[go: up one dir, main page]

KR100358934B1 - Injectable Pharmaceutical Compositions with Taxol - Google Patents

Injectable Pharmaceutical Compositions with Taxol Download PDF

Info

Publication number
KR100358934B1
KR100358934B1 KR1019960039723A KR19960039723A KR100358934B1 KR 100358934 B1 KR100358934 B1 KR 100358934B1 KR 1019960039723 A KR1019960039723 A KR 1019960039723A KR 19960039723 A KR19960039723 A KR 19960039723A KR 100358934 B1 KR100358934 B1 KR 100358934B1
Authority
KR
South Korea
Prior art keywords
taxol
peg
pharmaceutical composition
composition
polyethyleneglycol
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.)
Expired - Lifetime
Application number
KR1019960039723A
Other languages
Korean (ko)
Other versions
KR19980021001A (en
Inventor
한만우
홍남두
유재국
Original Assignee
주식회사한국신약
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 주식회사한국신약 filed Critical 주식회사한국신약
Priority to KR1019960039723A priority Critical patent/KR100358934B1/en
Publication of KR19980021001A publication Critical patent/KR19980021001A/en
Application granted granted Critical
Publication of KR100358934B1 publication Critical patent/KR100358934B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Landscapes

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

Abstract

PURPOSE: A pharmaceutical composition of injection containing taxol is provided, thereby improving the solubility of the pharmaceutical composition, stabilizing its formula, and decreasing undesirable adverse effects. CONSTITUTION: A pharmaceutical composition of injection contains taxol anhydrous ethanol and polyethyleneglycol, without polyoxyethylated castor oil, wherein polyethyleneglycol is added in the amount of 40 to 60%; the average molecular weight of polyethyleneglycol(PEG) is 200 to 600 dalton; the taxol is isolated from Taxus spp. and useful for treatment of cancer; and 6 mg of taxol and 50 vol.% of PEG are contained in 1 ml of the pharmaceutical composition.

Description

탁솔을 함유한 주사용 약제 조성물Pharmaceutical composition for injection containing taxol

본 발명은 종래의 탁솔(TAXOLR) 주사제에 비하여 용해성이 우수하고 제형이 안정하며 환자들에게 투여시 부작용이 적은, 탁솔을 함유한 주사용 약제 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for injection containing Taxol, which has better solubility, stable formulation, and fewer side effects when administered to patients compared to conventional TAXOL R injections.

주목나무(Taxus spp.)로부터 얻어지는 탁솔(TAXOLR: paclitaxel)은 20개 이상의 비대칭 중심을 갖는 극히 복잡한 디테르펜(diterpene)계 탁산(taxane) 화합물로, 특히 난소암, 유방암 등에 탁월한 치료 효과를 갖는 것으로 알려진 항암 물질이다. 탁솔에 관한 연구는 1960년대 미국 국립 암연구소가 35,000 종의 식물을 대상으로 실시한 항암 활성 물질의 대규모 스크리닝 프로그램에서 시작되어, 태평양 주목(Taxus brevifolia) 껍질의 추출물이 백혈병과 폐암을 포함하는 여러가지 종양에 대하여 강한 활성을 나타내는 것으로 보고된 후, 1969년에는 월(Wall) 등에 의해 활성 물질이 분리되었고, 1971년에는 활성물질의 본체로서 탁솔의 구조가 밝혀지게 되었다(Eric K. Rowinsky, Lorraine A. Cazenave, Ross C. Dondhower, J.National Cancer Inst., 82: 11247 (1990)).Taxol (TAXOL R : paclitaxel) from Taxus spp. It is known to be an anticancer substance. Taxol research began in the 1960s with a large-scale screening program of anticancer actives conducted by the National Cancer Institute of the United States on 35,000 species of plants, and extracts from the Pacificus ( Texus brevifolia ) bark on various tumors, including After being reported to have a strong activity against, the active material was separated by Wall et al. In 1969 and the structure of Taxol as the body of the active material was revealed in 1971 (Eric K. Rowinsky, Lorraine A. Cazenave , Ross C. Dondhower, J. National Cancer Inst., 82 : 11247 (1990)).

기존의 항암제인 콜키신(Colchicine)이나 빈카 알칼로이드(Vinca alkaloid)가 미세관(microtubule)을 분해하여 항암작용을 나타내는 것과는 달리, 탁솔은 미세관의 중합(microtubule assembly)을 촉진하고 그 다음 단계인 분해과정을 억제하는 특이한 작용기작을 나타낸다는 것이 쉬프(Schiff) 등에 의하여 알려지면서(Schiff, P. B., J. Fant and S. B. Horwitz,Nature, 277: 665 (1979)), 탁솔에 대한 연구가 활발히 이루어져 현재는 난소암과 유방암의 치료에 주로 이용되고 있다. 현재 미국 NCI 의 임상시험 결과를 보면, 탁솔은 기존의 항암제로 치료가 불가능한 말기 암환자중 특히 난소암 30 %, 유방암 50 %, 그리고 폐암 20 % 정도의 치료율을 보이는 것으로 알려져 있다(David G. I., Samaranayake, and C. A. Ivey, J,Nat. Prod., 53: 1, (1990)).Unlike conventional anticancer drugs, Colchicine or Vinca alkaloid, which decompose microtubules and show anticancer activity, Taxol promotes microtubule assembly and the next step, the decomposition process. Schiff et al. (Schiff, PB, J. Fant and SB Horwitz, Nature, 277 : 665 (1979)) indicate that they have a specific mechanism of action that inhibits ovaries. It is mainly used for the treatment of cancer and breast cancer. According to the current clinical trials of NCI, Taxol is known to treat 30% of ovarian cancer, 50% breast cancer, and 20% lung cancer among terminal cancer patients who cannot be treated with conventional anticancer drugs (David GI, Samaranayake). , and CA Ivey, J, Nat. Prod., 53 : 1, (1990)).

이처럼 항암제로서 크게 기대되고 있음에도 불구하고 탁솔에 대한 연구는 매우 느린 속도로 진전되고 있는데, 그 주된 원인은 탁솔의 공급이 매우 부족하고 대규모 추출 분리 및 조제가 어렵기 때문이다.Despite such anticipated anticancer drugs, studies on Taxol are progressing at a very slow rate, mainly due to the lack of Taxol supply and the difficulty of large-scale extraction and preparation.

또한, 탁솔은 비수용성이기 때문에 주사제로 제조하는 데에도 어려움이 따르고 있어, 이 문제를 해결하기 위한 연구도 활발히 진행되고 있다. 예를 들어, 미합중국 특허 제5,478,860호에서는 탁솔을 올리브 오일 또는 해바라기 오일 등의 오일과 폴리에틸렌글리콜-결합된 지질(PEG-linked lipids) 등을 혼합하여 미세유상액(micro-emulsion)으로 제조하는 방법을 개시하고 있으며, 유럽 특허출원 제639,577호에서는 탁솔에 포스포노옥시메틸(POM) 또는 메틸티오메틸(MTM) 등의 새로운 치환체를 도입하여 물에 대한 용해도를 향상시킨 탁솔 유도체를 제조하는 방법을, 그리고 PCT출원 국제공개 WO-9318757호에서는 새로운 의약전달체계(drug delivery system: DDS)로서 리포좀으로 캡슐화한 탁솔(liposome-encapsulated Taxol)을 개발하여 탁솔의 용해도 문제를 해결하고 안정성을 향상시킨 제조방법을 개시하고 있다.In addition, since Taxol is insoluble in water, it is difficult to prepare it as an injection, and studies to solve this problem have been actively conducted. For example, U.S. Patent No. 5,478,860 discloses a method of preparing a taxol in a micro-emulsion by mixing oils such as olive oil or sunflower oil with polyethylene glycol-linked lipids. European Patent Application No. 639,577 discloses a method for preparing Taxol derivatives having improved solubility in water by introducing new substituents such as phosphonooxymethyl (POM) or methylthiomethyl (MTM) to Taxol, and PCT Application International Publication No. WO-9318757 discloses a new drug delivery system (DDS) that develops a liposome-encapsulated taxo (liposome-encapsulated Taxol) to solve the problem of solubility and improve the stability of Taxol. Doing.

현재 탁솔 주사제의 제조방법으로서 가장 실용화되어 있는 방법은 탁솔의 용해제로서 무수에탄올과 폴리에톡실레이티드 캐스터 오일(Cremophor ELTM: BASF사 제품)을 사용하는 방법이다. 그러나, 이 방법에 의해 제조된 탁솔 주사제의 경우에도 제형의 안정성이 떨어져, 장기 보관시에는 탁솔이 분해되어 역가가 떨어질 뿐 아니라 부작용을 증대시키는 요인으로 작용하기도 한다는 문제가 있다.Currently, the most practical method for preparing Taxol injection is to use ethanol anhydride and polyethoxylated castor oil (Cremophor EL : manufactured by BASF) as a solvent for Taxol. However, in the case of Taxol injection prepared by this method, there is a problem that the formulation is inferior in stability, and in the case of long-term storage, the Taxol is decomposed to lower the titer and also act as a factor of increasing side effects.

본 발명에서는 탁솔을 함유하는 주사제에 있어서 상기와 같은 문제점을 고려하여 특정의 첨가제를 사용함으로써 제제의 안정성을 개선하고 탁솔의 부작용을 경감시킨 주사용 조성물을 제공하는 것을 목적으로 한다.It is an object of the present invention to provide an injectable composition which improves the stability of a preparation and reduces the side effects of Taxol by using a specific additive in consideration of the above problems in an injection containing Taxol.

상기 목적을 달성하기 위하여 본 발명에서는 탁솔, 무수에탄올 및 폴리에틸렌글리콜(PEG)을 포함하는 것을 특징으로 하는 탁솔을 함유하는 주사용 조성물을 제공한다.In order to achieve the above object, the present invention provides a taxol-containing injectable composition comprising Taxol, anhydrous ethanol and polyethylene glycol (PEG).

본 발명에서는 탁솔 용해제로서 무수 에탄올과 PEG 만을 사용한 간단한 조성에 의해서 제제의 안정성을 개선하고 탁솔의 부작용을 경감시킬 수 있다는 것을 특징으로 하는데, 여기에서 PEG는 수평균 분자량 200 내지 400 범위의 것을 사용하는 것이 바람직하고, 전체 조성물 부피의 40 내지 60 % 의 비율로 포함되는 것이 또한 바람직하다. 가장 바람직한 본 발명의 주사용 조성물은 조성물 1 ml 당 탁솔 6 mg이 포함되고 PEG 가 전체 조성물 부피의 50 % 인 것이다.In the present invention, a simple composition using only anhydrous ethanol and PEG as the Taxol dissolving agent can improve the stability of the formulation and reduce the side effects of Taxol, wherein PEG has a number average molecular weight in the range of 200 to 400. It is preferred that it is also included in a proportion of 40 to 60% of the total composition volume. Most preferred injectable compositions of the invention comprise 6 mg of Taxol per ml of composition and PEG is 50% of the total composition volume.

본 발명의 탁솔을 함유하는 주사용 조성물을 제조하는 방법은, 먼저 무수에탄올에 탁솔을 가하고 교반하여 용해시킨 용액에 일정량의 PEG 를 가하고 교반 혼화하여 최종적으로 주사용 조성물을 제조하는 것으로 이루어진다.The method for preparing the injectable composition containing Taxol of the present invention consists of first adding Taxol to anhydrous ethanol, adding a certain amount of PEG to a solution dissolved by stirring, and stirring and mixing to finally prepare the composition for injection.

이하 하기 실시예를 통하여 본 발명을 더욱 상세히 설명한다. 단, 하기의 실시예는 본 발명을 예시한 것일 뿐, 본 발명이 이들 만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely illustrative of the present invention, the present invention is not limited to these.

실시예 1Example 1

무수에탄올 30 ml에 탁솔 300 mg을 가하여 10 분 동안 교반하여 용해시켰다. 이 용액에 PEG 200을 첨가하여 전체 용량이 50 ml 가 되도록 조정한 후 10 분 동안 교반하여 최종액을 제조하였다.300 mg of Taxol was added to 30 ml of anhydrous ethanol, followed by stirring for 10 minutes to dissolve. PEG 200 was added to the solution to adjust the total volume to 50 ml, followed by stirring for 10 minutes to prepare a final solution.

실시예 2Example 2

무수에탄올 25 ml에 탁솔 300 mg을 가하여 10 분 동안 교반하여 용해시켰다. 이 용액에 PEG 400 을 첨가하여 전체 용량이 50 ml 가 되도록 조정한 후 10 분 동안 교반하여 최종액을 제조하였다.300 mg of Taxol was added to 25 ml of anhydrous ethanol, followed by stirring for 10 minutes to dissolve. PEG 400 was added to the solution to adjust the total volume to 50 ml, followed by stirring for 10 minutes to prepare a final solution.

실시예 3Example 3

무수에탄올 20 ml에 탁솔 300 mg을 가하여 10 분 동안 교반하여 용해시켰다. 이 용액에 PEG 200 을 첨가하여 전체 용량이 50 ml 가 되도록 조정한 후 10 분 동안 교반하여 최종액을 제조하였다.300 mg of Taxol was added to 20 ml of anhydrous ethanol, followed by stirring for 10 minutes to dissolve. PEG 200 was added to the solution to adjust the total volume to 50 ml, followed by stirring for 10 minutes to prepare a final solution.

탁솔 주사제에 용해제로서 무수에탄올과 폴리에틸렌글리콜을 사용한 본 발명의 주사용 조성물은, 제형의 안정성이 개선되고 탁솔의 부작용이 경감되는 효과를 나타내므로 항암제로서 임상에서 유용하게 사용될 수 있을 것으로 기대된다.The injectable composition of the present invention using anhydrous ethanol and polyethylene glycol as a dissolving agent in Taxol injectables is expected to be useful in clinical use as an anticancer agent because of the effect of improving the stability of the formulation and reducing the side effects of Taxol.

Claims (3)

탁솔 무수 에탄올 및 폴리에틸렌글리콜을 포함하고, 상기 폴리에틸렌글리콜의 함량이 전체 조성물 부피의 40 내지 60%이고, 폴리옥시에틸레이티드 캐스터 오일을 함유하지 아니하는 것을 특징으로 하는, 탁솔을 함유하는 주사용 조성물.Taxol-containing injectable composition comprising Taxol anhydrous ethanol and polyethylene glycol, characterized in that the content of polyethylene glycol is 40 to 60% of the total composition volume and does not contain polyoxyethylated castor oil . 제1항에 있어서, 상기 PEG의 수평균 분자량 범위가 200 내지 600 인 것을 특징으로 하는 조성물.The composition according to claim 1, wherein the PEG has a number average molecular weight range of 200 to 600. 제1항에 있어서, 조성물 1 ml 당 탁솔 6 mg이 포함되고 PEG가 전체 조성물 부피의 50% 인 것을 특징으로 하는 조성물.The composition of claim 1, comprising 6 mg Taxol per ml of composition and PEG being 50% of the total composition volume.
KR1019960039723A 1996-09-13 1996-09-13 Injectable Pharmaceutical Compositions with Taxol Expired - Lifetime KR100358934B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019960039723A KR100358934B1 (en) 1996-09-13 1996-09-13 Injectable Pharmaceutical Compositions with Taxol

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1019960039723A KR100358934B1 (en) 1996-09-13 1996-09-13 Injectable Pharmaceutical Compositions with Taxol

Publications (2)

Publication Number Publication Date
KR19980021001A KR19980021001A (en) 1998-06-25
KR100358934B1 true KR100358934B1 (en) 2003-01-29

Family

ID=37490433

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1019960039723A Expired - Lifetime KR100358934B1 (en) 1996-09-13 1996-09-13 Injectable Pharmaceutical Compositions with Taxol

Country Status (1)

Country Link
KR (1) KR100358934B1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994012198A1 (en) * 1992-11-27 1994-06-09 F.H. Faulding & Co. Limited Injectable taxol composition
US5403858A (en) * 1991-07-08 1995-04-04 Rhone-Poulenc Rorer, S.A. New compositions containing taxane derivatives
US5438072A (en) * 1992-12-02 1995-08-01 Rhone-Poulenc Rorer S.A. Taxoid-based compositions
US5504102A (en) * 1993-09-29 1996-04-02 Bristol-Myers Squibb Company Stabilized pharmaceutical composition and stabilizing solvent

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5403858A (en) * 1991-07-08 1995-04-04 Rhone-Poulenc Rorer, S.A. New compositions containing taxane derivatives
WO1994012198A1 (en) * 1992-11-27 1994-06-09 F.H. Faulding & Co. Limited Injectable taxol composition
US5438072A (en) * 1992-12-02 1995-08-01 Rhone-Poulenc Rorer S.A. Taxoid-based compositions
US5504102A (en) * 1993-09-29 1996-04-02 Bristol-Myers Squibb Company Stabilized pharmaceutical composition and stabilizing solvent

Also Published As

Publication number Publication date
KR19980021001A (en) 1998-06-25

Similar Documents

Publication Publication Date Title
AU724842B2 (en) Taxane composition and method
US5750561A (en) Compositions containing taxane derivatives
RU2134123C1 (en) Injection pharmaceutical composition, method of its preparing and pharmaceutical base-perfusion solution
Huizing et al. Taxanes: a new class of antitumor agents
ES2145115T4 (en) INJECTABLE COMPOSITIONS BASED ON TAXANOS DERIVATIVES.
RU2408362C2 (en) Pharmaceutical composition containing docetaxel and degradation inhibitor and method for preparing thereof
CN1382038A (en) New and improved formulation for paclitaxel
KR20100023862A (en) Solubilized formulation of docetaxel without tween 80
RU2398578C2 (en) Pharmaceutical composition containing taxan derivative and used for preparation of infusion solution, method for preparation and application
KR100330373B1 (en) Pharmaceutical composition for injection containing taxol
JP4805599B2 (en) Paclitaxel aqueous injection solution and preparation method thereof
KR100358934B1 (en) Injectable Pharmaceutical Compositions with Taxol
KR102401546B1 (en) Novel Pharmaceutical Formulation with Improved Stability Comprising Taxanes, Pharmaceutically Acceptable Salt or Hydrates Thereof
JP2011529930A (en) Injectable taxane pharmaceutical composition
WO2010023321A1 (en) Liquid formulation containing a taxane derivative
BG107764A (en) Stable pharmaceutical form of an anticancer drug and method for the preparation thereof
WO2004043375A2 (en) Pharmaceutical compositions and methods of using taxane derivatives
HK1006207B (en) Novel compositions based on taxane class derivatives
JP2018115178A (en) Docetaxel formulation
HK1106923B (en) Paclitaxel aqueous injection solution and methods for preparing the same
HK1106923A1 (en) Paclitaxel aqueous injection solution and methods for preparing the same
WO2005074889A1 (en) Novel compositions of taxol derivatives and the process for the manufacture thereof

Legal Events

Date Code Title Description
PA0109 Patent application

Patent event code: PA01091R01D

Comment text: Patent Application

Patent event date: 19960913

PG1501 Laying open of application
A201 Request for examination
PA0201 Request for examination

Patent event code: PA02012R01D

Patent event date: 19990424

Comment text: Request for Examination of Application

Patent event code: PA02011R01I

Patent event date: 19960913

Comment text: Patent Application

E902 Notification of reason for refusal
PE0902 Notice of grounds for rejection

Comment text: Notification of reason for refusal

Patent event date: 20010428

Patent event code: PE09021S01D

E902 Notification of reason for refusal
PE0902 Notice of grounds for rejection

Comment text: Notification of reason for refusal

Patent event date: 20020115

Patent event code: PE09021S01D

E701 Decision to grant or registration of patent right
PE0701 Decision of registration

Patent event code: PE07011S01D

Comment text: Decision to Grant Registration

Patent event date: 20020819

GRNT Written decision to grant
PR0701 Registration of establishment

Comment text: Registration of Establishment

Patent event date: 20021016

Patent event code: PR07011E01D

PR1002 Payment of registration fee

Payment date: 20021017

End annual number: 3

Start annual number: 1

PG1601 Publication of registration
PR1001 Payment of annual fee

Payment date: 20050916

Start annual number: 4

End annual number: 4

PR1001 Payment of annual fee

Payment date: 20061017

Start annual number: 5

End annual number: 5

PR1001 Payment of annual fee

Payment date: 20070920

Start annual number: 6

End annual number: 6

PR1001 Payment of annual fee

Payment date: 20080806

Start annual number: 7

End annual number: 7

PR1001 Payment of annual fee

Payment date: 20091006

Start annual number: 8

End annual number: 8

PR1001 Payment of annual fee

Payment date: 20101008

Start annual number: 9

End annual number: 9

PR1001 Payment of annual fee

Payment date: 20110921

Start annual number: 10

End annual number: 10

PR1001 Payment of annual fee

Payment date: 20120917

Start annual number: 11

End annual number: 11

FPAY Annual fee payment

Payment date: 20130829

Year of fee payment: 12

PR1001 Payment of annual fee

Payment date: 20130829

Start annual number: 12

End annual number: 12

FPAY Annual fee payment

Payment date: 20141002

Year of fee payment: 13

PR1001 Payment of annual fee

Payment date: 20141002

Start annual number: 13

End annual number: 13

FPAY Annual fee payment

Payment date: 20150909

Year of fee payment: 14

PR1001 Payment of annual fee

Payment date: 20150909

Start annual number: 14

End annual number: 14

EXPY Expiration of term
PC1801 Expiration of term