+

WO1994022461A1 - Formulation servant a administrer de l'insuline par voie nasale - Google Patents

Formulation servant a administrer de l'insuline par voie nasale Download PDF

Info

Publication number
WO1994022461A1
WO1994022461A1 PCT/EP1994/000892 EP9400892W WO9422461A1 WO 1994022461 A1 WO1994022461 A1 WO 1994022461A1 EP 9400892 W EP9400892 W EP 9400892W WO 9422461 A1 WO9422461 A1 WO 9422461A1
Authority
WO
WIPO (PCT)
Prior art keywords
insulin
nasal
cyclodextrin
administration
analogue
Prior art date
Application number
PCT/EP1994/000892
Other languages
English (en)
Inventor
Franciscus W. H. M. Merkus
Original Assignee
Merkus Franciscus W H M
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merkus Franciscus W H M filed Critical Merkus Franciscus W H M
Priority to AU64289/94A priority Critical patent/AU6428994A/en
Publication of WO1994022461A1 publication Critical patent/WO1994022461A1/fr

Links

Classifications

    • 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
    • A61K38/28—Insulins
    • 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
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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

Definitions

  • the invention is related to a pharmaceutical preparation of a form and composition suitable for nasal administration of insulin, or an analogue thereof, and to a process of preparing such preparation.
  • Insulin is a polypeptide hormone of 51 amino acids. It is synthesized in the pancreas and it functions as a physiological regulator of the carbohydrate metabolism in the body. For many years insulin has been therapeutically used in patients with diabetes mellitus, to lower increased blood sugar levels in these patients. Oral administration of insulin is not feasible because of its peptide structure, since it is broken down in the gastro-intestinal tract. Therefore, it is usual to administer the drug by parenteral injections, for example subcutaneously or intramuscularly. However, these invasive methods of administration are associated with delayed and irregular absorption from the site of injection, probably due to hexamer formation. Moreover, daily injection therapy causes the patients considerable inconvenience: injections are experienced as painful and traumatic, are irreversible, and the patient must learn the injection technique.
  • nasal route of administration For many years already industry and research centers are intensively investigating and testing non-invasive routes for the administration of insulin, in particular the nasal route of administration. Publications - such as patents and patent applications - show such developments and make clear that there is an urgent need for a successful technique of nasal administration of insulin.
  • Advantages of nasal administration the nasal cavity is easily accessible for drug administration; the nasal epithelial tissue has a rich vasculature; the nasal route avoids degradation of the drug in the gastro-intestinal tract, and the nasal route is eminently suitable for self-medication. Furthermore, intranasal insulin administration would not only circumvent the procedure of injection, but will probably also result in more predictable blood levels.
  • intranasal administration of insulin leads to poor bioavailability since insulin is a high molecular weight and hydrophilic substance and, therefore, is hardly capable of passing the lipophilic nasal epithelial barrier.
  • the nasal bioavailability can be improved by using so-called absorption enhancing adjuvants.
  • absorption enhancers have been described for nasal administration of insulin, including ionic and non-ionic surfactants such as bile salts (Gordon et al., Proc. Natl. Acad. Sci. U.S.A. 82 (1985) 7419-7421; EP-A-0 ill 841) and polyoxyethylene alcohol ethers (Hirai et al.. Int. J. Pharm. 9 (1981) 165-172; GB-A-1 527 605), fatty acids and phospholipids (Mishima et al., J. Pharmacobio-Dyn. 10 (1987) 624-631; Ilium et al., Int. J. Pharm.
  • ionic and non-ionic surfactants such as bile salts (Gordon et al., Proc. Natl. Acad. Sci. U.S.A. 82 (1985) 7419-7421; EP-A-0 ill 841) and polyoxy
  • cyclodextrins have been shown to be a class of absorption enhancers for nasal drug delivery. These compounds are cyclic oligosaccharides of 6, 7 or 8 glucose units, named ⁇ -cyclodextrin ( ⁇ -CD) , /9-cyclodextrin (3-CD) , and ⁇ -cyclodextrin ( ⁇ -CD) respectively.
  • ⁇ -CD cyclic oligosaccharides of 6, 7 or 8 glucose units
  • ⁇ -CD cyclodextrin
  • 3-CD /9-cyclodextrin
  • ⁇ -CD ⁇ -cyclodextrin
  • a lower alkylether of cellulose preferably hy- droxypropylmethylcellulose or methylcellulose
  • a cyclodextrin, . preferably ⁇ -cyclodextrin and
  • a phospholipid preferably didecanoyl-L- ⁇ - phosphatidylcholine.
  • WO-92/16196 teaches that one needs as absorption enhancers didecanoyl-L- ⁇ -phosphatidylcholine as well as a- cyclodextrin and an alkylether of cellulose.
  • a pharmaceutical preparation for nasal insulin administration in men is a solid (powder) or semi solid preparation comprising at least the polypeptide hormone insuline, or an analogue thereof, as an active agent, and a methylated ⁇ -cyclodextrin (methyl-9-cyclo- dextrin) having a degree of substitution (D.S.) between 0.5 and 3.0, preferably between 1.4 and 2.4, more preferably approximately 1.8 as an absorption enhancing agent.
  • D.S. degree of substitution
  • the nasal formulation according to the invention will in practice contain a pharmacologically active amount of insulin, or an analogue thereof, as the active agent present therein.
  • insulin analogues show a significantly reduced self-association, for instance products made by DNA techniques, like the insulin analogue Asp (BIO) , insulin analogue Asp (B 28) , insulin analogue Asp (B 29) and insulin analogue Glu (B 27) .
  • insulin analogue Lys (B 28)-Pro (B 29) is a good candidate for intranasal administration according to this invention, because it shows a reduced self-association and a short duration of action.
  • Preparations in the form of a powder formulation suitable for nasal administration may for instance contain 2 to 200 IU of the active agent per nasal dose.
  • the powder preparation will contain an amount thereof that enhances the absorption of the active agent present.
  • Methyl-?-cyclodextrin amounts of 0.3 to 30 ⁇ moles per dose are options, although amounts of 0.75 to 15 ⁇ moles per dose are preferable.
  • nasal preparations according to the invention may also contain one or more adjuvants conventionally used in nasal drug formulations, such as preservatives, stabilizers, excipients (e.g. lactose, maltose, cellulose, mannitol, sorbitol) , pH-controlling compounds and complexing agents etc.
  • adjuvants conventionally used in nasal drug formulations, such as preservatives, stabilizers, excipients (e.g. lactose, maltose, cellulose, mannitol, sorbitol) , pH-controlling compounds and complexing agents etc.
  • adjuvants conventionally used in nasal drug formulations, such as preservatives, stabilizers, excipients (e.g. lactose, maltose, cellulose, mannitol, sorbitol) , pH-controlling compounds and complexing agents etc.
  • Agents suitable for these and other purposes are known in the pharmaceutical literature and to men skilled in the art of
  • a process for preparing a solid or semi solid pharmaceutical preparation comprises at least the following steps: (1) producing a solution of at least the polypeptide hormone insulin, or an analogue thereof, and a methylated cyclodextrin having a degree of substitution between 0.5 and 3.0, preferably between 1.4 and 2.4, more preferably approx. 1.8, (2) freezing the said solution, and (3) lyophilizing the frozen substance.
  • the invention also relates to a dispenser for nasal administration containing a preparation according to the invention.
  • venous blood samples of approx. 5 ml were taken using Venoject evacuated blood collecting tubes. A part of these blood samples was used directly for assaying the glucose concentrations by means of Haemo- glucotest strips in combination with a Reflolux reflectance meter. Then the blood samples were processed into plasma by means of centrifugation. Finally, the plasma insulin and C- peptide concentrations were determined with commercially available radioimmunoassay kits specific for human insulin and C-peptide, respectively.
  • Fig. 1 shows three diagrams (A, B and C) reflecting the results of liquid administration in two persons
  • Fig. 2 shows three diagrams (A, B and C) reflecting the results of solid (powder) administration in two persons.
  • Diagrams A show plasma insulin concentrations in mIU/1; diagrams B show blood glucose concentrations in mmol/1, and diagrams C show plasma C-peptide concentrations in nmol/1, all during the indicated period.
  • Liquid nasal insulin preparations were prepared by dissolving human insulin powder (26 IU/mg) in physiological saline solutions containing 2.5 mM HC1. The solutions were neutralized with 0.1 M NaOH. Final insulin concentration was 17.2 mg/ml.
  • methyl-/9- cyclodextrin was added to the insulin solution, resulting in the following two liquid insulin/methyl-3-cyclodextrin formulations:
  • Solid (powder) insulin preparations were prepared by dissolving human insulin powder in 2.5 mM HCl to a concentration of 14.5 mg/ml. Methyl-/3-cyclodextrin was subsequently added to a molar concentration of 75 mM (9.5% w/v) . The insulin solutions were then frozen in liquid nitrogen and lyophilized at a pressure of about 0.01 mm Hg at least 16 hrs in a freeze dryer Modulyo (Edwards) .
  • the delivery was as follows:
  • Solid (powder) insulin/methyl-jS-cyclodextrin preparations were administered by inhalation through the nose.
  • the delivery was as follows:
  • the peak plasma concentration was 48 mIU/1. This peak concentration was already reached after 20 minutes, which indicates that the insulin powder was quickly absorbed. The insulin concentrations returned to endogenous levels after about 80 minutes. A decrease in blood glucose of 30% to a minimum of 3.2 mmol/1 was observed, and after the 2 hours of the experiment the glucose concentrations were still reduced. Moreover, plasma C-peptide levels were decreased.
  • insulin-methyl ⁇ -cyclodextrin powder For the intranasal insulin administration individual dosages of insulin-methyl ⁇ -cyclodextrin powder were prepared, containing 1.2 IU insulin/kg body weight, divided in two doses (one dose per nostril) . After nasal inhalation of the powder formulation, the insulin levels started to rise immediately. In the 6 volunteers, insulin peak levels were reached after about 15 minutes, returning to baseline 90 minutes after administration. The action profile of the absorbed insulin was determined by the glucose infusion rate according to the euglycemic clamp technique. The glucose infusion rate in the 6 volunteers showed also an immediate rise, with a peak after about 30 minutes and a slowly decreasing level up to 90 minutes. The glucose infusion could be discontinued after 120 minutes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Inorganic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation pharmaceutique servant à administrer de l'insuline par voie nasale chez l'homme et comprenant l'insuline d'hormone de polypeptide, ou un de ses analogues, et une β-cyclodextrine méthylée possédant un degré de substitution compris entre 0,5 et 3, ladite préparation se présentant sous forme solide (poudre) ou semi-solide. Elle peut être réalisée au moyen d'un procédé comprenant les étapes suivantes: (1) préparation d'une solution d'au moins l'insuline d'hormone de polypeptide, ou d'un de ses analogues, et d'une cyclodextrine méthylée; (2) congélation de ladite solution et (3) lyophilisation de la substance congelée.
PCT/EP1994/000892 1993-03-26 1994-03-18 Formulation servant a administrer de l'insuline par voie nasale WO1994022461A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64289/94A AU6428994A (en) 1993-03-26 1994-03-18 Formulation for nasal insulin delivery

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BE9300300 1993-03-26
BE9300300A BE1006873A6 (nl) 1993-03-26 1993-03-26 Toedieningsformulering voor nasale insuline toediening.

Publications (1)

Publication Number Publication Date
WO1994022461A1 true WO1994022461A1 (fr) 1994-10-13

Family

ID=3886933

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/000892 WO1994022461A1 (fr) 1993-03-26 1994-03-18 Formulation servant a administrer de l'insuline par voie nasale

Country Status (3)

Country Link
AU (1) AU6428994A (fr)
BE (1) BE1006873A6 (fr)
WO (1) WO1994022461A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5952008A (en) * 1993-06-24 1999-09-14 Ab Astra Processes for preparing compositions for inhalation
US6306440B1 (en) 1993-06-24 2001-10-23 Astrazeneca Ab Therapeutic preparation for inhalation
US6524557B1 (en) 1994-12-22 2003-02-25 Astrazeneca Ab Aerosol formulations of peptides and proteins
US6846801B1 (en) 1993-06-24 2005-01-25 Astrazeneca Ab Systemic administration of a therapeutic preparation
US6932962B1 (en) 1994-12-22 2005-08-23 Astrazeneca Ab Aerosol drug formulations containing hydrofluoroalkanes and alkyl saccharides
US7182960B2 (en) * 2001-07-19 2007-02-27 Les Laboratoires Servier Pharmaceutical compositions for nasal delivery of oestradiol and norethisterone
WO2007047948A3 (fr) * 2005-10-20 2007-10-11 Nastech Pharm Co Administration intranasale d'insuline a action rapide
WO2008016729A1 (fr) * 2006-08-04 2008-02-07 Nastech Pharmaceutical Company Inc. Compositions pour administration intranasale d'insuline humaine et leurs utilisations
WO2017064436A1 (fr) * 2015-10-16 2017-04-20 Roquette Freres Nouvelles cyclodextrines méthylées et leurs procédés de préparation
RU2677889C1 (ru) * 2013-12-13 2019-01-22 Рокетт Фрер Композиции на основе метилциклодекстринов для лечения и/или предупреждения заболеваний путем повышения уровня hdl-холестерина

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0094157A1 (fr) * 1982-04-30 1983-11-16 Takeda Chemical Industries, Ltd. Composition pharmaceutique et son application
EP0308181A1 (fr) * 1987-09-14 1989-03-22 Novo Nordisk A/S Formulations à délivrance transmucosale et méthode de préparation
JPH01117825A (ja) * 1987-10-28 1989-05-10 Sanwa Kagaku Kenkyusho Co Ltd 鼻くう、副鼻くう投与用製剤及びその使用方法並びにその形状及び使用器具
JPH0383915A (ja) * 1989-08-28 1991-04-09 Wako Pure Chem Ind Ltd 経粘膜製剤
WO1992001440A1 (fr) * 1990-07-24 1992-02-06 Rijksuniversiteit Te Leiden Preparations medicamenteuses transmuqueuses et administration de telles preparations par voie transmuqueuse
WO1992016196A1 (fr) * 1991-03-20 1992-10-01 Novo Nordisk A/S Composition renfermant un peptide pour administration nasale

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0094157A1 (fr) * 1982-04-30 1983-11-16 Takeda Chemical Industries, Ltd. Composition pharmaceutique et son application
EP0308181A1 (fr) * 1987-09-14 1989-03-22 Novo Nordisk A/S Formulations à délivrance transmucosale et méthode de préparation
JPH01117825A (ja) * 1987-10-28 1989-05-10 Sanwa Kagaku Kenkyusho Co Ltd 鼻くう、副鼻くう投与用製剤及びその使用方法並びにその形状及び使用器具
JPH0383915A (ja) * 1989-08-28 1991-04-09 Wako Pure Chem Ind Ltd 経粘膜製剤
WO1992001440A1 (fr) * 1990-07-24 1992-02-06 Rijksuniversiteit Te Leiden Preparations medicamenteuses transmuqueuses et administration de telles preparations par voie transmuqueuse
WO1992016196A1 (fr) * 1991-03-20 1992-10-01 Novo Nordisk A/S Composition renfermant un peptide pour administration nasale

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 117, no. 18, 2 November 1992, Columbus, Ohio, US; abstract no. 178241b *
DATABASE WPI Week 8925, Derwent World Patents Index; AN 89-181251 (25) *
DATABASE WPI Week 9120, Derwent World Patents Index; AN 91-146147, (20) *
Z.SHAO ET AL.: "CYCLODEXTRINS AS NASAL ABSORPTION PROMOTERS OF INSULIN:MECHANISTIC EVALUATIONS", PHARM.RES., vol. 9, no. 9, 1992, pages 1157 - 1163 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5952008A (en) * 1993-06-24 1999-09-14 Ab Astra Processes for preparing compositions for inhalation
US6306440B1 (en) 1993-06-24 2001-10-23 Astrazeneca Ab Therapeutic preparation for inhalation
US6846801B1 (en) 1993-06-24 2005-01-25 Astrazeneca Ab Systemic administration of a therapeutic preparation
US6524557B1 (en) 1994-12-22 2003-02-25 Astrazeneca Ab Aerosol formulations of peptides and proteins
US6932962B1 (en) 1994-12-22 2005-08-23 Astrazeneca Ab Aerosol drug formulations containing hydrofluoroalkanes and alkyl saccharides
US7182960B2 (en) * 2001-07-19 2007-02-27 Les Laboratoires Servier Pharmaceutical compositions for nasal delivery of oestradiol and norethisterone
WO2007047948A3 (fr) * 2005-10-20 2007-10-11 Nastech Pharm Co Administration intranasale d'insuline a action rapide
US20100210506A1 (en) * 2005-10-20 2010-08-19 Mdrna, Inc. Intranasal administration of rapid acting insulin
WO2008016729A1 (fr) * 2006-08-04 2008-02-07 Nastech Pharmaceutical Company Inc. Compositions pour administration intranasale d'insuline humaine et leurs utilisations
US9993425B2 (en) 2006-08-04 2018-06-12 Marina Biotech, Inc. Compositions for intranasal delivery of human insulin and uses thereof
RU2677889C1 (ru) * 2013-12-13 2019-01-22 Рокетт Фрер Композиции на основе метилциклодекстринов для лечения и/или предупреждения заболеваний путем повышения уровня hdl-холестерина
US11266680B2 (en) 2013-12-13 2022-03-08 Roquette Freres Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the HDL cholesterol level
WO2017064436A1 (fr) * 2015-10-16 2017-04-20 Roquette Freres Nouvelles cyclodextrines méthylées et leurs procédés de préparation
CN108137714A (zh) * 2015-10-16 2018-06-08 罗盖特兄弟公司 新颖的甲基化环糊精以及其生产方法
US11098135B2 (en) 2015-10-16 2021-08-24 Roquette Freres Methylated cyclodextrins and methods for the production thereof

Also Published As

Publication number Publication date
AU6428994A (en) 1994-10-24
BE1006873A6 (nl) 1995-01-10

Similar Documents

Publication Publication Date Title
Matsubara et al. Improvement of nasal bioavailability of luteinizing hormone-releasing hormone agonist, buserelin, by cyclodextrin derivatives in rats
Merkus et al. Absorption enhancing effect of cyclodextrins on intranasally administered insulin in rats
Rajewski et al. Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery
US7244709B2 (en) Compositions and methods for enhanced mucosal delivery of parathyroid hormone
EP1951198B1 (fr) Administration intranasale d'insuline a action rapide
US9993425B2 (en) Compositions for intranasal delivery of human insulin and uses thereof
US5516523A (en) Transmucosal delivery of macromolecular drugs
Merkus et al. The influence of absorption enhancers on intranasal insulin absorption in normal and diabetic subjects
US20080004218A1 (en) Methods for enhanced epithelial permeation of y2 receptor-binding peptides for treating and preventing obesity
US20080318861A1 (en) Mucosal Delivery of Stabilized Formulations of Exendin
JP6522144B2 (ja) 低血糖症の治療用経鼻粉末製剤
EP0308181A1 (fr) Formulations à délivrance transmucosale et méthode de préparation
US20100166811A1 (en) Gras composition for intranasal delivery of parathyroid hormone
US20020151467A1 (en) Methods and compositions for oral insulin delivery
US20060127320A1 (en) Method of delivering parathyroid hormone to a human
WO1994022461A1 (fr) Formulation servant a administrer de l'insuline par voie nasale
TW202400219A (zh) 用於鼻內給藥的索馬魯肽及其鹽的藥物組合物
JPH05509101A (ja) 経粘膜薬物製剤および経粘膜投与法
Gill et al. Cyclodextrins as protection agents against enhancer damage in nasal delivery systems II. Effect on in vivo absorption of insulin and histopathology of nasal membrane
Tokihiro et al. Improvement of subcutaneous bioavailability of insulin by sulphobutyl ether β‐cyclodextrin in rats
US20070173447A1 (en) Method for treating osteoporosis by intranasal delivery of teriparatide with an anti-resorptive agent
JPH08151332A (ja) 点鼻用水性懸濁液
CN103768017A (zh) 一种治疗阿尔兹海默病的碱性成纤维生长因子鼻腔喷雾剂
WO2004082589A2 (fr) Composition pharmaceutique biodisponible de loratadine a administration nasale

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR BY CA CH CN CZ DE DK ES FI GB HU JP KP KR KZ LK LU LV MG MN MW NL NO NZ PL PT RO RU SD SE SK UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载