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WO2012035561A2 - Système amélioré d'administration ciblée de médicaments par voie orale - Google Patents

Système amélioré d'administration ciblée de médicaments par voie orale Download PDF

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Publication number
WO2012035561A2
WO2012035561A2 PCT/IN2011/000642 IN2011000642W WO2012035561A2 WO 2012035561 A2 WO2012035561 A2 WO 2012035561A2 IN 2011000642 W IN2011000642 W IN 2011000642W WO 2012035561 A2 WO2012035561 A2 WO 2012035561A2
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Prior art keywords
drug
drug delivery
delivery system
colon
probiotics
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PCT/IN2011/000642
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English (en)
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WO2012035561A3 (fr
WO2012035561A4 (fr
Inventor
Monica Gulati
Sima Singh
Sanjiv Duggal
Rahul Satyakam
Mamta Sharma
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Lovely Professional University
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Priority to JP2013528836A priority Critical patent/JP2013537221A/ja
Priority to EP11824692.5A priority patent/EP2632902A4/fr
Priority to CN2011800551776A priority patent/CN103347863A/zh
Publication of WO2012035561A2 publication Critical patent/WO2012035561A2/fr
Publication of WO2012035561A3 publication Critical patent/WO2012035561A3/fr
Publication of WO2012035561A4 publication Critical patent/WO2012035561A4/fr
Priority to US13/909,159 priority patent/US20140154312A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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Definitions

  • the field of invention pertains to pharmaceutical formulations. More specifically, it pertains to an "Improved Oral Targetted Drug Delivery System (O-TDDS)".
  • O-TDDS Oral Targetted Drug Delivery System
  • the system is particularly suited for delivery of drugs having activity against the diseases located in the colon e.g. colon cancer, ulcerative colitis, protozoal infections etc.
  • the present invention discloses an "Improved Oral Targetted Drug Delivery System".
  • the system is particularly suited for delivery of drugs having activity against diseases located in the colon e.g. colon cancer, ulcerative colitis, protozoal infections etc.
  • diseases located in the colon e.g. colon cancer, ulcerative colitis, protozoal infections etc.
  • data pertaining to an anti-cancer agent, 5-Fluorouracil has been provided. However, the same is purely for illustrative purposes and is not restricting.
  • the drug 5-Fluorouracil is one of the most commonly used anti-tumor agents. It was first synthesized in 1957 (Heidelberger, C, Chaudhuri, N. K., Danneberg, P., Mooren, D., Griesbach, L, 1957. Fluorinated pyrimidines, a new class of tumor-inhibitory compounds. Nature179, 663-666.). At that time it was the only agent with clinical activity against colorectal cancer. Due to its structural resemblance to natural pyrimidines, 5-FU interferes with nucleic acid synthesis, inhibits DNA synthesis, and eventually halts cell growth (Langenbach, R.J., Dancenberg, P.
  • the drug not only kills tumor cells, but also the rapidly growing normal cells, including gastrointestinal (Gl) cells and bone marrow cells. This lack of target differentiation limits the use of the drug.
  • Toxicity is expressed as vomiting, diarrhoea, structural alteration of mucosal cells, decreased nutrient absorption, white blood cell (WBC) depression, and decreased platelet cells.
  • WBC white blood cell
  • the most serious toxicities are gastrointestinal toxicity, bone marrow inhibition and immunotoxicity.
  • Gastrointestinal toxicity and bone marrow inhibition are the dose limiting factors and hamper the use of higher and possibly more effective doses of 5-
  • Gl damage The gastrointestinal damage includes stomatistis, diarrhoea, denudation of villi, destruction of the integrity of mucosa, an increase of the permeability of intestine, and decrease of activities of intestinal enzymes such as thymidine-kinase. It has been reported that due to the cytotoxic effects of 5-FU on the mucous membrane, it causes mucositis when given via parenteral and intra peritoneal route (Mahood, D.J., Dose, A.M., Loblui, C.L., 1991. Inhibition of 5-f uorouracil-induced mucositis by oral cryotherapy. J. Clin. Oncol. 9, 449-452. and Pico, J.L., Avila-Garavito, A., Naccache P., 1998. Mucositis: its occurrence, consequences, and treatment in the oncology setting. Oncologist 3, 446-451)
  • Micro flora disturbance The ecological balance of normal micro flora is disturbed by the systemic administration of 5-FU. This leads to an alteration in the normal micro flora which, in turn, leads to a number of complications and multiple organ failure. This is accompanied by translocation of bacteria and diarrhoea. Moreover, there is a shift from gram (+) ve to gram (-) ve bacteria in the intestine, which increases the chances of secondary infections.
  • the existing formulations of 5-FU available in the market comprise either injections (parenteral) or capsules (oral intake).
  • both the existing formulations suffer from limitations as follows:
  • the drug is also available for oral intake in form of capsules.
  • the formulation has not become popular.
  • a major limiting factor is the erratic drug release profile and also undesirable side effects such as diarrhea and Gl hemorrhage leading to bloody stools.
  • the unpredictable release, wide variation in therapeutic effects and also undesirable side-effects has led to reliance of the clinicians on the parenteral formulation, despite its limitations and side-effects.
  • the drug 5-fluorouracil is not released at all ih We's ' fomach or small intestine, since its 'protective coat' of natural polymers cannot be digested. However, when it reaches the colon, specific bacteria in the colon digest the natural polymeric coat, leading to 'targetted release' of the drug only in the colon.
  • One more object of the invention is to disclose an Improved Oral Targetted Drug Delivery System comprising a unique combination of microspheres (drug + natural polymers) and probiotics in a single, pharmaceutically acceptable dosage form such as capsules.
  • a further object of the invention is to disclose an Improved Oral Targetted Drug Delivery System for anti-cancer drugs such as 5-FU in which the undesirable side-effects caused by the drug viz: diarrhea, vomiting, weight loss, hair loss etc. are either drastically reduced or eliminated altogether.
  • Yet another object is to disclose an oral drug delivery system in which the negative effects of the drug on the micro flora in the targeted region are overcome in an innovative manner by use of probiotics.
  • a still further object is to disclose an improved oral drug delivery system in which the limitations and drawbacks of the prior art are overcome.
  • the delivery system of the present invention comprises two elements packed in a single, pharmaceutically acceptable oral dosage form e.g. a capsule.
  • the two elements are:
  • Microspheres These comprise of the active drug 5-FU and natural polymers such as guar gum and xanthan gum.
  • Probiotics These are in the form of spray dried, lyophilized powder of an appropriate probiotic e.g. Bifidobacterium species (Bifidobacterium bifidum, Bifidobacterium longum etc.)
  • colonic drugs such as 5-FU do affect the colonic micro flora and thus functioning of natural polymer based, oral targeted drug delivery systems, how to solve the problem? How to ensure that functionality of delivery systems remained unaffected?
  • the inventors adopted an innovative experimental approach using a 'living biological system' comprising rats. All the experimental procedures were approved by the Institutional Animal Ethics Committee vide Approval Number 954/ac/06/CPCSEA/1919. The experimental study was conducted on thirty Wister Albino rats.
  • mice were divided into 6 groups of five each. Each animal in the group was given oral dose as indicated in Table 1 below:
  • the dosages were freshly prepared every day by suspending in milk. They were administered by oral gavage needle for first and subsequent exposure for a duration of five days each, at an interval of 20 days.
  • 5-FU considerably damages micro flora involved in release of drug from the 'natural gum based' delivery systems: Caecal contents of rats fed on 5-FU powder or 5-FU microspheres did not contain sufficiently active microbes. This is proven by the fact that when natural gum based drug delivery systems (compression coated tablets/microspheres) were exposed to the caecal contents of such rats, drug release was drastically reduced, ranging from 41%-54% compared to 83-92% in the control in which rats were not given any drug orally. This indicated that 'micro flora' in rats fed orally with 5-FU had been 'damaged' because it is these micro flora (bacteria) which are involved in digesting the natural gums in the 'targetted drug delivery systems'. Since release of drug was very less as compared to control, it indicated that the bacteria were being killed by the drug.
  • microspheres comprising mixture of 5-FU and natural polymeric gums viz. guar gum and xanthan gum (details of microsphere preparation duly given in Table 4).
  • the inventors used natural polymer based microspheres of 5-FU which has not been disclosed in the prior art.
  • Use of microspheres was attempted because of two reasons- Firstly to enhance 'drug dispersal' in the colon so that undesirable side-effects at the site of release could be reduced. Experimental evidence proved that use of microspheres significantly reduced the side effects as compared to 5-FU powder.
  • the 'microsphere based delivery system' of present invention does not require any specialized machinery and industrial scale batches can easily be manufactured.
  • Damage to micro flora can be overcome: The damage to colonic micro flora can be overcome by co-administration of appropriate probiotics.
  • test animals did not suffer from any weight loss and their weight was same as compared to the control animals
  • the present invention thus marks a turning point related to:
  • O-TDDS Improved Oral Targeted Drug Delivery System
  • O-TDDS for delivery of colon specific drugs and anti-cancer agents such as 5-Fluorouracil, comprising a combination of microspheres (mixture of drug + natural polymers such as guar gum and xanthan gum) and probiotics in a single, pharmaceutically acceptable oral dosage form such as a capsule, has not been disclosed anywhere in the prior art to best of knowledge of the inventors. It is thus novel.
  • the inventive step thus lies in the successful development by the inventors of an Improved Oral Targeted Drug Delivery System for delivery of colon specific drugs and anti-cancer agents such as 5-Fluorouracil, comprising a combination of microspheres (mixture of drug + natural polymers such as guar gum and xanthan gum) and probiotics in a single, pharmaceutically acceptable oral dosage form such as a capsule. It represents a significant technical advance over existing knowledge.
  • the inventive step lies in the complete elimination of the negative side-effects of the drug (e.g. 5-FU) on the micro flora of the colon.
  • the drug e.g. 5-FU
  • the inventive step lies in the complete elimination of the negative side-effects of the drug (e.g. 5-FU) on the micro flora of the colon.
  • the drug e.g. 5-FU
  • the problem of affect of 5-FU on micro flora had not been addressed, such targeted drug delivery systems in which micro flora played a critical and functional role, were technically flawed with a strong possibility of failure. This was because once the micro flora was upset; the next dosage form would not work as the natural polymer coat would not open due to lack of colonic bacteria to digest the same. This problem has been solved in the present invention.
  • the present invention discloses an improved oral targeted drug delivery system particularly suited for delivery of drugs having activity against the diseases located in the colon e.g. colon cancer, ulcerative colitis, protozoal infections etc.
  • the concept disclosed in the present invention can well be extrapolated to other drugs. It can be used to reduce the side-effects in delivery systems where natural gums/polymers have been utilized to bring about 'targeted delivery'. Examples of such drugs targeted to colon using combination of natural gums such as guar gum and xanthan gum or guar gum alone are given in Table 5 and Table 6 respectively, below:
  • present invention has successfully demonstrated a practical mechanism to maintain the integrity and intactness of the intestinal/colonic micro flora, in face of 'chemical attack' by colon specific drugs listed in Table 6 above. Since the approach used in the present invention primarily involves use of microspheres of the drug + probiotics 'packed' in a single, oral, pharmaceutically acceptable dosage form, the example of 5-FU given is not restrictive but may be regarded as an illustrative example to better explain the invention and promote understanding of the same.
  • Delivery systems can utilize any suitable drug apart from drugs disclosed in present application.
  • More than one probiotic can be used in a system.
  • a combination of more than one drug and more than one probiotic can be used.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Tropical Medicine & Parasitology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne un système amélioré d'administration ciblée de médicaments par voie orale ("O-TDDS") particulièrement approprié pour l'administration de médicaments présentant une activité dirigée contre les maladies localisées dans le côlon, par ex., le cancer du côlon, la recto-colite hémorragique, les infections causées par des protozoaires, etc. Le système comprend deux éléments ou parties, à savoir des microsphères (médicament + polymères naturels tels que la gomme de guar ou la gomme de xanthane) et des probiotiques. Les deux éléments sont conditionnés ensemble en une forme posologique orale pharmaceutiquement acceptable telle qu'une capsule. Le système offre les différents avantages d'une administration de médicaments sans les effets secondaires indésirables de diarrhée, nausée ou vomissement communément rencontrés en cas d'utilisation de médicaments anticancéreux tels que le 5-fluorouracile.
PCT/IN2011/000642 2010-09-17 2011-09-19 Système amélioré d'administration ciblée de médicaments par voie orale WO2012035561A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2013528836A JP2013537221A (ja) 2010-09-17 2011-09-19 改良された経口標的化薬物送達システム
EP11824692.5A EP2632902A4 (fr) 2010-09-17 2011-09-19 Système amélioré d'administration ciblée de médicaments par voie orale
CN2011800551776A CN103347863A (zh) 2010-09-17 2011-09-19 改进的口服靶向药物递送系统
US13/909,159 US20140154312A1 (en) 2010-09-17 2013-06-04 Oral targetted drug delivery system

Applications Claiming Priority (2)

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IN2220DE2010 2010-09-17
IN2220/DEL/2010 2010-09-17

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US13/909,159 Continuation US20140154312A1 (en) 2010-09-17 2013-06-04 Oral targetted drug delivery system

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102871983A (zh) * 2012-10-31 2013-01-16 中国人民解放军第四军医大学 藤黄酸结肠定位控释片及其制备方法
CN103142494A (zh) * 2013-03-19 2013-06-12 河北凯盛医药科技有限公司 奥硝唑口服制剂及其制备方法
RU2554739C1 (ru) * 2014-03-25 2015-06-27 Александр Александрович Кролевец Способ получения нанокапсул албендазола
CN105997937A (zh) * 2016-07-04 2016-10-12 中北大学 5-氟尿嘧啶印迹凝胶微球制备方法
WO2018039087A1 (fr) * 2016-08-20 2018-03-01 Gregg John Malcolm Hall Méthodes d'utilisation de médicament antimicrobien et compositions thérapeutiques

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017088540A (ja) * 2015-11-10 2017-05-25 ビオフェルミン製薬株式会社 ５−フルオロウラシル誘発性腸疾患の予防及び／又は治療剤
CN108653341B (zh) * 2018-05-30 2021-04-30 华中科技大学 一种用于恶性肿瘤免疫治疗的药盒及其应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100219918B1 (ko) * 1997-07-03 1999-09-01 김윤 대장선택적 약물전달용 조성물
AUPQ132599A0 (en) * 1999-07-01 1999-07-22 Commonwealth Scientific And Industrial Research Organisation Nasogastric enteral formulations
DK1429802T3 (da) * 2001-09-28 2013-02-18 Tntgamble Inc Tilførselssystem for biologisk komponent
US20070098784A1 (en) * 2001-09-28 2007-05-03 Nutraceutix, Inc. Delivery system for biological component
US20050266069A1 (en) * 2002-09-06 2005-12-01 Simmons Donald L Stable probiotic microsphere compositions and their methods of preparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None
See also references of EP2632902A4

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102871983A (zh) * 2012-10-31 2013-01-16 中国人民解放军第四军医大学 藤黄酸结肠定位控释片及其制备方法
CN103142494A (zh) * 2013-03-19 2013-06-12 河北凯盛医药科技有限公司 奥硝唑口服制剂及其制备方法
RU2554739C1 (ru) * 2014-03-25 2015-06-27 Александр Александрович Кролевец Способ получения нанокапсул албендазола
CN105997937A (zh) * 2016-07-04 2016-10-12 中北大学 5-氟尿嘧啶印迹凝胶微球制备方法
WO2018039087A1 (fr) * 2016-08-20 2018-03-01 Gregg John Malcolm Hall Méthodes d'utilisation de médicament antimicrobien et compositions thérapeutiques

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Publication number Publication date
WO2012035561A3 (fr) 2012-07-19
JP2013537221A (ja) 2013-09-30
EP2632902A2 (fr) 2013-09-04
EP2632902A4 (fr) 2014-05-28
CN103347863A (zh) 2013-10-09
WO2012035561A4 (fr) 2012-08-16

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