EP0648129A1 - A drug delivery device and a method of making such device - Google Patents
A drug delivery device and a method of making such deviceInfo
- Publication number
- EP0648129A1 EP0648129A1 EP93914649A EP93914649A EP0648129A1 EP 0648129 A1 EP0648129 A1 EP 0648129A1 EP 93914649 A EP93914649 A EP 93914649A EP 93914649 A EP93914649 A EP 93914649A EP 0648129 A1 EP0648129 A1 EP 0648129A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cross
- drug
- polymer
- matrix
- delivery device
- 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- Withdrawn
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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- 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
Definitions
- Polymeric materials such as hydrogels have been widely used in drug carrier systems for controlled release or used as stimuli sensitive devices. Such devices are for instance described in "Hydrogels in Medicine and Pharm ⁇ acy", N.A. Peppas (Ed.), CRC Press, 1987.
- the formula ⁇ tions described therein are generally not biodegradable.
- the release of pharmacologically active agents "loaded” into such gels is typically controlled by simple diffu ⁇ sion in the device which depends on the water content in the gel. These gels are therefore not suitable for drug delivery to specific regions of the intestines after oral administration.
- These devices comprise a laminated membrane surrounding a compartment containing a drug.
- the membrane results in a time delay in the commencement of substantial release of the drug.
- Such osmotic drug de ⁇ vices have the same disadvantages as the device described in GB Patent Application 2 066 070.
- modified dextran instead of ordinary dextran it is possible to obtain a hydrogel matrix with a more hydrophobic or a more hydrophilic as well as charged character. This can be used to control the swelling pro ⁇ perties of the hydrogel matrix.
- the dextranase degradable polymer is also chosen depending on which drug is to be loaded into the hydrogel matrix, so that the dextranase degradable polymer will not react with the drug in a manner which irreversibly inactivates the drug. Particularly preferred is sulfated, alcoxylated, oxydated or esterificated dextran.
- the dextranase degradable polymer may have a molecular weight between 10,000 and 2,000,000 g/mol, preferably between 40,000 and 2,000,000 g/mol.
- the drug can in principle be any type of drug.
- the device according to the invention is especially advantageous for use when administering drugs for treatment of diseases in the colon, e.g. steroids, 5-aminosalicylic acid, anti- inflammatory agents, anti-cancer agents, enzymatic agent, and bacterial cultures, or for administration of drugs which are unstable in the stomach and/or the small intes ⁇ tine, e.g. peptides such as insulin, vasopressin, or growth hormones, proteins, enzymes, and vaccines.
- drugs for treatment of diseases in the colon e.g. steroids, 5-aminosalicylic acid, anti- inflammatory agents, anti-cancer agents, enzymatic agent, and bacterial cultures
- drugs which are unstable in the stomach and/or the small intes ⁇ tine e.g. peptides such as insulin, vasopressin, or growth hormones, proteins, enzymes, and vaccines.
- the drug is homogeneously dispersed in the cross-linked hydrogel matrix.
- the hydrogel matrices can be formed into capsules, tablets, films, microspheres, or the like.
- the compositions formulated using the hydrogel matrices can include conventional pharmaceutical carriers or excipients, adjuvants, etc.
- the device according to the invention can contain more than one drug, e.g. the device can contain one drug of high molecular weight in the lumen of the hydrogel matrix and another drug of lower molecular weight dispersed homogeneously in the matrix.
- Another object of the invention is to provide a method of making a drug delivery device according to the invention.
- the hydrogel matrix is predried, preferably to a water content lower than 30 weight-% and particularly lower than 10 weight-%,
- This last method provides a very simple and easy method of making a device according to the invention by which the drug is homogeneously dispersed.
- Fig. 2 is a graph showing the equilibrium degree of swel ⁇ ling of a device according to the invention depending on the contents of cross-linking agents.
- Fig. 3 is a graph showing the equilibrium degree of swel- ling of a device according to the invention depending on the molecular weight of dextran.
- Fig. 4 is a graph showing the degradation in the cecum and in the stomach, respectively, of a device according to the invention depending on time.
- Fig. 5 shows the release profiles of hydrocortisone from a device according to the invention.
- 70,000, commercially available from Pharmacia was dis ⁇ solved in 8.5 ml (85 vol-%) anhydrous dimethylsulphoxide (DMSO).
- DMSO dimethylsulphoxide
- 86 ⁇ l (0.46 mmol ⁇ 5 mol- %) of hexamethylenediisocyanatp (HDI, cross-linking agent) was added. This was done in a thoroughly dried glass bowel, as the cross-linking reaction is obstructed by traces of water.
- the solution was transferred to the reaction mould for fabrication of films by means of a needle and syringe.
- the mould consists of two water- jacketed teflon-coated aluminum blocks, between which blocks the solution was placed. By controlling the distance between the blocks using a spacer ring, it is possible to control the thickness of the resulting hydro- gel film.
- the temperature was set to 70 °C.
- the cross- linking reaction took place at this temperature for 24 hours.
- dextran was varied. Hydro- gels were made with dextran 10, 500 and 2000 (MW 10,000, 500,000 and 2,000,000, respectively).
- Table 1 shows a scheme of the synthesized hydrogels.
- the vol-% is calculated in relation to the volume of the resulting reaction mixture.
- the mol-% is calculated on the basis of the molar content of glucose in the amount of dextran used.
- Figure 1 illustrates the dependence of equilibrium degree of swelling of hydrogels containing various amounts of DMSO in the reaction mixture. An increasing amount of DMSO in the reaction mixture results in an increase of the equilibrium degree of swelling of the resulting hydrogel. This is more distinct in DMSO than in water.
- hydrogels The in-vitro degradability of hydrogels was investigated using dextranase (50 kilo Dextranase Units/g). Discs, 5 mm in diameter and 1.6 mm in thickness, of hydrogel films prepared as described in example 1, were cut and swollen to equilibrium in 0.1 M acetate buffer pH 5.4. After swelling equilibrium was reached, the discs were trans ⁇ ferred to the enzyme mixture consisting of 1 ml 0.1 M acetate buffer pH 5.4 and 0.5, 3 or 12 nl dextranase. The mixture was incubated in a water bath at 37 °C, and the time required for complete dissolution of the discs, T, was recorded. Degradation of the gels was followed by a decrease in thickness.
- dextranase 50 kilo Dextranase Units/g
- Table 2 shows t for different gels when the enzyme mix ⁇ ture consisted of 12 ul dextranase/ml buffer. As cross- linking density increases, r increases, and thus the degradability decreases. This also relates to the equilibrium degree of swelling; the higher the degree of swelling, the higher the degradability of the hydrogel. However, the results also indicate that structural factors, too, influence on the degradability of the hydrogels.
- Table 3 shows that as the amount of dextranase increases, the rate of degradation increases.
- Figure 4 shows that after 3 days the gels implanted in cecum were degraded, whereas gels implanted in the stomach did not degrade. This shows that degradation of the gels takes place in-vivo and that this takes place in the cecum and not in the stomach.
- Hydrogel discs prepared as described in example 1, 5 mm in diameter and 1.6 mm in thickness (sample B), were washed in water and dried. After drying, the discs were immersed in a drug solution of hydrocortisone in DMSO (72.5 mg/ml). After 24 hours the gels were dried in vacuum af 50 °C for 2 days. Release of hydrocortisone from the discs was studied in 0.1 M acetate buffer pH 5.4 with (24 ul dextranase/ml buffer) and without dextranase present. A gel was immersed in 5 ml release medium and kept in a water bath at 37 °C.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK92895A DK89592D0 (da) | 1992-07-07 | 1992-07-07 | Laegemiddelafgivelsesindretning samt fremgangsmaade til fremstilling deraf |
DK895/92 | 1992-07-07 | ||
PCT/DK1993/000227 WO1994001136A1 (en) | 1992-07-07 | 1993-07-06 | A drug delivery device and a method of making such device |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0648129A1 true EP0648129A1 (en) | 1995-04-19 |
Family
ID=8098759
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP93914649A Withdrawn EP0648129A1 (en) | 1992-07-07 | 1993-07-06 | A drug delivery device and a method of making such device |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP0648129A1 (ru) |
JP (1) | JPH07508735A (ru) |
KR (1) | KR950702437A (ru) |
AU (1) | AU671651B2 (ru) |
BR (1) | BR9306700A (ru) |
CA (1) | CA2139747A1 (ru) |
CZ (1) | CZ3895A3 (ru) |
DK (1) | DK89592D0 (ru) |
FI (1) | FI950065A (ru) |
HU (1) | HUT75665A (ru) |
NZ (1) | NZ253678A (ru) |
PL (1) | PL172724B1 (ru) |
RU (1) | RU2139093C1 (ru) |
SK (1) | SK1795A3 (ru) |
WO (1) | WO1994001136A1 (ru) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5783214A (en) * | 1994-06-13 | 1998-07-21 | Buford Biomedical, Inc. | Bio-erodible matrix for the controlled release of medicinals |
WO1998000170A1 (en) * | 1996-07-01 | 1998-01-08 | Universiteit Utrecht | Hydrolysable hydrogels for controlled release |
GEP20053427B (en) | 1999-12-23 | 2005-01-25 | Pfizer Prod Inc | Pharmaceutical Compositions Providing Enhanced Drug Concentrations |
WO2011123416A1 (en) * | 2010-03-29 | 2011-10-06 | Surmodics, Inc. | Injectable drug delivery formulation |
KR20190090048A (ko) | 2011-12-05 | 2019-07-31 | 인셉트, 엘엘씨 | 의료용 유기젤 방법 및 조성물 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2550750A (en) * | 1947-09-22 | 1951-05-01 | Arthur C Abelt | Differential for automobiles |
US4024073A (en) * | 1972-01-08 | 1977-05-17 | Toray Industries, Inc. | Hydrogel and production thereof |
IT1131833B (it) * | 1980-06-20 | 1986-06-25 | Crinos Industria Farmaco | Eccipienti per sostanze spermicide |
JPS5997346A (ja) * | 1982-11-24 | 1984-06-05 | Komatsu Ltd | 車両のデイフアレンシヤル装置 |
SE9002339L (sv) * | 1990-07-04 | 1992-01-05 | Kabi Pharmacia Ab | Terapeutisk komposition och foerfarande foer dess framstaellning |
-
1992
- 1992-07-07 DK DK92895A patent/DK89592D0/da not_active Application Discontinuation
-
1993
- 1993-07-06 AU AU44178/93A patent/AU671651B2/en not_active Ceased
- 1993-07-06 SK SK17-95A patent/SK1795A3/sk unknown
- 1993-07-06 RU RU95105519A patent/RU2139093C1/ru active
- 1993-07-06 KR KR1019950700048A patent/KR950702437A/ko not_active Application Discontinuation
- 1993-07-06 CA CA002139747A patent/CA2139747A1/en not_active Abandoned
- 1993-07-06 CZ CZ9538A patent/CZ3895A3/cs unknown
- 1993-07-06 EP EP93914649A patent/EP0648129A1/en not_active Withdrawn
- 1993-07-06 NZ NZ253678A patent/NZ253678A/en unknown
- 1993-07-06 JP JP6502843A patent/JPH07508735A/ja not_active Expired - Lifetime
- 1993-07-06 PL PL93307050A patent/PL172724B1/pl unknown
- 1993-07-06 WO PCT/DK1993/000227 patent/WO1994001136A1/en not_active Application Discontinuation
- 1993-07-06 HU HU9500042A patent/HUT75665A/hu unknown
- 1993-07-06 BR BR9306700A patent/BR9306700A/pt not_active Application Discontinuation
-
1995
- 1995-01-05 FI FI950065A patent/FI950065A/fi unknown
Non-Patent Citations (1)
Title |
---|
See references of WO9401136A1 * |
Also Published As
Publication number | Publication date |
---|---|
NZ253678A (en) | 1996-07-26 |
FI950065A (fi) | 1995-03-02 |
BR9306700A (pt) | 1998-12-08 |
AU4417893A (en) | 1994-01-31 |
CA2139747A1 (en) | 1994-01-20 |
PL172724B1 (pl) | 1997-11-28 |
PL307050A1 (en) | 1995-05-02 |
SK1795A3 (en) | 1995-09-13 |
WO1994001136A1 (en) | 1994-01-20 |
CZ3895A3 (en) | 1995-09-13 |
JPH07508735A (ja) | 1995-09-28 |
HU9500042D0 (en) | 1995-03-28 |
AU671651B2 (en) | 1996-09-05 |
RU2139093C1 (ru) | 1999-10-10 |
FI950065A0 (fi) | 1995-01-05 |
KR950702437A (ko) | 1995-07-29 |
DK89592D0 (da) | 1992-07-07 |
HUT75665A (en) | 1997-05-28 |
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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: 19950119 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE |
|
17Q | First examination report despatched |
Effective date: 19980602 |
|
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: 20000213 |