CN102309448B - Pulmonary delivery ciprofloxacin pharmaceutical composition and preparation method thereof - Google Patents
Pulmonary delivery ciprofloxacin pharmaceutical composition and preparation method thereof Download PDFInfo
- Publication number
- CN102309448B CN102309448B CN201010212441.XA CN201010212441A CN102309448B CN 102309448 B CN102309448 B CN 102309448B CN 201010212441 A CN201010212441 A CN 201010212441A CN 102309448 B CN102309448 B CN 102309448B
- Authority
- CN
- China
- Prior art keywords
- ciprofloxacin
- liposome
- preparation
- composition
- peg
- 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.)
- Active
Links
Abstract
The invention belongs to the field of drugs and pharmaceutics and relates to a pulmonary delivery ciprofloxacin pharmaceutical composition. In particular, a liposome modified by PEG (Polyethylene Glycol) is used as a drug carrier in the composition; the liposome modified by the PEG is that PEG molecules are directly connected to the liposome; or the liposome is coated by the PEG molecules. The invention further relates to the preparation method of the composition. According to the composition disclosed by the invention, the stability is good; the action time is prolonged; the better antibacterial effect is obtained; furthermore, the pulmonary effective treatment concentration can be achieved rapidly; the bioavailability is high; the composition is convenient to carry; and the composition can be taken independently.
Description
Technical field
The invention belongs to medicine and pharmaceutics field, relate to ciprofloxacin Pharmaceutical composition of a kind of pulmonary administration and preparation method thereof.
Background technology
Ciprofloxacin is third generation carbostyril family antibacterial drugs, the various features such as tool has a broad antifungal spectrum, antimicrbial power are strong, simple in structure, convenient drug administration.It is by acting on the A subunit of DNA of bacteria helicase, suppresses the synthetic of DNA and copies and cause antibacterial death.Ciprofloxacin has broad-spectrum antibacterial action, very strong to the antibacterial activity of gram negative bacteria.Following antibacterial is had to good antibacterial action in vitro: most of antibacterial of enterobacteriaceae, comprises that citrobacter belongs to, the Enterobacters such as cloaca, clostridium perfringen, escherichia coli, Klebsiella, Proteus, Salmonella, Shigella, vibrio and Ye Ersen Pseudomonas etc.Multi-drug resistant bacteria is also had to antibacterial activity, as the Diplococcus gonorrhoeae to Penicillin-resistant, product enzyme hemophilus influenza and Moraxella all have antibacterial activity highly.To most of bacterial strain tool antibacterial actions of the Rhodopseudomonass such as Pseudomonas aeruginosa (bacillus pyocyaneus being commonly called as).The staphylococcus of methicillin-sensitivity is also had to an antibacterial activity, to streptococcus pneumoniae, Hemolytic streptococcus and the medium antibacterial activity of enterococcus faecalis tool.To chlamydia trachomatis, mycoplasma, anti-microbial effect that legionella tool is good, mycobacterium and atypical mycobacteria are also had to antibacterial activity; Poor to the antibacterial activity of anaerobe.
The onset of ciprofloxacin oral administration is slow, drug administration by injection patient poor compliance.And that pulmonary administration has sorbent surface is long-pending large, absorption site blood flow is abundant, avoids the first pass effect of liver,, enzymatic activity is low, and the thinner and membrane permeability high of epithelium barrier, therefore, can reach pulmonary effectively to treat concentration fast, and bioavailability is high.Pulmonary inhalation novel form mainly contains aerosol, spray and powder spray, easy to use, onset feature rapidly that inhalation has.Powder spray, for breathing initiatively, has overcome drug release and has sucked inharmonic problem.
Liposome has following characteristics as the carrier of pulmonary administration: alveolar surfactant is mainly by Lipid composition, and main component is dipalmitoyl phosphatidyl choline.Liposome is to be formed by phospholipid bilayer equally, identical with pulmonary endogenous material, thereby both have good biocompatibility; In topical therapeutic, make that medicine directly acts on target spot, rapid-action, dosage is low, long action time, the medication amount that enters body circulation is few, and side effect is low; Medicine, with after liposomal encapsulated, can reduce drug toxicity, alleviates local excitation and injury of lung after pulmonary administration.
Existing Canadian document discloses the preparation (Desai of a kind of ciprofloxacin liposome for Pulmonary inhalation, T.R.et al.2003.Delivery of liposomes in drypowder form:a erodynamic dispersion properties.Eur.J.Pharm.Sci.20,459-467, Jonathan P.Wong, et al.2003.Liposomedelivery of ciprofloxacin against intracellular Francisellatularensis infection.Journal of Controlled Release.92, 265-273.), after it forms ciprofloxacin liposome by lecithin or dipalmitoyl phosphatidyl choline and cholesterol preparation, the powder that spraying lyophilizing makes mixes with lactose, make pulmonary's Foradil Aerolizer formoterol fumarate or directly ciprofloxacin liposome is made to spray (Lyle G.Sweeney et al.2005.Spray-freeze-dried liposomal ciprofloxacin powder for inhaledaerosol drug deliveryInternational Journal ofPharmaceutics.305, 180-185, Tejas R.Desai et al.2001.Determination of surface free energy of interactive dry powderliposome formulations using capillary penetration technique.Colloids and Surfaces B:Biointerfaces.22,107-113, W.H.Finlay, J.P.Wong, 1998, Regional lung deposition of nebulizediposome-encapsulated iprofloxacin.International Journal ofPharmaceutics.167,121-127.).The liposome that this method makes is stable not, and the seepage of liposome easily occurs, and then affects the quality of the pharmaceutical preparations.
The present invention is by phospholipid material directly being connected to PEG molecule or with PEG molecule coated-liposome, obtaining the liposome of PEGization, to improve the stability of liposome, and prolongation action time.The present invention adds absorption enhancer simultaneously, reduces pulmonary's clearance rate, is beneficial to the pulmonary absorption of ciprofloxacin.
Summary of the invention
One aspect of the present invention relates to a kind of ciprofloxacin Pharmaceutical composition of pulmonary administration, and its liposome of modifying using PEG is as the carrier of ciprofloxacin.Particularly, the liposome that described PEG modifies be PEG molecule by covalent bond the nitrogenous base on phospholipid molecule after being combined, prepare liposome, or be injected in PEG solution and form coated-liposome preparing gained liposome.
In one embodiment of the invention, described PEG is PEG1500, PEG2000 or PEG4000, particularly, is PEG2000.
In one embodiment of the invention, described ciprofloxacin is ciprofloxacin or ciprofloxacin lactate, particularly, is ciprofloxacin.
In one embodiment of the invention, described liposome is the complex that phospholipid or itself and other material are connected to form, described phospholipid is selected from one or more in PC (EPC), dipalmitoyl phosphatidyl choline (DPPC), two nutmeg phosphatidyl cholines (DMPC), two nutmeg acyl phosphatidyl glycerols (DMPG), and described complex is selected from one or more in EPC-PEG, DPPC-PEG, DMPC-PEG, DMPG-PEG.Described other material can be, for example, and cholesterol.The mol ratio of described ciprofloxacin and phospholipid and/or phosphatide complexes is 1/1 to 1/10, particularly, is 1/5.
In one embodiment of the invention, described compositions is aerosol, spray or powder spray, particularly, is powder spray.
In one embodiment of the invention, described compositions also comprises propellant, cosolvent, surfactant, absorption enhancer or excipient.
In one embodiment of the invention, described propellant is tetrafluoroethane (HFA134a) and/or heptafluoro-propane (HFA227), described cosolvent is ethanol and/or propylene glycol, described surfactant is selected from one or more in Tween 80, sorbester p37, oleic acid, phosphatidylcholine, and described absorption enhancer is selected from one or more in sodium cholate, sodium caprylate, Brij 78, rare earth compound Gadolinium trichloride.
In one embodiment of the invention, described excipient is selected from lactose, mannitol, aminoacid or phospholipid, particularly, is lactose, and the mass ratio of described ciprofloxacin and excipient lactose is 1/3 to 1/10, and preferably 1/5.
In one embodiment of the invention, the particle size range of described compositions is 100 μ m to 200 μ m, particularly, is 150 μ m.The present invention is by using nano particle size and Zeta potential and molecular weight analyse instrument to measure the granularity of lactose, and selecting its particle size range is 100 μ m to 200 μ m, and preferably 150 μ m, to reach the demand of lactose as powder spray carrier.
Also aspect of the present invention relates to the preparation method of above-mentioned compositions, comprise by PEG molecule by covalent bond the nitrogenous base on phospholipid molecule after being combined, prepare again liposome, or or be injected in PEG solution and form coated-liposome preparing gained liposome.
The beneficial effect of the invention
1) it is stable not that compositions of the present invention has overcome in the ciprofloxacin compositions of existing pulmonary administration liposome, easily there is the deficiency of liposome seepage, the good stability of compositions (comprising the liposome in compositions), and extend action time, obtained better antibacterial effect;
2) it is slow that the present invention has overcome the onset of ciprofloxacin oral administration, and the shortcoming of drug administration by injection patient poor compliance can reach fast pulmonary and effectively treat concentration, and bioavailability is high, and easy to carry, independently medication.
The specific embodiment
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example is only for the present invention is described, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, carries out according to the condition of normal condition or manufacturer's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
Embodiment 1: the preparation of control sample
With reference to preparing control sample as Publication about Document:
Tejas R.Desai et al.2001.Determination of surface freeenergy of interactive dry powder liposome formulations usingcapillary penetration technique.Colloids and Surfaces B：Biointerfaces.22，107-113；W.H.Finlay，J.P.Wong，1998，Regional lung deposition of nebulized iposome-encapsulatediprofloxacin.International Journal of Pharmaceutics.167，121-127.
Particularly, prescription is as follows:
Ciprofloxacin 0.11g
DPPC 0.55g
Cholesterol 0.45g
Lactose 2.2g
0.6M ammonium sulfate solution 20ml
Preparation method: DPPC and the cholesterol of getting recipe quantity are dissolved in chloroform reduction vaporization, with the ammonium sulfate hydration of 0.6M, ultrasonic granulate, with a certain amount of normal saline dialysis 12h, add the medicine of recipe quantity, 50 ℃ of water-baths hatching 5min, make superfine powder after lyophilizing, powder is mixed homogeneously with lactose pack particular container into and obtain sample 1.
Embodiment 2: the preparation of spray dosage form sample of the present invention
Write out a prescription as follows:
Ciprofloxacin 0.11g
DPPC-PEG2000 0.55g
Cholesterol 0.45g
Tween 80 0.1ml
0.6M ammonium sulfate solution 20ml
Preparation method: DPPC-PEG2000 and the cholesterol of getting recipe quantity are dissolved in chloroform reduction vaporization, with the ammonium sulfate hydration of 0.6M, ultrasonic granulate, with a certain amount of normal saline dialysis 12h, adds the medicine of recipe quantity, 50 ℃ of water-bath hatching 5min.This sample is mixed homogeneously with Tween 80 pack in specific spray bottle and obtain sample 2.
Embodiment 3: the preparation of aerosol dosage forms sample of the present invention
Write out a prescription as follows:
Ciprofloxacin 0.11g
DPPC-PEG2000 0.55g
Cholesterol 0.45g
Tween 80 0.1ml
Tetrafluoroethane (HFA134a) 3ml
0.6M ammonium sulfate solution 20ml
Make method: DPPC-PEG2000 and the cholesterol of getting recipe quantity are dissolved in chloroform reduction vaporization, with the ammonium sulfate hydration of 0.6M, ultrasonic granulate, with a certain amount of normal saline dialysis 12h, adds the medicine of recipe quantity, 50 ℃ of water-bath hatching 5min.This sample is mixed homogeneously and packed into after particular container with Tween 80, and filling tetrafluoromethane obtains sample 3.
Embodiment 4: the preparation of powder spray dosage form sample of the present invention
Write out a prescription as follows:
Ciprofloxacin 0.11g
DPPC-PEG2000 0.55g
Cholesterol 0.45g
0.6M ammonium sulfate solution 20ml
Lactose 2.2g
Preparation method: DPPC-PEG2000 and the cholesterol of getting recipe quantity are dissolved in chloroform reduction vaporization, with the ammonium sulfate hydration of 0.6M, ultrasonic granulate, with a certain amount of normal saline dialysis 12h, add the medicine of recipe quantity, 50 ℃ of water-baths hatching 5min, make superfine powder after spraying lyophilizing, powder are mixed homogeneously with lactose pack particular container into and obtain sample 4.
Embodiment 5: streptococcus pneumoniae antibacterial tests
1. material therefor and reagent
Animal: Kunming mouse body weight 18-22g, male and female half and half.
Bacterial strain: streptococcus pneumoniae.
Be subject to reagent group: administration is sample 4.
Matched group: administration is sample 1.
Streptococcus pneumoniae group: give normal saline.
2. test method
(1) mensuration of the MLD of bacterial strain: clinical isolates strain is incubated on broth bouillon in test the previous day, make certain density bacteria suspension with 5% yeast soln, get mice some, lumbar injection 5% yeast, the streptococcus pneumoniae of variable concentrations, volume injected is 0.5ml/, records the animal dead number of a week, finds out the MLD of above-mentioned animal dead.The MLD that records streptococcus pneumoniae is 10
6/ ml.
(2) antibacterial tests: get 110 mices, body weight 18-22g, male and female half and half, are divided into 11 groups at random, 10 every group.The present invention is subject to reagent group and positive control drug group, within first four days, gives medicine by inbalation administration device in infection, be administered once every day, totally four days.Streptococcus pneumoniae abdominal cavity infection amount is 10
6individual/above-mentioned 5% yeast soln of milliliter is made certain density bacteria suspension.Then observe 1 week, record animals survived situation, calculate ED
50and 95% fiducial limit.
3. antibacterial tests result
Table 1: to the anti-bacterial result of streptococcus pneumoniae infection mice
The result of table 1 shows, the present invention has the effect of anti-streptococcus pneumoniae, and its antibacterial effect is better than contrasting medicine.
Embodiment 6: staphylococcus aureus antibacterial tests
In the present embodiment, except bacterial strain uses therefor is staphylococcus aureus, all the other test materials and method are as in Example 5.The MLD that records staphylococcus aureus is 10
6individual/ml.Infection of staphylococcus aureus amount is 10
6individual/ml.Result as shown in Table 2 below.
Table 2: to the anti-bacterial result of infection of staphylococcus aureus mice
The result of table 2 shows, the effect that the present invention has anti-Staphylococcus aureus to infect, and effect is better than contrasting medicine.
Embodiment 7: uncle pneumobacillus antibacterial tests
In the present embodiment, except bacterial strain uses therefor is uncle pneumobacillus, all the other test materials and method are as in Example 5.The MLD that records uncle pneumobacillus is 10
5individual/ml.Uncle pneumobacillus infective dose is 10
5individual/ml.Result as shown in Table 3 below.
Table 3: to the anti-bacterial result of uncle pneumobacillus infecting mouse
The result of table 3 shows, the effect that the present invention has anti-uncle pneumobacillus to infect, and effect is better than contrasting medicine.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (2)
1. a ciprofloxacin Pharmaceutical composition for pulmonary administration, it is powder spray, and it is composed as follows:
2. the preparation method of the ciprofloxacin Pharmaceutical composition of pulmonary administration claimed in claim 1, comprises the steps:
Get DPPC-PEG2000 and cholesterol and be dissolved in chloroform reduction vaporization, with the ammonium sulfate solution hydration of 0.6M, ultrasonic granulate, with a certain amount of normal saline dialysis 12h, add ciprofloxacin, 50 ℃ of water-bath hatching 5min, make superfine powder after spraying lyophilizing, and powder is mixed homogeneously and packed particular container into and get final product with lactose.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010212441.XA CN102309448B (en) | 2010-06-29 | 2010-06-29 | Pulmonary delivery ciprofloxacin pharmaceutical composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010212441.XA CN102309448B (en) | 2010-06-29 | 2010-06-29 | Pulmonary delivery ciprofloxacin pharmaceutical composition and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102309448A CN102309448A (en) | 2012-01-11 |
| CN102309448B true CN102309448B (en) | 2014-07-09 |
Family
ID=45423271
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010212441.XA Active CN102309448B (en) | 2010-06-29 | 2010-06-29 | Pulmonary delivery ciprofloxacin pharmaceutical composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102309448B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9532986B2 (en) | 2014-04-08 | 2017-01-03 | Aradigm Corporation | Liposomal ciprofloxacin formulations with activity against non-tuberculous mycobacteria |
| CN105232464A (en) * | 2015-11-11 | 2016-01-13 | 郑州后羿制药有限公司 | Hydrochloric acid ciprofloxacin lipidosome preparation and preparation method thereof |
| CN113456590B (en) * | 2021-07-22 | 2023-02-03 | 药大制药有限公司 | Salbutamol lipid aerosol |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5013556A (en) * | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
| WO2001015750A1 (en) * | 1999-08-27 | 2001-03-08 | Department Of National Defence | Hydrogel wound dressing containing liposome-encapsulated therapeutic agent |
| CN1295465A (en) * | 1998-04-02 | 2001-05-16 | 阿尔扎有限公司 | Quinolone-containing liposome composition |
| CN1351495A (en) * | 1999-04-29 | 2002-05-29 | 阿尔萨公司 | Liposome compositions for improved drugretention |
| CN101095659A (en) * | 2006-06-28 | 2008-01-02 | 蔡海德 | Liposome combined medicine and method for preparing the same |
| CN101401790A (en) * | 2008-11-14 | 2009-04-08 | 山东大学 | Lavo-ofloxacin liposome and preparation method thereof |
| CN101553209A (en) * | 2006-10-24 | 2009-10-07 | 阿拉迪姆公司 | Dual action, inhaled formulations providing both an immediate and sustained release profile |
-
2010
- 2010-06-29 CN CN201010212441.XA patent/CN102309448B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5013556A (en) * | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
| CN1295465A (en) * | 1998-04-02 | 2001-05-16 | 阿尔扎有限公司 | Quinolone-containing liposome composition |
| CN1351495A (en) * | 1999-04-29 | 2002-05-29 | 阿尔萨公司 | Liposome compositions for improved drugretention |
| WO2001015750A1 (en) * | 1999-08-27 | 2001-03-08 | Department Of National Defence | Hydrogel wound dressing containing liposome-encapsulated therapeutic agent |
| CN101095659A (en) * | 2006-06-28 | 2008-01-02 | 蔡海德 | Liposome combined medicine and method for preparing the same |
| CN101553209A (en) * | 2006-10-24 | 2009-10-07 | 阿拉迪姆公司 | Dual action, inhaled formulations providing both an immediate and sustained release profile |
| CN101401790A (en) * | 2008-11-14 | 2009-04-08 | 山东大学 | Lavo-ofloxacin liposome and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| 周建平.第十六章 气雾剂、粉雾剂与喷雾剂，第十八章 制剂新技术.《药剂学》.东南大学出版社,2007,(第1版),第263,265-269，273,316页. * |
| 王志宣等.脂质体肺部给药系统的应用.《中国医药工业杂志》.2007,第38卷(第1期),第58-62页. |
| 王绍宁等.盐酸环丙沙星脂质体的制备及小鼠体内分布.《中国药学杂志》.2003,第38卷(第4期),第274-277页. |
| 盐酸环丙沙星脂质体的制备及小鼠体内分布;王绍宁等;《中国药学杂志》;20030430;第38卷(第4期);第274-277页 * |
| 脂质体肺部给药系统的应用;王志宣等;《中国医药工业杂志》;20070131;第38卷(第1期);第58-62页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102309448A (en) | 2012-01-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Bassetti et al. | Inhaled liposomal antimicrobial delivery in lung infections | |
| US11116765B2 (en) | Liposomal ciprofloxacin formulations with activity against non-tuberculous mycobacteria | |
| Khuller et al. | Liposome technology for drug delivery against mycobacterial infections | |
| Schiffelers et al. | Liposome-encapsulated aminoglycosides in pre-clinical and clinical studies | |
| JP5797217B2 (en) | Dual-action inhalation formulation providing both immediate release and sustained release properties | |
| Bakker-Woudenberg et al. | Long-circulating sterically stabilized liposomes in the treatment of infections | |
| Patterson et al. | Treatment of experimental invasive aspergillosis with novel amphotericin B/cholesterol-sulfate complexes | |
| Garcia et al. | Nanoemulsion delivery systems for enhanced efficacy of antimicrobials and essential oils | |
| PT1909759E (en) | Sustained release of antiinfective aminoglycosides | |
| US6613352B2 (en) | Low-rigidity liposomal formulation | |
| TW202011941A (en) | Inhalable sustained release composition for use in treating pulmonary disease | |
| WO2020040818A1 (en) | Compositions of clofazimine, combinations comprising them, processes for their preparation, uses and methods comprising them | |
| US20160120806A1 (en) | Nanocrystals formed in a microenvironment | |
| WO2008080369A1 (en) | Steady liposomal composition | |
| CN102309448B (en) | Pulmonary delivery ciprofloxacin pharmaceutical composition and preparation method thereof | |
| KR20090115856A (en) | Pharmaceutical composition comprising a campothecin derivative | |
| Ghosh et al. | Liposome-Based Antibacterial Delivery: An Emergent Approach to Combat Bacterial Infections | |
| US20240000779A1 (en) | Compositions of Clofazimine, Combinations Comprising Them, Processes for Their Preparation, Uses and Methods Comprising Them | |
| EP4054524A1 (en) | Compositions of clofazimine, combinations comprising them, processes for their preparation, uses and methods of treatment comprising them | |
| Beaulac et al. | In vitro bactericidal evaluation of a low phase transition temperature liposomal tobramycin formulation as a dry powder preparation against Gram negative and Gram positive bacteria | |
| US20210007985A1 (en) | Liposomal anti-infective formulations to inhibit non-tuberculous mycobacteria (ntm) microaggregate formation and establishment of ntm biofilm | |
| WO2024013152A1 (en) | Inhalable formulation for use in the treatment of bacterial lung infections | |
| Yahya Rahimpour et al. | ipidic Micro-and Nano-Carriers for Pulmonary Drug Delivery–A | |
| Alipour et al. | Liposome-Entrapped Antibiotics: Recent | |
| Alipour et al. | Liposome-entrapped antibiotics: recent progress and clinical applications |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |