CN106265666B - Improve the composition and its preparation method and application of insoluble drug Loratadine release - Google Patents

Improve the composition and its preparation method and application of insoluble drug Loratadine release Download PDF

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Publication number
CN106265666B
CN106265666B CN201610828611.4A CN201610828611A CN106265666B CN 106265666 B CN106265666 B CN 106265666B CN 201610828611 A CN201610828611 A CN 201610828611A CN 106265666 B CN106265666 B CN 106265666B
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loratadine
composition
method described
polymer
mixing
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CN106265666A (en
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傅强
畅瑞苗
曾爱国
杜玮
常春
陈国宁
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Xian Jiaotong University
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Xian Jiaotong University
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K47/30—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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses a kind of compositions and its preparation method and application for improving insoluble drug Loratadine release.The preparation method comprises the following steps: Loratadine solution is rapidly injected polymer solution, dry after mixing, obtains the unformed composition of Loratadine-polymer.The composition being prepared can be obviously improved the release performance of Loratadine, improve the bioavilability of Loratadine.The preparation method of the composition is simple, can be used for the industrialized production of Loratadine preparation.

Description

Improve insoluble drug Loratadine release composition and preparation method thereof and Using
Technical field
The present invention relates to biomedicine technical fields, are related to a kind of antiallergic compositions, and in particular to a kind of H1By The preparation of the unformed composition of body blocking agent.
Background technique
Allergic reaction is a kind of allergic disease, is human contact's certain special anaphylactogen (such as foreign seras, disease Poison, bacterium, plant pollen and dust etc.) when the abnormal response that is occurred.When allergic reaction occurs, the group that is discharged from cell Amine can generate red swelling of the skin, itch, allergic rhinitis, the symptom of bronchial asthma in conjunction with the specific receptor on target cell, Simultaneously also with clinical manifestations such as blood pressure decline, increased heart rate and oedema, it is even dead that serious person there is also shock.Due to group Amine plays a significant role in the pathophysiological mechanism of anaphylactic disease, therefore studies antihistamine approach as research antiallergic Effective ways.The antihistamine drug of Present clinical application is mainly H1Receptor antagonist.
Entitled 4- (chloro- 5,6- dihydro -11H- benzo [5,6] suberyl [1,2- of 8- of Loratadine (Loratadine) chemistry B] and pyridine -11- alkene) -1- piperidine carboxylate, molecular structure is as follows, is opened by Schering-Plough company, the U.S. The second generation H of hair1Receptor antagonist.
Relevant report about Loratadine are as follows: United States Patent (USP) US 4,282,233 make public for the first time antihistamine chlorine thunder he It is fixed, and disclose its synthetic method.United States Patent (USP) US 4,731,447 and Chinese patent CN02824346.3 describe chlorine thunder he Fixed different synthetic routes.United States Patent (USP) US6,335,347 discloses the purification process of Loratadine crystal form.
Loratadine is not easily accessible central nervous system, optionally blocks periphery H1Receptor, have it is potent selectivity, The characteristics of no cholinergic acts on clinically is mainly used for treating allergic rhinitis.Loratadine bulk pharmaceutical chemicals are white crystalline powder End, odorless, tasteless is readily soluble in methanol, ethyl alcohol, acetone, dissolved in ether and indissoluble in water.Loratadine is in aqueous solution Dissolubility is poor, leads to poor bioavailability after human administration, therefore improve Loratadine solubility, so as to improve its biological utilisation The method of degree is that extremely have application value.
Summary of the invention
It is an object of that present invention to provide a kind of composition for improving insoluble drug Loratadine release and its preparation sides Method and application.
In order to achieve the above objectives, the invention adopts the following technical scheme:
It is a kind of improve insoluble drug Loratadine release composition, the composition be Loratadine-polymer without Hairstyling composition, the unformed composition include 0.1~30% Loratadine and 70%~99.9% as mass fraction Hydrotropy polymer.
The hydrotropy polymer is one of hydroxypropyl methyl cellulose, polyvinylpyrrolidone, Macrogol 4000 Or two kinds (if it is two kinds, mass ratio is preferably 1:1)；Using Cu-K α target, the unformed composition in scanning range X-ray powder diffraction pattern circlewise, the characteristic absorption peak without crystal.
The preparation method of the composition of above-mentioned raising insoluble drug Loratadine release, comprising the following steps:
Loratadine bulk pharmaceutical chemicals are dissolved in organic solvent miscible with water and Loratadine solution is made, by hydrotropy polymer Obtained aqueous solutions of polymers soluble in water, Loratadine solution and aqueous solutions of polymers are filtered after mixing, will be filtered The filter residue vacuum drying or spray drying arrived, obtain the unformed composition of Loratadine-polymer.
Preferably, the organic solvent is methanol, ethyl alcohol or acetonitrile.
Preferably, the concentration of the Loratadine solution is 10 μ g/mL~100mg/mL.
Preferably, the polymer is hydroxypropyl methyl cellulose, one kind of polyvinylpyrrolidone, Macrogol 4000 Or two kinds (if it is two kinds, mass ratio is preferably 1:1).
Preferably, the mass fraction of the aqueous solutions of polymers is 0.05%~5%.
Preferably, the mixed volume ratio of the Loratadine solution and aqueous solutions of polymers is 1:5~1:25.
Preferably, the mixing being mixed under stirring, mixing temperature are 20 DEG C~30 DEG C, and mixing speed is 100r/min~700r/min, mixing time are 5~25min.
Preferably, the vacuum drying condition are as follows: be placed in 20~60 DEG C of vacuum ovens dry 6~12h.
Application of the composition of above-mentioned raising insoluble drug Loratadine release in preparation antihistamine drug.
The invention has the benefit that
Composition provided by the invention is the unformed composition of Loratadine-polymer, can be obviously improved Loratadine Release performance, improve the bioavilability of Loratadine.The preparation method of the composition is simple, can be used for Loratadine system The industrialized production of agent.
Detailed description of the invention
Fig. 1 is Loratadine-polymer composition-I X-ray powder diffraction figure；
Fig. 2 is Loratadine-polymer composition-II X-ray powder diffraction figure；
Fig. 3 is Loratadine bulk pharmaceutical chemicals, the concentration time curve of Loratadine-polymer composition in water；A-chlorine Lei Tading bulk pharmaceutical chemicals, b-Loratadine-polymer composition-I, c-Loratadine-polymer composition-II.
Specific embodiment
Below will by embodiment, the present invention is further explained, but the protection scope being not intended to restrict the invention.
X-ray powder diffraction figure acquires on Shimadzu XRD-6100X x ray diffractometer x in the present invention.X-ray diffractometer ginseng Number: Cu-K α target is used, fixed tube voltage: 40kV, tube current: 30mA, step-length: 0.02 °, 2 θ: 5 °~45 ° of scanning range, scanning Speed: 2 °/min, the duration: 0.06s.
Loratadine bulk pharmaceutical chemicals are first public in United States Patent (USP) US 4,282,233 in the present invention.
Embodiment 1
Loratadine-polymer composition-I preparation method:
Loratadine bulk pharmaceutical chemicals are dissolved in the Loratadine methanol solution for obtaining that concentration is 100 μ g/mL in methanol, take 10mL The Loratadine methanol solution that concentration is 100 μ g/mL and the hydroxypropyl methyl cellulose that 200mL mass fraction is 0.1% are water-soluble Liquid quickly mixes two kinds of solution under 25 DEG C ± 5 DEG C, 200r/min mixing speed, stirs 20min, filters, filter residue is set Dry 8h, is recycled solid (being denoted as Loratadine-polymer composition-I) in 50 DEG C of vacuum ovens.Obtained chlorine thunder he In fixed-polymer composition-I, the content of Loratadine is 0.5% (mass fraction), and the content of hydroxypropyl methyl cellulose is 99.5% (mass fraction).
Through detecting, the composition that the present embodiment is prepared is unformed state, X-ray powder diffraction figure such as Fig. 1 institute Show.
Embodiment 2
Loratadine-polymer composition-II preparation method:
Loratadine bulk pharmaceutical chemicals are dissolved in the Loratadine methanol solution for obtaining that concentration is 100 μ g/mL in methanol, take 10mL The Loratadine methanol solution that concentration is 100 μ g/mL and the polyvinylpyrrolidone-K30 that 200mL mass fraction is 0.1% or K15 aqueous solution quickly mixes two kinds of solution under 25 DEG C ± 5 DEG C, 200r/min mixing speed, stirs 20min, filters, will Filter residue is placed in 50 DEG C of vacuum ovens dry 8h, recycles solid (being denoted as Loratadine-polymer composition-II).It obtains In Loratadine-polymer composition-II, the content of Loratadine is 0.5% (mass fraction), and polyvinylpyrrolidone contains Amount is 99.5% (mass fraction).
Through detecting, the composition that the present embodiment is prepared is unformed state, X-ray powder diffraction figure such as Fig. 2 institute Show.
Loratadine-the polymer composition I and II for taking Loratadine bulk pharmaceutical chemicals, embodiment 1,2 to be prepared respectively is each 25.0mg, according to 2015 editions four 0931 dissolution rates of Chinese Pharmacopoeia and the first method of drug release determination method, revolving speed 100r/min is molten Medium is the brand-new distilled water of 500mL out, is operated according to methods, respectively 0,5,10,15,20,30,45,60,90,120,180, 240,300,360,420 and 480min samples 5mL, and 0.45 μm of miillpore filter filtration takes subsequent filtrate, carries out at 247nm ultraviolet Measurement, calculates the concentration at each time point.As a result as shown in figure 3, from figure 3, it can be seen that the dissolution rate of composition I and II and molten Degree is all apparently higher than bulk pharmaceutical chemicals out, wherein and there is obvious saturation-supersaturation in Loratadine in composition I, and Composition II kind Loratadine concentration reaches level ground after increasing, and is finally reached the concentration for being higher than composition I.

Claims (7)

1. a kind of prepare the method for improving the composition of insoluble drug Loratadine release, it is characterised in that: including following Step: Loratadine bulk pharmaceutical chemicals being dissolved in organic solvent miscible with water and Loratadine solution be made, and hydrotropy polymer is molten Aqueous solutions of polymers is made in Yu Shuizhong, and Loratadine solution and aqueous solutions of polymers are taken out after mixing under stirring Filter, mixing time are 5~25min, and filter residue is dried in vacuo or is spray-dried, obtains the unformed combination of Loratadine-polymer Object；The unformed composition includes that 0.1%~0.5% Loratadine and 99.5%~99.9% help as mass fraction Insoluble polymer.
2. according to the method described in claim 1, it is characterized by: the organic solvent is methanol, ethyl alcohol or acetonitrile.
3. according to the method described in claim 1, it is characterized by: the concentration of the Loratadine solution be 10 μ g/mL~ 100mg/mL。
4. according to the method described in claim 1, it is characterized by: the polymer is hydroxypropyl methyl cellulose, polyethylene One or both of pyrrolidones, Macrogol 4000.
5. according to the method described in claim 1, it is characterized by: the mass fraction of the aqueous solutions of polymers be 0.05%~ 5%.
6. according to the method described in claim 1, it is characterized by: the mixing of the Loratadine solution and aqueous solutions of polymers Volume ratio is 1:5~1:25.
7. according to the method described in claim 1, mixing speed is it is characterized by: the mixing temperature is 20 DEG C~30 DEG C 100r/min~700r/min；The vacuum drying condition are as follows: be placed in 20~60 DEG C of vacuum ovens dry 6~12h.
CN201610828611.4A 2016-09-18 2016-09-18 Improve the composition and its preparation method and application of insoluble drug Loratadine release Expired - Fee Related CN106265666B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100998551A (en) * 2006-12-22 2007-07-18 江苏奥赛康药业有限公司 Oral cavity quick dissolved film containing civeran, and method for preparing the same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8313774B1 (en) * 2012-06-26 2012-11-20 Magnifica Inc. Oral solid composition

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100998551A (en) * 2006-12-22 2007-07-18 江苏奥赛康药业有限公司 Oral cavity quick dissolved film containing civeran, and method for preparing the same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Dissolution rate enhancement of loratadine in polyvinylpyrrolidone K-30 solid Dispersions by solvent methods;Fernando Frizon等;《Powder Technology》;20121022;第235卷;第532-539页，尤其是第532页左栏第1段，第533页右栏第3段，第536页左栏倒数第1段，右栏第1段，右栏倒数第1段
Physicochemical characterization and dissolution enhancement of loratadine by solid dispersion technique;Suresh Bandari等;《Korean J.Chem.Eng》;20131231;第30卷(第1期);第238-244页，尤其是第238页摘要，第239页左栏第6段

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