WO1994013270A1 - Improving effectiveness of drugs - Google Patents

Improving effectiveness of drugs Download PDF

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Publication number
WO1994013270A1
WO1994013270A1 PCT/GB1993/002503 GB9302503W WO9413270A1 WO 1994013270 A1 WO1994013270 A1 WO 1994013270A1 GB 9302503 W GB9302503 W GB 9302503W WO 9413270 A1 WO9413270 A1 WO 9413270A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
drug
cells
culture medium
cell
Prior art date
Application number
PCT/GB1993/002503
Other languages
French (fr)
Inventor
Margaret Joan Taylor
Original Assignee
Kappa Pharmaceuticals Limited
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 Kappa Pharmaceuticals Limited filed Critical Kappa Pharmaceuticals Limited
Priority to AU55735/94A priority Critical patent/AU5573594A/en
Priority to JP6513926A priority patent/JPH08504204A/en
Priority to DE69312963T priority patent/DE69312963T2/en
Priority to EP94900974A priority patent/EP0673243B1/en
Publication of WO1994013270A1 publication Critical patent/WO1994013270A1/en

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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
    • A61K9/48—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
    • A61K9/5005—Wall or coating material
    • A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
    • A61K9/5068—Cell membranes or bacterial membranes enclosing drugs
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes

Definitions

  • This invention relates to improving the effectiveness of drugs.
  • Certain drugs are known to be effective against cancerous tissue, but have severe side effects on healthy tissue.
  • the concept of targeting has been discussed for some time, in which a drug is delivered, usually in minute but effective doses, directly to disease tissue but without also dosing surrounding healthy cells.
  • Another approach is pharmaceutical targeting, in which specially designed delivery devices direct the activity of a non-selective drug.
  • a "magic gun” system guidance is imposed on the device such that it permeates only relevant areas, instead cf inertly diffusing throughout the tissues until a recognition event occurs .
  • a targetted drug can reach widely disseminated cells. Most primary tumours produce secondary or metastatic growths which often prove fatally resistant. A device that killed these growths would be a significant step forward.
  • Tumour cells are known to exhibit surface antigens, which are capable of provoking immunity despite the host's failure to counter a fostering tumour.
  • drugs have been attached, by various means, to a specific monoclonal antibody. When in contact with tumour cells in vitro, this worked well, but it failed in vivo.
  • the present invention provids an effective drug delivery technique which does not have rhe problems of prior suggestions.
  • the invention comprises a method for improving the effectiveness of a drug comprising the steps of encapsulating the drug in liposome membranes and loading the thus encapsulated drug into cells extracted from the intended patient.
  • the cells may be macrophages or related onocytes, and may be taken from the peritoneum of the patient or from blood.
  • the extracted cell fraction may be added to a culture medium combined with an agent preventing cell adhesion. Without such an agent, the cells may adhere to the walls of a culture flask, for example, which can make harvesting difficult.
  • an agent may comprise PVP coated colloidal silica, which is sold under the name Percoll by Pharmacia Inc.
  • a suitable culture medium is RPMI 40, and a suitable composition is one part ten-fold strength RPMI 40 culture medium and nine parts Percoll.
  • a cell activator may be added, such as adjuvent peptide or MDP, with or without the addition of liposomes at this stage. This, especially with liposomes, rapidly activates macrophages to a tumouricidal state.
  • the cells are cultured in the composition until activated, as may be determined microscopically by inspection from time to time. This may take several hours at body temperature.
  • the liposome encapsulated drug nay then be added and the composition further incubated until phagocytosis occurs, i.e. the cells imbibe the liposome encapsulated drug. After this, the drug loaded cells may be separated centrifugally and re-suspended into a drug-free saline solution for re-introduction into the patient.
  • the invention also comprises a kit for carrying out the method above described comprising a culture flask containing a composition of culture medium and cell adhesion preventive agent.
  • the invention also comprises a composition for carrying out the method above described or for use in a kit as described containing a culture medium and a cell adhesion preventive agent.
  • composition can include also the optional elements referred to above.
  • made-up preparations and culture flasks must all be aseptic, and likewise techniques for introducing the cell fraction and additives.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Botany (AREA)
  • Virology (AREA)
  • Cell Biology (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

There is disclosed a method for improving the effectiveness of a drug comprising the steps of encapsulating the drug in liposome membranes and loading the thus encapsulated drug into cells extracted from the intended patient.

Description

IMPROVING EFFECTIVENESS OF DRUGS
This invention relates to improving the effectiveness of drugs.
Certain drugs are known to be effective against cancerous tissue, but have severe side effects on healthy tissue. The concept of targeting has been discussed for some time, in which a drug is delivered, usually in minute but effective doses, directly to disease tissue but without also dosing surrounding healthy cells.
Some approaches depend upon the synthesis of new chemicals which, for example, mainly affect cells with a high nucleic acid turnover, due to their fast reproduction. This "magic bullet" or pharmacological approach, however, is difficult where a tumour cell is only quantitatively different from normal cells and has a tendency to produce toxicity.
Another approach is pharmaceutical targeting, in which specially designed delivery devices direct the activity of a non-selective drug. In a "magic gun" system, guidance is imposed on the device such that it permeates only relevant areas, instead cf inertly diffusing throughout the tissues until a recognition event occurs . A targetted drug can reach widely disseminated cells. Most primary tumours produce secondary or metastatic growths which often prove fatally resistant. A device that killed these growths would be a significant step forward.
An obvious possibility is to harness the cognitive powers of the natural immune system. Tumour cells are known to exhibit surface antigens, which are capable of provoking immunity despite the host's failure to counter a thriving tumour. In this approach, drugs have been attached, by various means, to a specific monoclonal antibody. When in contact with tumour cells in vitro, this worked well, but it failed in vivo.
The present invention provids an effective drug delivery technique which does not have rhe problems of prior suggestions.
The invention comprises a method for improving the effectiveness of a drug comprising the steps of encapsulating the drug in liposome membranes and loading the thus encapsulated drug into cells extracted from the intended patient.
The cells may be macrophages or related onocytes, and may be taken from the peritoneum of the patient or from blood. The extracted cell fraction may be added to a culture medium combined with an agent preventing cell adhesion. Without such an agent, the cells may adhere to the walls of a culture flask, for example, which can make harvesting difficult. Such an agent may comprise PVP coated colloidal silica, which is sold under the name Percoll by Pharmacia Inc.
A suitable culture medium is RPMI 40, and a suitable composition is one part ten-fold strength RPMI 40 culture medium and nine parts Percoll.
A cell activator may be added, such as adjuvent peptide or MDP, with or without the addition of liposomes at this stage. This, especially with liposomes, rapidly activates macrophages to a tumouricidal state.
In any event, the cells are cultured in the composition until activated, as may be determined microscopically by inspection from time to time. This may take several hours at body temperature.
The liposome encapsulated drug nay then be added and the composition further incubated until phagocytosis occurs, i.e. the cells imbibe the liposome encapsulated drug. After this, the drug loaded cells may be separated centrifugally and re-suspended into a drug-free saline solution for re-introduction into the patient.
The invention also comprises a kit for carrying out the method above described comprising a culture flask containing a composition of culture medium and cell adhesion preventive agent.
The invention also comprises a composition for carrying out the method above described or for use in a kit as described containing a culture medium and a cell adhesion preventive agent.
Such composition can include also the optional elements referred to above.
Obviously, made-up preparations and culture flasks must all be aseptic, and likewise techniques for introducing the cell fraction and additives.

Claims

1. A method for improving the effectiveness of a drug comprising the steps of encapsulating the drug in liposome membranes and loading the thus encapsulated drug into cells extracted from the intended patient.
2. A method according to claim 1, wherein the cells are macrophages or related monocytes.
3. A method according to claim 1 or claim 2, wherein the cells are taken from the peritoneum of the patient or from blood.
4. A method according to any one of the preceding claims, wherein the extracted cell fraction is added to a composition comprising a culture medium combined with an agent preventing cell adhesion.
5. A method according to claim 4, wherein the agent comprises PVP coated coloidal silica.
6. A method according to claim 4, wherein the culture medium is RPMI 40.
7. A method according to any one of claims 4 to 6, wherein the composition comprises one part ten-fold strength RPMI 40 culture medium and nine parts PVP coated coloidal silica.
8. A method according to any one of claims 4 to 7, wherein the composition further comprises a cell activator such as adjuvent peptide or MDP, with or without the addition of liposomes at this stage.
9. A method according to any one of claims 4 to 8, wherein the cells are cultured in the composition until activated.
10. A method according to claim 9, wherein cell activation is determined by microscopial inspection.
11. A method according to any one of claims 4 to 10, wherein the liposome encapsulated drug is incubated in the composition until phagocytosis occurs, i.e. the cells imbibe the liposome encapsulated drug.
12. A method according to claim 11, wherein the drug loaded cells are separated centrifugally and re-suspended into a drug-free saline solution for re-introduction into the patient.
13. A kit for carrying out the method disclosed in claims 1 to 12, comprising a culture flask containing a composition of culture medium and cell adhesion preventive agent.
14. A composition for carrying out the method disclosed in claims 1 to 12 or for use in a kit as described in claim 13 containing a culture medium and a cell adhesion preventive agent.
15. A composition according to claim 14 also comprising a cell activator such as adjuvent peptide or MDP.
PCT/GB1993/002503 1992-12-08 1993-12-07 Improving effectiveness of drugs WO1994013270A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU55735/94A AU5573594A (en) 1992-12-08 1993-12-07 Improving effectiveness of drugs
JP6513926A JPH08504204A (en) 1992-12-08 1993-12-07 Increased drug efficacy
DE69312963T DE69312963T2 (en) 1992-12-08 1993-12-07 INCREASING THE EFFECTIVENESS OF MEDICINAL PRODUCTS
EP94900974A EP0673243B1 (en) 1992-12-08 1993-12-07 Improving effectiveness of drugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9225588.4 1992-12-08
GB929225588A GB9225588D0 (en) 1992-12-08 1992-12-08 Improving effectiveness of drugs

Publications (1)

Publication Number Publication Date
WO1994013270A1 true WO1994013270A1 (en) 1994-06-23

Family

ID=10726271

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/002503 WO1994013270A1 (en) 1992-12-08 1993-12-07 Improving effectiveness of drugs

Country Status (8)

Country Link
EP (1) EP0673243B1 (en)
JP (1) JPH08504204A (en)
AT (1) ATE156351T1 (en)
AU (1) AU5573594A (en)
DE (1) DE69312963T2 (en)
ES (1) ES2106495T3 (en)
GB (1) GB9225588D0 (en)
WO (1) WO1994013270A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994023706A1 (en) * 1993-04-20 1994-10-27 Endocon, Inc. Foam cell drug delivery

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9023384B2 (en) 2004-11-02 2015-05-05 Tokyo Medical And Dental University Liposome and method for injecting substance to cell using this liposome

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0001104A2 (en) 1977-09-06 1979-03-21 Studiengesellschaft Kohle mbH Modified intact erythrocytes, blood or blood preserves containing them and process for their preparation
WO1990004972A1 (en) * 1988-11-02 1990-05-17 Klehr Nikolaus Walther The use of bodily fibroblasts and skin cells as effective substance vehicles for intra-corporal/local therapy

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0001104A2 (en) 1977-09-06 1979-03-21 Studiengesellschaft Kohle mbH Modified intact erythrocytes, blood or blood preserves containing them and process for their preparation
WO1990004972A1 (en) * 1988-11-02 1990-05-17 Klehr Nikolaus Walther The use of bodily fibroblasts and skin cells as effective substance vehicles for intra-corporal/local therapy

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994023706A1 (en) * 1993-04-20 1994-10-27 Endocon, Inc. Foam cell drug delivery

Also Published As

Publication number Publication date
DE69312963D1 (en) 1997-09-11
ATE156351T1 (en) 1997-08-15
GB9225588D0 (en) 1993-01-27
JPH08504204A (en) 1996-05-07
DE69312963T2 (en) 1998-03-05
AU5573594A (en) 1994-07-04
EP0673243A1 (en) 1995-09-27
ES2106495T3 (en) 1997-11-01
EP0673243B1 (en) 1997-08-06

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