所述液体吸入制剂中钾的摩尔浓度为0.001～2,500mmol/L，较佳地为0.001～1,500mmol/L，更佳地为3～1,000mmol/L，较进一步更佳地为20～400mmol/L，甚至更佳地为50～200mmol/L；
    较佳地，所述液体吸入制剂中，所述钾盐为氯化钾，所述氯化钾的摩尔浓度为0.001～4,700mmol/L，例如为25.5mmol/L、154mmol/L、537mmol/L或1,221mmol/L；
    较佳地，所述液体吸入制剂中，所述钾盐为醋酸钾，所述醋酸钾的摩尔浓度为0.001～27,410mmol/L，例如为10,000mmol/L；
    和/或，所述液体吸入制剂的pH为3.0～9.0，较佳地为4.0～8.0，更佳地为5.0～7.0，进一步更佳地为5.5～6.5。
  4. 根据权利要求1～3中至少一项所述的吸入制剂，其特征在于，所述液体吸入制剂 还包含药学上可接受的附加剂，所述附加剂包括稀释剂、酸度调节剂、等渗调节剂和防腐剂中的一种或多种；
    其中，所述稀释剂较佳地选自乙醇、异丙醇、丙二醇、甘油、甘露醇、乳糖、明胶、淀粉、预胶化淀粉、糊精、环糊精、蔗糖、牛磺酸，氨基酸，微晶纤维素、硫酸钙、磷酸氢钙、氧化镁、碳酸钙、羟丙基甲基纤维素、聚维酮、淀粉浆、糖浆、羧甲基淀粉钠和交联聚维酮中的一种或多种；
    所述酸度调节剂为酸、碱、中和剂或缓冲剂，较佳地选自葡甲胺、硼酸、无水醋酸钠、三水醋酸钠、结晶醋酸钠、氨丁三醇、醋酸、氨基酸、盐酸、磷酸、氯化铵、枸橼酸钠、稀氨溶液、醋酸钙、无水磷酸氢二钠、无水碳酸钠、碳酸氢钾、醋酸铵、乙酸、酒石酸、甲磺酸和琥珀酸中的一种或多种；所述酸度调节剂的含量较佳地为0.05％-20％，百分比为重量百分比；
    所述等渗调节剂较佳地选自葡萄糖、蔗糖、甘油和木糖醇中的一种或多种；所述等渗调节剂的含量较佳地为0.01％-20％，百分比为重量百分比；
    所述防腐剂较佳地为苯酚取代物、阳离子表面活性物质、卤素、氧化剂、苯胺染料、吖啶染料、重金属盐、醇类、醛类或食品防腐剂；其中，所述苯酚取代物较佳地为联苯酚、甲酚或二甲苯酚；所述氧化剂较佳地为过氧化氢或高锰酸盐；所述食品防腐剂较佳地为苯甲酸、苯甲酸钠、山梨酸、山梨酸钾或丙酸钙；所述防腐剂的含量较佳地为0.01％-20％，百分比为重量百分比。
  5. 根据权利要求1～4中至少一项所述的吸入制剂，其特征在于，所述液体吸入制剂为氯化钾水溶液、醋酸钾水溶液、碳酸钾水溶液、碳酸氢钾水溶液、酒石酸钾水溶液、酒石酸氢钾水溶液、柠檬酸钾水溶液或柠檬酸氢钾水溶液。
  6. 根据权利要求1～5中至少一项所述的吸入制剂，其特征在于，所述干粉吸入制剂中所述钾盐的含量为0.1％～90％，较佳地为1％～50％，更佳地为1％～20％；
    和/或，所述干粉吸入制剂的药物载体选自甘露醇、乳糖、明胶、淀粉、氨基酸、预胶化淀粉、糊精、环糊精、蔗糖、牛磺酸、氨基酸、微晶纤维素、硫酸钙、磷酸氢钙、氧化镁、碳酸钙、羟丙基甲基纤维素、聚维酮、淀粉浆、糖浆、羧甲基淀粉钠和交联聚 维酮中的一种或多种。
  7. 根据权利要求1～6中至少一项所述的吸入制剂，其特征在于，所述干粉吸入剂包括氯化钾和乳糖；其中，所述氯化钾的含量较佳地为2％～10％，更佳地为2％～6％；例如为2.2％、5.7％或9.3％，百分比为所述氯化钾占所述干粉吸入制剂的质量百分比。
  8. 根据权利要求1～7中至少一项所述的吸入制剂，其特征在于，所述干粉吸入制剂的平均粒径为0.05～1,000μm，较佳地为0.1～500μm，更佳地为0.2～250μm，例如74μm；或者0.2～5μm，较佳地为0.5～2μm，例如1μm或4μm；或者5～10μm，例如7μm；或者10～20μm，例如15μm。
  9. 一种权利要求1～8中任一项所述吸入制剂的制备方法，其包括将各组分混合均匀即可。
  10. 根据权利要求9所述的吸入制剂的制备方法，其特征在于，当所述吸入制剂为液体吸入制剂时，所述制备方法包括将各组分混合均匀形成溶液即可；
    当所述吸入制剂为干粉吸入制剂时，所述制备方法包括将各组分混合均匀形成具有特定颗粒度的固体混合物或者特定颗粒度的钾盐颗粒即可；
    较佳地，所述干粉吸入制剂的制备方法包括：先将钾盐溶解在水中，然后将所得的钾盐水溶液与药物载体混合，干燥后制粉；
    更佳地，所述干粉吸入制剂的制备方法包括：先将氯化钾溶解在水中，然后将所得的氯化钾水溶液用喷雾的方式加到乳糖中，干燥后制粉。
  11. 一种权利要求1～8中任一项所述吸入制剂在制备治疗高血压的药物或在制备镇静药物中的应用。
  12. 一种给药方法，其包括将权利要求1～8中任一项所述吸入制剂施加至口腔或呼吸道。
  13. 根据权利要求12所述的给药方法，其特征在于，所述液体吸入制剂的施加方式包括喷雾、滴加或洗涤；较佳地为喷雾；
    其中，所述喷雾的喷雾装置较佳地为按压式手动雾化器、电动喷雾装置、气动喷雾装置、机械喷雾装置或超声雾化器；所述喷雾装置可为定量或非定量；
    其中，所述喷雾装置将液体吸入制剂分散成细小的雾滴，以气雾状喷岀，使其悬浮在气体中；所述气雾的平均粒径为0.05～1000μm，较佳地为0.1～500μm，更佳地为0.2～250μm，例如74μm；或者0.2～4μm，例如1μm；或者5～10μm，例如7μm；或者10～20μm，例如15μm；
    和/或，以钾离子计，所述液体吸入制剂的单次剂量为0.01～0.5mmol；当所述钾盐为氯化钾时，以氯化钾计，所述液体吸入制剂的单次剂量较佳地为0.74～37.3mg，或者为0.74～140mg。
    和/或，所述干粉吸入制剂的施加方式为直接吸入或采用干粉吸入装置；其中，所述干粉吸入装置较佳地为定量压力吸入装置或干粉雾化吸入装置；
    和/或，以钾离子计，所述干粉吸入制剂的单次剂量为0.01～0.5mmol；当所述钾盐为氯化钾时，以氯化钾计，所述干粉吸入制剂的单次剂量较佳地为0.74～37.3mg，或者为0.74～140mg。
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CN107753472A (zh) * 2017-03-24 2018-03-06 北京北朋科技有限公司 雾化吸入用柠檬酸氢钾钠溶液
CN111110662A (zh) * 2018-10-30 2020-05-08 北京盈科瑞创新药物研究有限公司 一种吸入用溶液制剂的制备方法

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