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WO2005058289A1 - Technique de preparation de produit d'hinalation en poudres deshydratees intranasale de calcitonine - Google Patents

Technique de preparation de produit d'hinalation en poudres deshydratees intranasale de calcitonine Download PDF

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Publication number
WO2005058289A1
WO2005058289A1 PCT/CN2004/001363 CN2004001363W WO2005058289A1 WO 2005058289 A1 WO2005058289 A1 WO 2005058289A1 CN 2004001363 W CN2004001363 W CN 2004001363W WO 2005058289 A1 WO2005058289 A1 WO 2005058289A1
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WIPO (PCT)
Prior art keywords
calcitonin
surfactant
self
drug
dry powder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2004/001363
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English (en)
Chinese (zh)
Inventor
Fang Jin
Xusheng Kong
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Individual
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Publication of WO2005058289A1 publication Critical patent/WO2005058289A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • 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
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the invention relates to a calcitonin nasal dry powder inhalant and a preparation method thereof.
  • peptide and protein drugs are used for clinical treatment.
  • Most of the peptide drugs have biological activity and are unstable to many factors such as heat and enzymes. Therefore, injections are often used to medicine.
  • long-term injection administration brings great pain to patients and requires special injection technology. It is difficult for patients to administer medicines on their own, the finished products are high, and the medical expenses are high. Therefore, pharmacists at home and abroad have been committed to the research of non-injection routes of peptide drugs, such as nasal cavity, rectum, oral, lung, eye, and transdermal absorption.
  • nasal administration is the most likely non-injectable route of administration for protein drugs.
  • the first object of the present invention is to improve on the basis of the above-mentioned original patent technology, and provide a method capable of increasing the absorption rate and transmucosal capacity of the calcitonin of the peptide drug, and improving the bioavailability of the drug for nasal administration.
  • Calcitonin Dry Nasal Powder Inhaler
  • a second object of the present invention is to provide a method for preparing the calcitonin nasal dry powder inhalant of the present invention.
  • the first object of the present invention is achieved as follows:
  • the calcitonin nasal dry powder inhalant of the present invention is composed of 1-99% of a self-emulsifying nanometer drug-containing agglomerate and 1-99% of a carrier.
  • Nano drug-containing agglomerates from 0.1- 55% calcitonin, 0.5- 50% gel adhesive, 5-50% surfactant, 2-30% oleyl ester, 0- It consists of 10% co-surfactant and 0-90% diluent.
  • the particle size of the self-emulsifying nano-drug-containing agglomerates is 10-150um, which can self-emulsify into nano-sized w / o / w milk droplets;
  • the carrier consists of 0-10% gel adhesive, 0-20% water-insoluble adhesive, 70-100% diluent, 0-1% lubricant; the foregoing
  • the percentages of each component are percentages by weight.
  • the gel adhesive in the present invention is a polymer material capable of absorbing water and forming a gel, and one or more of natural-derived gum materials, artificial polymer materials, and starch dextrin materials are selected.
  • Naturally extracted gums such as alginate, acacia, shellac, chitosan, tragacanth, pectin, agar, etc.
  • the artificially synthesized polymer materials such as hydroxypropyl methylcellulose, hydroxy Propyl cellulose, carboxymethyl cellulose, etc.
  • the starch dextrin substances are starch and derivatives thereof, ⁇ , ⁇ , hydrazone-cyclodextrin and derivatives thereof, and the like.
  • the gel adhesive in the present invention is preferably a naturally-derived gum-like substance, such as chitosan and its derivatives.
  • the water-insoluble adhesive in the present invention is a polymer material that can absorb water but is insoluble in water, such as microcrystalline cellulose, ethyl cellulose, methyl cellulose, low-substituted hydroxypropyl cellulose, acrylic resin, etc. Species or species.
  • the surfactant used in the present invention is selected from polysorbate, poloxamer, Mjri, Brij, lecithin, soybean phospholipid, sodium lauryl sulfate, glyceryl monostearate, and sucrose ester.
  • the co-surfactant is one or more of natural extracted gums, synthetic polymer materials, ethanol, and propylene glycol.
  • the naturally extracted gums are alginate, acacia gum, and insects. Gum, chitosan, tragacanth, pectin, agar and the like, and the synthetic high-grade material is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose and the like.
  • Ester oil of the present invention is a natural extract selected vegetable oils such as soybean oil, synthetic fatty acid glycerides such as c 6 ⁇ c 16 in c 6 ⁇ c 16 fatty acid glycerides is preferably ODO.
  • the diluent is selected from one or more of starch and its derivatives, lactose, mannitol, sorbitol, cyclodextrin and its derivatives.
  • the preparation method of the present invention includes the following steps:
  • microemulsion hydrogel Dissolve calcitonin and gel adhesive separately or together in an appropriate amount of water. After the gel adhesive is swollen completely, mix the two and add water to the formula to obtain a medicated solution. Gel, ready for use; after mixing the surfactant, co-surfactant, oleyl ester, and diluent in proportion, mix it with the previously swollen medicated hydrogel to obtain bioadhesive microemulsion coagulation
  • the composition of the non-aqueous portion of the microemulsion hydrogel is (weight percent), calcitonin 0.1 to 55%, gel adhesive 0.5 to 50%, and surfactant 5-50 %, Oil ester 2-30%, co-surfactant 0-10%, diluent 0-90%, the weight ratio of non-aqueous portion to water is 1: 2-20;
  • Preparation of nasal dry powder inhalation agent Take 1-99% of self-emulsifying nanometer drug-containing agglomerate and 1-99% of the carrier, so that each gram of powder contains 1500-8000IU of calcitonin, according to the required dose Divided into vesicles, the calcitonin dry powder inhalant of the present invention is obtained.
  • the preparation process of the carrier is the same as that of the original patent application No. 01105431.X.
  • the gel adhesive in the carrier of the present invention corresponds to the bioadhesive material and diluent in the carrier of the original patent application.
  • the lubricant is a substance that improves the fluidity of the carrier. It can be magnesium stearate, sodium benzoate, leu (isoleucine), sodium dodecyl sulfate One kind, and the microcrystalline cellulose in the carrier of the original patent application is one of the water-insoluble adhesives in the present invention.
  • Nanoemulsion refers to a special emulsion with the diameter of the droplets at the nanometer scale.
  • Shah proposed the definition of microemulsions as: Microemulsions are two mutually incompatible liquids, which are thermodynamically stable, isotropic, and transparent dispersion systems produced by the action of a surfactant molecular interface film.
  • the surface tension of water is 72 mN ⁇ ⁇ ', which can be reduced to 30 ⁇ 40 mN-m-' by adding a surfactant
  • the interfacial tension of oil-water is ⁇ N ' ⁇ 1 , which can be reduced after adding a surfactant To several to a dozen mN 'riT ⁇ when the ratio of the three (oil, water, surfactant) is appropriate or In the presence of a suitable co-surfactant (alcohol), the oil-water interfacial tension is greatly reduced, and when it is as low as 10 mN'nf 1 , microemulsions are formed.
  • a suitable co-surfactant alcohol
  • the gel region and the microemulsion region are determined, and in these two regions, the drug-containing droplets exist in a nanometer size (within 500 nm, more preferably within 100 nm).
  • region II the three-phase mixture is a semitransparent, almost transparent solid that cannot flow freely; in I, it is a liquid with a viscosity similar to that of water, a free-flowing liquid with little or no blue fluorescence.
  • the freeze-drying or spray-drying method is used to remove the water in the microemulsion to obtain a self-emulsifying nano-liquid.
  • Powder which is a self-emulsifying nano-drug-containing agglomerate.
  • the medicinal solution can fully contact the surface of the nasal mucosa; the drug is wrapped in the interfacial film formed by the surfactant, which can increase Its stability in the nasal cavity; the hydrophilic aqueous solution of calcitonin is dispersed into a w / o / w type microemulsion in a colloidal solution composed of surfactant and oil, which increases its fat solubility and makes the drug easier from the side Increases absorption through the lipid bilayer of the nasal mucosa. There are abundant lymphatics in the nasal cavity.
  • the fat solubility of the drug increases, it can be absorbed into the systemic circulation through the lymphatic system, thereby further improving its bioavailability.
  • the microemulsion is added with a bioadhesive that can be dissolved in water to form a gel, so that the drug can adhere to the nasal mucosa for a longer period of time and exert its curative effect.
  • the nasal mucosal toxicity test of the surfactant and other auxiliary materials used in the preparation showed that no damage and inhibition were caused to the nasal mucosa and nasal cilia.
  • Experimental device Install a transmembrane device as shown in Figure 2. Cut the chicken capsule into a suitable size, fix it between the diffusion chamber and the receiving chamber, and inject physiological saline into the receiving chamber to make the liquid level of the sampling tube slightly higher. On the membrane, record the amount of solution added. Turn on the magnetic stirrer and constant temperature oil bath, keep constant stirring, 37 ° C constant temperature, use a micropipette to transfer 200 ⁇ 1 calcitonin solution into the diffusion chamber, take 1ml at each time point, and replenish in the receiving chamber 1 ml of fresh saline. Put the obtained samples in the refrigerator in time for testing.
  • Fig. 2 1 is a stirrer, 2 is a relay, 3 is a receiving chamber, 4 is a diffusion chamber, 5 is a heating wire, 6 is an oil bath, 7 is a probe, 8 is a chicken capsule, and 9 is a thermometer.
  • Mobile phase B acetonitrile: 0. 0222mol / L tetramethylammonium hydroxide solution 2 5: 45, pH adjusted to 2.5 by phosphoric acid,
  • the elution was programmed, and the mobile phase A linearly increased from 35% (65% for mobile phase B) to 57% (43% for mobile phase B) over 21 minutes.
  • UV detection wavelength 220nm
  • Sample 2 microemulsion before lyophilization (diluted with water to lmg / ml);
  • the irritation test of the calcitonin nasal dry powder inhalant of the present invention is as follows:
  • Calcitonin nasal dry powder inhalation at 300 IU / rabbit is equivalent to about 52. 5-210 times the dose of a human, and about 18-71 times the dose of a human by surface area) Nasal spray was used for the maximum dose test, and no death was observed. Twenty-four hours after the administration, the animals were sacrificed, and the local mucosal tissue was removed. No mucosal congestion and redness were seen. The maximum dose of calcitonin dry powder inhaler is 300 mg / rabbit.
  • Calcitonin dry nasal powder inhaler at 200 IU / rabbit (approximately 48 times as much as a human dose based on body surface area and approximately 140 times as much as a human dose by weight). A single dose of 200IU / rabbit) and multiple times (administration for 7 consecutive days, the total dose is 1400IU / rabbit) were sprayed into the nasal mucosal stimulation test, and no obvious morphological and pathological observation was observed with the drug. Related irritating reactions and symptoms.
  • the salmon calcitonin according to the present invention has faster drug absorption and more complete absorption than the original patent application technology after administration through the dry nasal powder, and the duration is basically the same. Therefore, this patent can more effectively promote calcitonin to penetrate the nasal mucosal barrier, absorb into the blood, and exert its function.
  • the technical effects of the present invention are as follows:
  • the present invention combines the self-emulsifying microemulsion technology and bioadhesion technology for the first time in a dry powder inhaler for respiratory tract administration, prepares calcitonin into a concentrated microemulsion, and composites it with a polymer material It forms a bioadhesive solid powder. After the drug is administered into the nasal cavity, it absorbs water and self-emulsifies into W / 0 / W, nano-sized microemulsions.
  • lymph vessels enter the body to play a curative effect, which can significantly improve the bioavailability of the drug, rapid absorption, and non-irritating to the nasal mucosa;
  • the drug-containing agglomerates swell after absorbing water, and can stay in the nasal mucosa for a long time, making the drug Absorption and utilization are more complete.
  • FIG. 1 is a three-phase diagram of an oil phase, a water phase, and a surfactant phase.
  • Figure 2 is a diagram of a transmembrane device.
  • Figure 3 shows the results of the transmucosal test of calcitonin.
  • Figure 4 is a graph of blood calcium versus time after nasal administration.
  • Figure 5 is a graph of blood concentration versus time after nasal administration.
  • the hydrogel was lyophilized in a freeze drier for 20 hrs. After taking out the lyophilisate, sieving a 100-400 mesh powder (particle size: 37.5 ⁇ 150um) to obtain a drug-containing microemulsion agglomerate. After dissolving the drug-containing agglomerate in water, a microemulsion having an average particle diameter of less than 100 nm can be obtained. Take 1.31 g of the aforesaid medicated microemulsion agglomerate, based on calcitonin titer of 5000IU / mg, powder dose of 50IU / capsule or 100, 200IU / capsule, and Example 1 in the specification of Patent No. 01105431 The carrier is mixed with 25g, so that each gram of powder contains calcitonin 1500-8000IU, and it is divided into two-dose blister according to the required dose to obtain the preparation of the present invention.
  • Embodiment two is
  • Example three Take salmon calcitonin 0.01g, hydroxypropyl methylcellulose lg, water 20g (20ml), polysorbate 0.4g, benzyl 0.2g, refined soybean oil 0.3g, lactose lg and dissolve according to the procedure in Example 1. After mixing or mixing, freeze-dry for 20 hours and sieve 100-400 mesh powder (particle size: 37.5 ⁇ 150 ⁇ m) to obtain the drug-containing microemulsion agglomerate.
  • Oil ester refined soybean oil 3g,
  • Carrier 50g of lactose.
  • Embodiment 8 The preparation method is the same as in Example 1. Embodiment 8:
  • Surfactants 20g sodium lauryl sulfate, 20g glyceryl monostearate, 10g sucrose ester,
  • Oil ester 30g of refined soybean oil
  • Carrier lactose 50g,
  • Carrier 12g of lactose.
  • the preparation method is the same as that of the first embodiment and the tenth embodiment:
  • the amount of each raw material in this embodiment is as follows: salmon calcitonin lg,
  • Surfactant Maize 40g, co-surfactant: 10g propylene glycol, oil ester: glyceryl caprylate, 24g, carrier: 5g lactose.
  • the preparation method is the same as in Example 1.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
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  • Orthopedic Medicine & Surgery (AREA)
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  • Otolaryngology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

La présente invention concerne un produit d'inhalation en poudre sèche intranasale de calcitonine et une technique de préparation de celui-ci. Ce produit d'inhalation est constitué d'un agglomérat et d'excipients contenant un médicament de taille nanométrique qui s'auto-émulsifie, dont la formule est constituée de 0.1-55% de calcitonine, de 0.5-50% d'adhésifs en gel, de 5-50% de tensioactifs, de 2-30% d'huiles et de corps gras, de 0-10% de tensioactifs d'assistance et de 0-90% de diluants et, le diamètre de ces poudres d'agglomérat est compris entre 10 et 150 um et, lorsqu'elles sont en contact avec un milieu aqueux, elles s'auto-émulsifient en gouttelettes w/o/w de taille nanométrique. Avec l'effet du tensioactif, la calcitonine et la phase d'huile forment un gel de micro-émulsion avec une matière bioadhésive hydrophile. Après avoir été déshydratées, des poudres solides bioadhésives qui contiennent la calcitonine et qui peuvent s'auto émulsifier dans une taille nanomanométrique sont obtenues. Ensuite le mélange des poudres avec des nanoexcipients et l'emballage, le produit d'inhalation en poudre déshydratée intranasale est produit. Cette invention présente pour la première fois une technologie d'auto-émulsion avec une technologie bio-adhésive, le médicament résultant possédant une capacité trans mucosale forte et une bio-disponibilité élevée, de même qu'il peut être rapidement absorbé.
PCT/CN2004/001363 2003-12-16 2004-11-26 Technique de preparation de produit d'hinalation en poudres deshydratees intranasale de calcitonine Ceased WO2005058289A1 (fr)

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CN200310117465.7 2003-12-16
CNA2003101174657A CN1546169A (zh) 2003-12-16 2003-12-16 一种降钙素经鼻干粉吸入剂及制备方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118453519A (zh) * 2024-05-28 2024-08-09 南京康舟医药科技有限公司 一种鲑降钙素鼻喷制剂及其制备方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100400097C (zh) * 2005-08-22 2008-07-09 上海医药工业研究院 一种胰岛素经鼻给药液体制剂
CN104208029B (zh) * 2013-05-30 2017-06-06 上海医药工业研究院 一种鼻用疫苗组合物粉体制剂及其制备方法
CN115920010B (zh) * 2022-09-27 2023-09-19 深圳大佛药业股份有限公司 一种鲑降钙素组合物喷雾剂及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032149A1 (fr) * 1995-04-14 1996-10-17 Inhale Therapeutic Systems Administration par voie pulmonaire de medicaments en aerosols
CN1179723A (zh) * 1995-08-15 1998-04-22 旭化成工业株式会社 含有生理活性肽的经粘膜给药制剂
CN1370523A (zh) * 2001-02-27 2002-09-25 国家医药管理局上海医药工业研究院 一种鼻用鲑降钙素粉末吸入剂及制备方法
CN1422160A (zh) * 2000-02-04 2003-06-04 尤尼金实验室公司 鼻内降钙素制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032149A1 (fr) * 1995-04-14 1996-10-17 Inhale Therapeutic Systems Administration par voie pulmonaire de medicaments en aerosols
CN1179723A (zh) * 1995-08-15 1998-04-22 旭化成工业株式会社 含有生理活性肽的经粘膜给药制剂
CN1422160A (zh) * 2000-02-04 2003-06-04 尤尼金实验室公司 鼻内降钙素制剂
CN1370523A (zh) * 2001-02-27 2002-09-25 国家医药管理局上海医药工业研究院 一种鼻用鲑降钙素粉末吸入剂及制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118453519A (zh) * 2024-05-28 2024-08-09 南京康舟医药科技有限公司 一种鲑降钙素鼻喷制剂及其制备方法

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