EP0120061A1 - Encapsulated genetically programmed living organisms producing therapeutic substances - Google Patents

Encapsulated genetically programmed living organisms producing therapeutic substances

Info

Publication number
EP0120061A1
EP0120061A1 EP83903132A EP83903132A EP0120061A1 EP 0120061 A1 EP0120061 A1 EP 0120061A1 EP 83903132 A EP83903132 A EP 83903132A EP 83903132 A EP83903132 A EP 83903132A EP 0120061 A1 EP0120061 A1 EP 0120061A1
Authority
EP
European Patent Office
Prior art keywords
organisms
wall
therapeutic
human
enclosed
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.)
Withdrawn
Application number
EP83903132A
Other languages
German (de)
French (fr)
Other versions
EP0120061A4 (en
Inventor
Theodore E. Spielberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP0120061A1 publication Critical patent/EP0120061A1/en
Publication of EP0120061A4 publication Critical patent/EP0120061A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings

Definitions

  • the invention relates to therapeutic agents for internal administration to an animal body such as a human and to methods of their manufacture and administration.
  • Prior Art Internally administered therapeutic agents usually ' encompass drugs and other non-living materials which are ingested by a user, or implanted or inserted in the user for therapeutic purposes. They are delivered to the body of the user in a variety of ways, such as in the form of capsules for oral administration or or by insertion as suppositories, or in the form of liquids for oral administration or injection, among other techniques. Also, living organisms have been administered by injection e.g., small pox, vaccination, or- by the oral route in the form of liquid droplets e.g., Sabin polio immunization. These agents are prepared by a variety of manufacturing processes, and are stored until their administration to the end user.
  • Objects of the Invention Accordingly, it is an object of the invention to provide an improved mechanism for administering selected therapeutic agents derived from genetically altered organism to an animal body. Further, it is an object of my invention to provide an improved method of generating therapeutic agents derived from genetically altered organisms for administration to an animal body.
  • genetically programmed organisms which produce the desired therapeutic agents to be administered to an animal m body such as a human are prepared in situ and enclosed within a protective membrane providing mechanical confinement to the organisms while they are being administered to the animal body.
  • the membrane may include an inner layer containing material providing sustenance to the enclosed bacteria for at least the time they are outside the human body, or a nutrient material may be included in the organism section of the chamber itself.
  • a microporous membrane that contains the organisms but allows passage of nutrients from a nutrient source or culture medium may be employed.
  • the membrane and its contents may be orally ingested by the human, or may be inserted as a suppository or otherwise implanted within the body.
  • the capsule may either remain intact, exchanging its therapeutic product for nutrients until removed or excreted, or may dissolve, allowing the therapeutic organisms to colonize the target areas releasing their therapeutic products there.
  • a genetically altered strain is preselected that itself produces the therapeutic agent which is to be utilized by the body.
  • altered bacteria of the type E. Coli produce insulin which is used to treat diseases such as diabetes.
  • the membrane dissolves within the body to a sufficient extent to release the enclosed bacteria.
  • the bacteria then operate, within the body environment, to produce the selected therapeutic agent [e_.g, insulin].
  • the number of bacteria are, of course, proportioned to the desired dosage of agent to be administered to the body, taking into consideration the type of bacteria, the specific portion of the body in which they were lodged, and their expected lifetime and productivity time within that body portion.
  • the therapeutic agent is generated by the bacteria within the membrane and is transferred across the membrane walls by A-
  • the membrane walls 5 may be such as to be dissolvable when ingested or 6 inserted into the body, or may be such that the walls 7 are relatively resistant to degradation within the 8 body but allow passage of therapeutic products 9 generated by the bacteria into the body.
  • dissolvable capsules may be modified 1 to dissolve under optimal conditions for specific 2 locality colonization and as such may be acid 3 resistant and more soluable in an alkaline environment 4 for intestinal colonization, or by other physical or 5 chemical modifications designed to enhance successful
  • 27 capsules may be stored at cold or freezing
  • Fig. 1 is a cross-sectional view of a
  • Fig. 2 is a cross-sectional view of a
  • a therapeutic device in the form of 1 a capsule comprises a membraneous wall 10 enclosing, 2 on the interior thereof, selected organisms 12 for 3 manufacture of therapeutic agents to be internally 4 administered to a human body.
  • Wall 10 may comprise a 5 material such as gelatin which is essentially 6 impermeable both to the organism and to the 7 therapeutic agents formed thereby, but which is broken 8 down by the body on ingestion or insertion of the 9 device into it or, alternatively, may comprise a 0 material such as a icroporous membrane which has a 1 pore size sufficient to allow passage of the 2 therapeutic agents formed by the organisms through the 3 membrane wall and into the body on ingestion or 4 insertion therein, while blocking escape of the 5 organism therethrough, and which is relatively inert 6 to degradation by the body when ingested or inserted.
  • the therapeutic agent is formed 8 within the body largely outside the membraneous wall, - while in the second case the therapeutic agent is formed within the membraneous enclosure.
  • Fig. 2 a further alternative version of my invention is shown.
  • a first or inner membraneous wall 20 encloses organisms 22 therein.
  • a second or outer membraneous wall 24 encloses a layer
  • the inner and outer chamber may be reversed.
  • This embodiment of the invention is expected to be useful in cases where extended pe.riods of time are expected to elapse between the preparation of the device and its ultimate utilization.
  • the membraneous walls 20 and 24 may be selected to allow escape of the enclosed organism 22 into the body following ingestion or insertion, or may be resistant to degradation by the body but sufficiently permeable to the organism that the therapeutic agent generated by the organism escape through these walls, and through the nutrient layer 26.
  • the layer 26 may also, in addition to, or instead of, providing nutrient to the organism 22, provide an absorptive layer which selectively absorbs constituents generated by the organism which it is desired to preclude from passage into the body.

Abstract

Un dispositif consiste en des organismes programmés génétiquement enfermés dans une variété de structures à membranes pour former une capsule thérapeutique. Cette capsule, lorsqu'elle est administrée en une personne, produit des agents thérapeutiques et peut, soit rester intacte jusqu'à être expulsée ou retirée, soit dissoudre sa paroi pour permettre aux organismes enfermés de coloniser les régions désirées pour ensuite produire les agents thérapeutiques.One device consists of genetically programmed organisms enclosed in a variety of membrane structures to form a therapeutic capsule. This capsule, when administered in a person, produces therapeutic agents and can either remain intact until expelled or removed, or dissolve its wall to allow the enclosed organisms to colonize the desired regions and then produce the therapeutic agents .

Description

ENCAPSULATED GENETICALLY PROGRAMMED LIVING ORGANISMS PRODUCING
THERAPEUTIC SUBSTANCES Background of the Invention A. Field of the Invention The invention relates to therapeutic agents for internal administration to an animal body such as a human and to methods of their manufacture and administration.
B. Prior Art Internally administered therapeutic agents usually 'encompass drugs and other non-living materials which are ingested by a user, or implanted or inserted in the user for therapeutic purposes. They are delivered to the body of the user in a variety of ways, such as in the form of capsules for oral administration or or by insertion as suppositories, or in the form of liquids for oral administration or injection, among other techniques. Also, living organisms have been administered by injection e.g., small pox, vaccination, or- by the oral route in the form of liquid droplets e.g., Sabin polio immunization. These agents are prepared by a variety of manufacturing processes, and are stored until their administration to the end user. Presently, through techniques of genetic engineering, living organisms can be genetically programmed to produce therapeutic substances such as interferon, antibiotics, and insulin. These programmed organisms are subjected to a complex fermentation, extraction, and purification process before the therapeutic substance is administered to the patient. Moreover, since there is uncertainty about the potential pathogenicity of genetically altered organisms (viruses, bacteria, or yeast for example) , elaborate safeguards have been enforced to prevent these altered organisms from contacting or "infecting" people. However, by deliberately selecting non-pathogenic organisms for genetic manipulation, or other organisms with finite longevity, the safety precautions have been able to be relaxed as contamination fears have lessened. * Description of the Invention
A. Objects of the Invention Accordingly, it is an object of the invention to provide an improved mechanism for administering selected therapeutic agents derived from genetically altered organism to an animal body. Further, it is an object of my invention to provide an improved method of generating therapeutic agents derived from genetically altered organisms for administration to an animal body.
B. Detailed Description of the Invention In accordance with the invention genetically programmed organisms which produce the desired therapeutic agents to be administered to an animal m body such as a human are prepared in situ and enclosed within a protective membrane providing mechanical confinement to the organisms while they are being administered to the animal body. The membrane may include an inner layer containing material providing sustenance to the enclosed bacteria for at least the time they are outside the human body, or a nutrient material may be included in the organism section of the chamber itself. Alternatively, a microporous membrane that contains the organisms but allows passage of nutrients from a nutrient source or culture medium may be employed. The membrane and its contents (hereinafter referred to collectively as a "capsule") may be orally ingested by the human, or may be inserted as a suppository or otherwise implanted within the body. The capsule may either remain intact, exchanging its therapeutic product for nutrients until removed or excreted, or may dissolve, allowing the therapeutic organisms to colonize the target areas releasing their therapeutic products there. In the case of bacteria, a genetically altered strain is preselected that itself produces the therapeutic agent which is to be utilized by the body. For example, altered bacteria of the type E. Coli produce insulin which is used to treat diseases such as diabetes. In one embodiment of my invention, the membrane dissolves within the body to a sufficient extent to release the enclosed bacteria. The bacteria then operate, within the body environment, to produce the selected therapeutic agent [e_.g, insulin]. The number of bacteria are, of course, proportioned to the desired dosage of agent to be administered to the body, taking into consideration the type of bacteria, the specific portion of the body in which they were lodged, and their expected lifetime and productivity time within that body portion. In an alternative embodiment, the therapeutic agent is generated by the bacteria within the membrane and is transferred across the membrane walls by A-
1 diffusion, the bacteria remaining within the membrane.
2 in this embodiment, the effective pore size of the
3 membrane is such that the bacteria are prevented from
4 transfer across the membrane wall, while the
5 therapeutic agent which they produce passes relatively
6 freely across this membrane and into the body in
7 exchange for nutrients.
8 In a further embodiment of the invention, a
9 double-walled membrane is used, the bacteria being 0 enclosed within a first or inner wall, and a layer of 1 material providing nourishing sustenance to the 2 bacteria being enclosed between the first. all and a 3 second or outer wall. In this embodiment, as with the 4 previously-described embodiments, the membrane walls 5 may be such as to be dissolvable when ingested or 6 inserted into the body, or may be such that the walls 7 are relatively resistant to degradation within the 8 body but allow passage of therapeutic products 9 generated by the bacteria into the body. Moreover, in 0 the case of dissolvable capsules, they may be modified 1 to dissolve under optimal conditions for specific 2 locality colonization and as such may be acid 3 resistant and more soluable in an alkaline environment 4 for intestinal colonization, or by other physical or 5 chemical modifications designed to enhance successful
26 colonization in their desired area. Furthermore, the
27 capsules may be stored at cold or freezing
28 temperatures to retard bacterial growth until 25. administration.
30 The foregoing and other and further objects and
31 features of this invention will be more readily
32 understood on reference to the accompanying drawings
33 showing an insertable capsule in accordance with the
34 present invention in which: 1 Detailed Description of the Invention
2 Fig. 1 is a cross-sectional view of a
3 therapeutic device having a single membrane wall
4 enclosing selective therapeutic organisms on the
5 interior thereof; and
6 Fig. 2 is a cross-sectional view of a
7 therapeutic device in accordance with the invention
8 having dual a membraneous wall enclosing the -9 organisms. 0 In Fig. 1, a therapeutic device in the form of 1 a capsule comprises a membraneous wall 10 enclosing, 2 on the interior thereof, selected organisms 12 for 3 manufacture of therapeutic agents to be internally 4 administered to a human body. Wall 10 may comprise a 5 material such as gelatin which is essentially 6 impermeable both to the organism and to the 7 therapeutic agents formed thereby, but which is broken 8 down by the body on ingestion or insertion of the 9 device into it or, alternatively, may comprise a 0 material such as a icroporous membrane which has a 1 pore size sufficient to allow passage of the 2 therapeutic agents formed by the organisms through the 3 membrane wall and into the body on ingestion or 4 insertion therein, while blocking escape of the 5 organism therethrough, and which is relatively inert 6 to degradation by the body when ingested or inserted. 7 In the first case, the therapeutic agent is formed 8 within the body largely outside the membraneous wall, - while in the second case the therapeutic agent is formed within the membraneous enclosure. Turning now to Fig. 2, a further alternative version of my invention is shown. A first or inner membraneous wall 20 encloses organisms 22 therein. A second or outer membraneous wall 24 encloses a layer
OMPI λrm IPO , of nutrient 26 which provides sustenance to the organism. Alternatively, the inner and outer chamber may be reversed. This embodiment of the invention is expected to be useful in cases where extended pe.riods of time are expected to elapse between the preparation of the device and its ultimate utilization. As was the case with the embodiments of Fig. 1, the membraneous walls 20 and 24 may be selected to allow escape of the enclosed organism 22 into the body following ingestion or insertion, or may be resistant to degradation by the body but sufficiently permeable to the organism that the therapeutic agent generated by the organism escape through these walls, and through the nutrient layer 26. In the latter case, the layer 26 may also, in addition to, or instead of, providing nutrient to the organism 22, provide an absorptive layer which selectively absorbs constituents generated by the organism which it is desired to preclude from passage into the body.
Conclusion From the foregoing it will seen that I have provided an improved therapeutic device incorporating live genetically programmed organisms producing therapeutic agents to a body such as a human body. In some cases, a single dosage will be sufficient to produce a desired agent for extended periods of time. Alternatively, the removal of an intact capsule or the administration of the appropriate antibiotic in the case of the colonized alternative will discontinue the administration of the therapeutic agent. Moreover, complex and costly manufacturing steps including fermentation, extraction, and purification may be avoided altogether. This device also avoids
OMPI many of the problems associated with degradation of therapeutic agent during shipment or storage. It accomodates itself to generation and administration of a variety of therapeutic agents, and is expected to be simple, yet effective in use. Having illustrated and described my invention, I claim:

Claims

0
1. A therapeutic device for insertion into .an animal body comprising genetically altered living organisms enclosed within a membraneous wall.
2. A therapeutic device according to claim 1 in which said wall is formed of a material selected to degrade in the body to thereby discharge the enclosed genetically altered living organisms into said body.
3. A therapeutic device according to claim 1 in which said wall is formed of a material that is relatively inert to degradation by said body on insertion therein and has a permeability sufficient to confine said organisms while facilitating the passage therethrough of therapeutic agents generated by said organisms.
4. A therapeutic device according to claim 1 including a second membraneous wall surrounding said first wall and forming therewith a chamber enclosing a nutrient material for said organisms.
5. A therapeutic device according to claim 1 including a second membraneous wall surrounding said first wall and forming therewith a chamber enclosing a filtration layer for blocking the passage of selected products of said organisms while facilitating the passage of products forming therapeutic agents.
__ 6. A therapeutic device for administration to a human for treatment of a disease, comprising genetically altered living organisms for producing a therapeutic agent specific to said disease and a wall confining said organisms at least until ingestion or insertion of the device into a human.
7, A therapeutic device according to claim 6 in which said wall comprises a membrane permeable to said therapeutic agent for passage of said agent therethrough while said device is within the human body.
8. A therapeutic device according to claim 6 in which said wall comprises a material degradable by the human body after ingestion or insertion therein to release the enclosed organisms.
9. A method of treating a human for a specific illness, comprising administering to said human genetically altered living organisms selected to produce a therapeutic agent specific to the illness for relief thereof, said agent being enclosed within a wall preventing release of said organisms prior to administration to the human and allowing passage of at least the organism-produced therapeutic agent therethrough within the human body after administration thereto.
EP19830903132 1982-09-29 1983-09-09 Encapsulated genetically programmed living organisms producing therapeutic substances. Withdrawn EP0120061A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US42842482A 1982-09-29 1982-09-29
US428424 1982-09-29

Publications (2)

Publication Number Publication Date
EP0120061A1 true EP0120061A1 (en) 1984-10-03
EP0120061A4 EP0120061A4 (en) 1986-08-21

Family

ID=23698842

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19830903132 Withdrawn EP0120061A4 (en) 1982-09-29 1983-09-09 Encapsulated genetically programmed living organisms producing therapeutic substances.

Country Status (3)

Country Link
EP (1) EP0120061A4 (en)
JP (1) JPS59501747A (en)
WO (1) WO1984001287A1 (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6097918A (en) * 1983-11-01 1985-05-31 Sumitomo Chem Co Ltd Long action pharmaceutical preparation of interferon
US4753799A (en) * 1985-10-23 1988-06-28 Plant Genetics, Inc. Production of hydrogel encapsulated nematodes
US4701326A (en) * 1985-10-23 1987-10-20 Plant Genetics, Inc. Membrane-coated hydrogel encapsulated nematodes
US4615883A (en) * 1985-10-23 1986-10-07 Plant Genetics, Inc. Hydrogel encapsulated nematodes
WO1991000119A1 (en) * 1989-06-30 1991-01-10 Baxter International Inc. Implantable device
US5314471A (en) * 1991-07-24 1994-05-24 Baxter International Inc. Tissue inplant systems and methods for sustaining viable high cell densities within a host
US5344454A (en) * 1991-07-24 1994-09-06 Baxter International Inc. Closed porous chambers for implanting tissue in a host
US5545223A (en) * 1990-10-31 1996-08-13 Baxter International, Inc. Ported tissue implant systems and methods of using same
US5713888A (en) * 1990-10-31 1998-02-03 Baxter International, Inc. Tissue implant systems
JP3508023B2 (en) * 1990-10-31 2004-03-22 バクスター、インターナショナル、インコーポレイテッド Closely vascularized implant material
JP4215273B2 (en) * 1991-04-25 2009-01-28 ブラウン ユニヴァーシティ リサーチ ファンデーション Implantable and biocompatible immunoblocking vehicle for the release of selected therapeutic agents
US5800829A (en) * 1991-04-25 1998-09-01 Brown University Research Foundation Methods for coextruding immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US6773458B1 (en) * 1991-07-24 2004-08-10 Baxter International Inc. Angiogenic tissue implant systems and methods
ATE183078T1 (en) * 1993-08-10 1999-08-15 Gore & Ass CELL ENCAPSULATING DEVICE
AU7568094A (en) * 1993-08-12 1995-03-14 Cytotherapeutics, Inc. Improved compositions and methods for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
US5908623A (en) * 1993-08-12 1999-06-01 Cytotherapeutics, Inc. Compositions and methods for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
WO1997010807A1 (en) * 1995-09-22 1997-03-27 Gore Hybrid Technologies, Inc. Improved cell encapsulation device
US20030229335A1 (en) * 2002-04-30 2003-12-11 Payne Richard Grady Apparatus and method for delivery of constrained beneficial bacteria to the vaginal tract

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE605803C (en) * 1931-06-26 1934-11-19 Iwan Arbatsky Capsule for means to combat putrefactive processes in the large intestine
GB1540461A (en) * 1975-08-20 1979-02-14 Damon Corp Chemical processes

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3317393A (en) * 1964-06-08 1967-05-02 Robert M Chanock Immunization by selective infection of the intestinal tract with an encapsulated live virus
US3823228A (en) * 1971-09-29 1974-07-09 Univ Illinois Tge virus vaccine
US3767790A (en) * 1972-02-11 1973-10-23 Nat Patent Dev Corp Microorganisms
JPS5544725B2 (en) * 1973-05-10 1980-11-13
US4235871A (en) * 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4322790A (en) * 1979-11-26 1982-03-30 General Electric Company Calibration source for instruments to measure power and negative sequence current of dynamoelectric machines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE605803C (en) * 1931-06-26 1934-11-19 Iwan Arbatsky Capsule for means to combat putrefactive processes in the large intestine
GB1540461A (en) * 1975-08-20 1979-02-14 Damon Corp Chemical processes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO8401287A1 *

Also Published As

Publication number Publication date
EP0120061A4 (en) 1986-08-21
JPS59501747A (en) 1984-10-18
WO1984001287A1 (en) 1984-04-12

Similar Documents

Publication Publication Date Title
EP0120061A1 (en) Encapsulated genetically programmed living organisms producing therapeutic substances
Gazzaniga et al. Time-controlled oral delivery systems for colon targeting
US3760805A (en) Osmotic dispenser with collapsible supply container
FI914765A0 (en) FREQUENTIAL ORAL MEDICINE FORM.
Hawgood Doctor Albert Calmette 1863–1933: founder of antivenomous serotherapy and of antituberculous BCG vaccination
TW200800298A (en) Compressed microparticles for dry injection
KR890001598A (en) Dosing device with dosing member for administering beneficial agent
KR880013586A (en) Dosage device comprising a removable substrate with a solid state property
DE69319258D1 (en) CONTROLLED RELEASE DEVICE
CN105163722A (en) Multi-stage biodegradable drug delivery platform
GB2155335A (en) Device for sustained release of medicinal substances
Ashwini et al. Chronotherapy: A novel drug delivery system
HU186995B (en) Process for the preparation of devices suitable for prolonged liberation of drug or other chemical substance in aqueous liquid medium
Hartley et al. Use of antibiotic impregnated polymethylmethacrylate beads for the treatment of chronic mandibular osteomyelitis in a Bennett's wallaby (Macropus rufo‐griseus rufogriseus)
Aslam et al. Techniques and polymers used to design Gastroretentive drug delivery systems–a review
Nief et al. Pulsatile drug delivery system-A review article
Dineen The in vivo production of penicillinase by hemolytic Staphylococcus aureus
Kamalpuria et al. The Latest Methods and Technologies of Pulsatile Drug Delivery System: A Review.
Gorbach The toxigenic diarrheas
Pathak Novel concept of drug delivery based on chronotherapy: a review
JP2005501671A5 (en)
Zubair et al. A Review on Laboratory Investigation of Anthrax as Causative Infectious Disease and Future Perspectives
Karale et al. Pros and cons of pulsatile drug delivery system
CN109223825A (en) Hydrogen peroxide is in the drug for preparing application and preparation in Helicobacter pylori eradication drug
US10342828B1 (en) Fecal oxygenation

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19840720

AK Designated contracting states

Designated state(s): CH DE FR GB LI SE

A4 Supplementary search report drawn up and despatched

Effective date: 19860821

17Q First examination report despatched

Effective date: 19880729

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19900320