AP86A - Implant - Google Patents
Implant Download PDFInfo
- Publication number
- AP86A AP86A APAP/P/1989/000117A AP8900117A AP86A AP 86 A AP86 A AP 86A AP 8900117 A AP8900117 A AP 8900117A AP 86 A AP86 A AP 86A
- Authority
- AP
- ARIPO
- Prior art keywords
- drug
- devices
- homidium
- bromide
- release
- Prior art date
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- 239000007943 implant Substances 0.000 title description 3
- 230000000654 trypanocidal effect Effects 0.000 claims abstract description 9
- 238000012377 drug delivery Methods 0.000 claims description 7
- 229920002988 biodegradable polymer Polymers 0.000 claims description 6
- 239000004621 biodegradable polymer Substances 0.000 claims description 6
- QTANTQQOYSUMLC-UHFFFAOYSA-O Ethidium cation Chemical compound C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 QTANTQQOYSUMLC-UHFFFAOYSA-O 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000003814 drug Substances 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 19
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 14
- 229960005542 ethidium bromide Drugs 0.000 description 14
- 239000000203 mixture Substances 0.000 description 9
- -1 poly(β-hydroxybutyrate) Polymers 0.000 description 8
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 7
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000223107 Trypanosoma congolense Species 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 229920001610 polycaprolactone Polymers 0.000 description 4
- 239000004632 polycaprolactone Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000002690 trypanocidal agent Substances 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001125 extrusion Methods 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 229910021653 sulphate ion Inorganic materials 0.000 description 3
- UGKOYGZYLRKTJH-UHFFFAOYSA-O 3-[2-(3-amino-5-ethyl-6-phenylphenanthridin-5-ium-8-yl)iminohydrazinyl]benzenecarboximidamide Chemical compound C12=CC(N=NNC=3C=C(C=CC=3)C(N)=N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 UGKOYGZYLRKTJH-UHFFFAOYSA-O 0.000 description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 241001502121 Glossina brevipalpis Species 0.000 description 2
- 208000009182 Parasitemia Diseases 0.000 description 2
- 208000030852 Parasitic disease Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- XNYZHCFCZNMTFY-UHFFFAOYSA-N diminazene Chemical class C1=CC(C(=N)N)=CC=C1N\N=N\C1=CC=C(C(N)=N)C=C1 XNYZHCFCZNMTFY-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229920001519 homopolymer Polymers 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 1
- URSFPCGNENDEFB-UHFFFAOYSA-N 3-[2-(3-amino-5-ethyl-6-phenylphenanthridin-5-ium-8-yl)iminohydrazinyl]benzenecarboximidamide;chloride;hydrochloride Chemical compound Cl.[Cl-].C12=CC(N=NNC=3C=C(C=CC=3)C(N)=N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 URSFPCGNENDEFB-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000020897 Formins Human genes 0.000 description 1
- 108091022623 Formins Proteins 0.000 description 1
- QNZJTSGALAVCLH-UHFFFAOYSA-N Isometamidium chloride Chemical compound [Cl-].C12=CC(\N=N\NC=3C=C(C=CC=3)C(N)=N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 QNZJTSGALAVCLH-UHFFFAOYSA-N 0.000 description 1
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- 229950010741 aceturate Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000003618 dip coating Methods 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001746 injection moulding Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 229950004591 isometamidium chloride Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920005597 polymer membrane Polymers 0.000 description 1
- 229920000307 polymer substrate Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- PQFRTXSWDXZRRS-UHFFFAOYSA-N ronidazole Chemical compound CN1C(COC(N)=O)=NC=C1[N+]([O-])=O PQFRTXSWDXZRRS-UHFFFAOYSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 201000002311 trypanosomiasis Diseases 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nanotechnology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A trypanocide drug
Description
This invention relates to controlled release deliverysystems containing a trypanocids.
Trypanocida1ly active phenanthr id i ne compounds, such as homidium bromide or chloride, are widely used against animal trypanosomiasis such as that spread by tsetse fly in Africa. The present formulations are water soluble and as a result the drug is only bioavailable for a short period of time and usually no more than about 60 days. Since the tsetse fly challenge extends for a much longer period, it is highly desirable that the drug can be made available for as long a period as possible. The present invention relates to a system of such drugs whereby the drug is slowly released into the bloodstream over a period of time thus maintaining therapeutic levels over a long period.
In various articles, reviews and books e.g. in Controlled Drug Delivery by S Bruck (CRC Press, Boca Raton 1983) and Sustained and Controlled Release Drug Delivery Systems, 2nd edition. by J Robinson and V Lee (Marcel Dekker 1985) a variety of drug delivery systems proposed for the administration cf various drugs have been described. Until now no drug delivery system based on biodegradable polymers, has been reported for the delivery of trypanocides in animals.
DeLoach reported on a delivery system for trypanocidal drugs, e.g. horaidium bromide that was based on an inclusion of the active agent in erythrocytes (Res Exp Med., 53 5 , 1-9 . 1985 ). D Fluck (I . 5 . C . R . T. C . report 520, 1985) described the use of lipsomes as drug dosage forms for iometamidium. Finally D James (Trans Roy Soc Trop Med Hyg 72, 471-476, 1987) attempted to enhance the duration of activity of isometamidium chloride by preparing ionic complexes with dextran sulphate. A distinct disadvantage of the erythrocyte and lipsome systems is the risk of
BAD ORIGINAL early leakage of the enclose! drugs. In the case of the dextran sulphate complex the pharmacokinetic properties are significantly changed which results in a loss of the prophylactic action of the complexed isometamidium (D Schilinger et al, Abstracts of the 18th Meeting
I.S.C.T.R.C. Harare, Zimbabwe, 4-8 March. 1985).
The present invention overcomes these disadvantages.
According to the invention there is provided a trypanocide drug delivery system which comprises a trypanocide dispersed in least one biodegradable polymer.
The invention is especially applicable to formulations of salts of homidium (3,8-diamino-5-ethyl-6-phenylphenanthridium), eg the chloride and especially the bromide. This latter salt is also sold as Ethidium. Other phenanthradine compounds include that sold under the trade name Samorin (3-amino-8-(2-amino-6-methylpyrimidin-4-ylamino-5-ethyl-6-phenylJphenanthridinium chloride hydrochloride; common name, isometamidium). Other trypanocides include quinpyramine sulphate (4-amino20 6-(2-amino-6-methylpyrimidin-4-ylamino)-2-methyl1,1'-dimetho(methyl sulphate)) and salts of diminazine (p,p'-diamidinodiazoaminobenzene). eg the aceturate, which is sold under the trade name Berenil, pyrethidium bromide, ronidazol, MF-nitroimidazol and α-D.L-difluoromethyl ornithine.
The system preferably also comprises other additives such as a) substances to facilitate the fabrication of the device, b) substances to increase the stability of the devices and/or c) substances to adjust the release characteristics of the drug.
The device can contain two or more bioactive agents. The drug content in the delivery systems can vary between over a wide range, e.g. from 5¾ and 60%, preferably 20-35%, by weight.
The polymer can be a homopolymer or a copolymer. If
AP 0 0 0 0 8 6
BAD ORIGINAL desired a mixture of two or more biodegradable polymers cat be used The biodegradable polymers are those which upon administration to the body degrade to harmless products. Examples of suitble polymers include:
polyglyco1ide. poly (L-1 actide), poly(D.L-lactide), polycaprolaclone, poly(β-hydroxybutyrate). poly(β-hydroxyvalerate) and poly(α-aminoacids), in addition to copolymers composed of two or more of the following structural units: glycolide, L-lactide,
D,L-lactide, D-lactide, caprolactone or valerolactone.
This also include stereocopolymers of L-lactide and D,L-lactide. A system based on polycaprolactone is especially preferred.
The delivery systems are preferably fabricated in the shape of cylinders, as tablets or spherical particles. The devices prepared according to this invention can be administered to animals by intramuscular or subcutaneous injection or by surgical implantation. Cylinders are especially preferred as these can be most satisfactorally implanted into an animal. The diameter of such cylindershaped devices can vary between e.g. 1 mm and 7 mm and the length can range from e.g. 1 to 7 cm. The diameter of spheres can vary between 20 microns and 1 mm. The cylindrical devices can be prepared by extrusion or injection moulding of the the appropriate mixture of biodegradable polmer(s), drug(s) and possible adcitive(s). The tablets can be prepared by compression of the appropriate mixture. The spherical devices can be prepared e.g. by a solvent-evaporation technique, eg as described by M. Morishita et al. U.S, Patent 3,560,757. The devices, prepared in the various geometrical forms described before, can. if necessary, be subsequently coated with a biodegradable polymer belonging to the class of polymers cited before as candidate carrier materials. Coating can be achieved eg by dip coating or spraying techniques. In
BAD ORIGINAL ft coated devices the surrounding polymer membrane can act as a barrier controlling the release of the drug enclosed in the device. The drug delivery systems loaded with trypanocidal drug(s) and prepared according to this invention will, after subcutaneous or intra-muscular administration, release the drug over a period varying from one week to over one year. The duration of the release and the release rate can be controlled and varied over a broad range and depends on the chemical composition of the polymer substrate, the nature of the drug retained within the device, the drug loading, the additives, the shape of the device, and the presence of a coating membrane. The release of the drug retained within the device occurs by diffusion and or erosion of the polmer material used as a constructive part of the device.
The examples described hereafter illustrate the preparation of devices containing homidium bromide and the in vitro and in vivo evaluation of these devices.
Homopolymers and copolymers of c-caprolactone as well as copolymers with L,L- and D.L-dilactides were prepared by ring opening polymerisation of the purified monomers, using 1000 ppm stannous bis(2~ethylenehexenoate) in toluene as catalyst, at a temperature of 130°C. Polymerisations were carried out in bulk, in silanised glass tubes under vacuum and after several freeze-thaw cycles for degassing. After sealing, the tubes were immersed and rotated in a silicone oil bath at 130°C for 7 days to give polymers with molecular weights in the range 40,000 to 90,000. Polymers were collected by cooling to room temperature, dissolving in chloroform, precipitating with hexane and dried in vacuo.
AP000086
BAD original £
Example 1
Small scale preparation of cylindrical devices composed of a po’.:aorolactor.e matrix loaded with homidium bromide.
2.5 g Polycaprolactone (MW ca.: 56,000) is dissolved in 25 ml dichloromethane and 750 mg homidium bromide is added. From this mixture a film is cast. After drying, the film is cut in small pieces which are transferred into a melt index apparatus, provided with a 1.2 mm nozzle and heated at 120°C. A pressure of about 300 KPa is applied to force the mixture of drug and polymer through the nozzle. The extruded fibres are cut in pieces of ca. 1 cm. The diameter of the fibres ranges from 1.5 to 1.7 mm depending on the speed of the extrusion process.
The cylindrical pieces are sterilized by ethylene oxide vapor treatment and stored in vacuum-sealed polyethylene bags.
Example 2
r. Larger scale preparation of cylindrical devices composed of a pclycaprolactone matrix loaded with homidium bromide
500 g Polycaprolactone (MW ca.: 56,000) is mixed for min with 150 g homidium using a Erabender mixer, heated at 60°C. The mixture is transferred to a lab-scale extruder, provided with a 1.2 mm nozzle and is extruded at 100-150°C. The extruded fibres are cut in pieces of ca.
1 cm. The diameter of the fibres ranges from 1.5 to 1.7 mm depending on the speed of the extrusion process.
Example 3
Preparation of cylindrical devices loaded with homidium bromide coated with a biodegradable membrane
Poly(caprolactone-co-D,L-lactide) cylindrical devices loaded with homidium bromide are coated by dipping the devices in a 10¾ (by weight) solution of polycaprolactone in chloroform (MW ca 60.000). The dipcoating-drying cycle is repeated to obtain the desired coating thickness. A typical coating thickness is 50-100 microns.
BAD ORIGINAL
Example 4
In vitro evaluation of devices loaded with trypanocidal drugs, e.g. polycsprolactone cylinders loaded with homidium bromide.
Medium used for in vitro release: phosphate buffer pH 7.4; 30.4 ml 0.5 NaOH + 40.3 mo 0.5 M KH2PC>4 adjusted to 1 1 with distilled water. 250 ml Buffer is transferred to a silanized glass-stoppered Erlenmeyer flask, maintained at 37°C. One or more devices (e.g. cylinders of
1-2 mm diameter and 0.5-2 cm length) are transferred to that solution. At regular time intervals, samples are withdrawn for analysis of the amount of drug released. Analysis of the homidium bromide content was carried out by HPLC using the method of Perschke and Vollmert (Acta tropica 42. 209-216, 1985).
Example 5
In a similar manner to the previous Examples various other cylinders are prepared and evaluated. The release rates and details of all such devices are shown in Figures
1-6
Example 6
In vivo evaluation of poly(e-caprolactoneco-L,L-lactide) (75/25) cylindrical devices loaded with
25% homidium bromide, using rabbits as test animals.
Cylinders of 1 cm length each were subcutaneously administered to rabbits infected with different strains of T. congolense. At regular intervals blood samples were taken and analysed for homidium bromide by HPLC. For comparison, in a separate experiment rabbits were given homidium bromide intra-muscularly at a 1 mg/kg dose. Blood samples were taken regularly and assayed for homidium bromide. The results of these experiments are summarized in figure 7, expressing the plasma concentration in ng/ml (average value for 5 rabbits) as a function of time after subcutaneous implantation. AP 0 0 0 0 8 6
bad ORIGINAL
Example 7
Evaluation of the therapeutic effectiveness of the delivery system aga ir.s t pre-established T. congolense infection.
The method described in Example 6 is used. At days 28, and 150 the rabbits were reinfected with different strains of T. congolense. No positive parasitemia was observed over the total duration of the experiment in rabbits treated with the device prepared according to this invention and specified in Example 6. Rabbits treated with an intra-muscular dose of homidium bromide gave a positive result when reinfected 23 days after the start of the treatment. Upon removal of the subcutaneous implant, at day 120 after implantation and reinfection with
T. congolense. positive parasitemia was observed, thus P proving that the observed prophylactic effect is not an Λ immunological phenomenon but solely caused by the implant of the invention.
Claims (2)
1, A trypanocide drug delivery system which comprises a trypanocide dispersed in least one biodegradable polymer .
2. A system according to claim 1 in which the trypanocide is a salt of homidium.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888805286A GB8805286D0 (en) | 1988-03-05 | 1988-03-05 | Trypanocides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP8900117A0 AP8900117A0 (en) | 1989-04-30 |
| AP86A true AP86A (en) | 1990-05-28 |
Family
ID=10632911
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1989/000117A AP86A (en) | 1988-03-05 | 1989-03-03 | Implant |
Country Status (3)
| Country | Link |
|---|---|
| AP (1) | AP86A (en) |
| GB (2) | GB8805286D0 (en) |
| OA (1) | OA09237A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5444113A (en) * | 1988-08-08 | 1995-08-22 | Ecopol, Llc | End use applications of biodegradable polymers |
| AU651084B2 (en) * | 1990-01-30 | 1994-07-14 | Akzo N.V. | Article for the controlled delivery of an active substance, comprising a hollow space fully enclosed by a wall and filled in full or in part with one or more active substances |
| ES2416004B1 (en) * | 2012-01-24 | 2014-01-28 | Investigaciones Farmaceuticas Y Veterinarias, S.L. | PHARMACEUTICAL COMPOSITION THAT INCLUDES ISOMETAMIDIUM CHLORIDE IN SOLUTION FOR THE TREATMENT OF TRIPANOSOMIASIS IN ANIMALS. |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4331652A (en) * | 1979-09-12 | 1982-05-25 | Eli Lilly And Company | Controlled release parasitic formulations and method |
| AU538984B2 (en) * | 1979-07-09 | 1984-09-06 | Seth Thomas Shaw Jr. | Iud arrangement |
| US4489056A (en) * | 1982-06-30 | 1984-12-18 | Merck & Co., Inc. | Acid anhydrides as rate controlling agent for the erosion of polymers which latter polymers have beneficial substances dispersed throughout their matrix or where the polymer matrix surrounds the beneficial substance |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB923076A (en) * | 1958-07-24 | 1963-04-10 | Wellcome Found | Antiprotozoal pharmaceutical preparations and the manufacture thereof |
| BE845365A (en) * | 1975-08-25 | 1977-02-21 | COMPOSITIONS FOR THE CONTROL OF PARASITES | |
| CA1098443A (en) * | 1977-05-20 | 1981-03-31 | Namassivaya Doddi | Absorbable p-dioxanone polymer-drug compositions |
| PH17900A (en) * | 1979-09-12 | 1985-01-25 | Lilly Co Eli | Growth promotant controlled release formulations and method of treatment |
| NZ194898A (en) * | 1979-09-12 | 1983-04-12 | Lilly Co Eli | Controlled release parasiticidal formulation containing fenbendazole dispersed in lactic acid-glycolic acid copolymer |
| CA1196864A (en) * | 1983-06-10 | 1985-11-19 | Mattheus F.A. Goosen | Controlled release of injectable and implantable insulin compositions |
| DE3463211D1 (en) * | 1983-07-01 | 1987-05-21 | Battelle Memorial Institute | Biodegradable polypeptide and its use in the sustained release of medicaments |
| FR2557459B1 (en) * | 1984-01-02 | 1986-05-30 | Lhd Lab Hygiene Dietetique | POLYCAPROLACTONE-BASED INERT MATRIX FOR ORAL ADMINISTRATION OF A MEDICAMENT, AND METHOD FOR PREPARING THE GALENIC FORM COMPRISING THE SAME |
| US4764364A (en) * | 1986-02-25 | 1988-08-16 | S R I International | Method of preparing bioerodible polymers having pH sensitivity in the acid range and resulting product |
-
1988
- 1988-03-05 GB GB888805286A patent/GB8805286D0/en active Pending
-
1989
- 1989-03-01 GB GB8904597A patent/GB2216411A/en not_active Withdrawn
- 1989-03-02 OA OA59535A patent/OA09237A/en unknown
- 1989-03-03 AP APAP/P/1989/000117A patent/AP86A/en active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU538984B2 (en) * | 1979-07-09 | 1984-09-06 | Seth Thomas Shaw Jr. | Iud arrangement |
| US4331652A (en) * | 1979-09-12 | 1982-05-25 | Eli Lilly And Company | Controlled release parasitic formulations and method |
| US4489056A (en) * | 1982-06-30 | 1984-12-18 | Merck & Co., Inc. | Acid anhydrides as rate controlling agent for the erosion of polymers which latter polymers have beneficial substances dispersed throughout their matrix or where the polymer matrix surrounds the beneficial substance |
Also Published As
| Publication number | Publication date |
|---|---|
| AP8900117A0 (en) | 1989-04-30 |
| GB2216411A (en) | 1989-10-11 |
| GB8805286D0 (en) | 1988-04-07 |
| GB8904597D0 (en) | 1989-04-12 |
| OA09237A (en) | 1992-06-30 |
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