GB2216411A - Sustained-release trypanocide compositions - Google Patents
Sustained-release trypanocide compositions Download PDFInfo
- Publication number
- GB2216411A GB2216411A GB8904597A GB8904597A GB2216411A GB 2216411 A GB2216411 A GB 2216411A GB 8904597 A GB8904597 A GB 8904597A GB 8904597 A GB8904597 A GB 8904597A GB 2216411 A GB2216411 A GB 2216411A
- Authority
- GB
- United Kingdom
- Prior art keywords
- poly
- trypanocide
- release
- lactide
- drug
- 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.)
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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
- A61K9/0087—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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (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 delivery system comprises a trypanocide dispersed in least one biodegradable polymer. Suitable trypanocides include homidium chloride or bromide, isometamidium, quinpyramine sulphate and diminazine aceturate. The polymer may be polyglycolide, poly-(L-lactide), poly-(D, L-lactide), polycaprolactone, poly-( beta -hydroxy butyrate), poly-( beta - hydroyvalerate) or poly-( alpha -aminoacids). The composition may be administered by intramuscular or subcutaneous injection or by surgical implantation.
Description
IMPLANT
This invention relates to controlled release delivery systems containing a trypanocide.
Trypanocidally active phenanthridine 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 1986) a variety of drug delivery systems proposed for the administration of 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. homidium bromide that was based on an inclusion of the active agent in erythrocytes (Res Exp
Med., 535, 1-9, 1985). D Fluck (I.S.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 early leakage of the enclosed 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-phenyl)phenanthridinium chloride hydrochloride; common name, isometamidium). Other trypanocides include quinpyramine sulphate (4-amino 6- (2-amino-6-methylpyrimidin-4-ylamino) -2-methyl- l,l'-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 a-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 5% and 60%, preferably 20-35%, by weight.
The polymer can be a homopolymer or a copolymer. If desired a mixture of two or more biodegradable polymers can be used The biodegradable polymers are those which upon administration to the body degrade to harmless products. Examples of suitble polymers include: polyglycolide, poly(L-lactide), poly(D,L-lactide), polyeaprolactone, poly(ss-hydroxybutyrate), poly(ss-hydroxyvalerate) and poly(a-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 additive(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 3,960,757. 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 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 1300C.
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 1300C 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.
Example 1
Small scale preparation of cylindrical devices composed of a polycaProlactone 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 1200C. 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
Larger scale preparation of cylindrical devices composed of a polycaprolactone matrix loaded with homidium bromide
500 g Polycaprolactone (MW ca.: 56,000) is mixed for 10 min with 150 g homidium using a Brabender mixer, heated at 600C. The mixture is transferred to a lab-scale extruder, provided with a 1.2 mm nozzle and is extruded at 100-1500C. The extruded fibres are cut in pieces of ca.
1 cm. The diameter of the fibres ranges from 1.5 to 1.7 nun 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 10% (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.
Example 4
In vitro evaluation of devices loaded with trypanocidal drugs, e.g. polycaprolactone 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 KH2P04 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, in which:
Figure 1 shows the cumulative in vitro release of homidium bromide (HBr) from poly(c-caprolactone), MW 50,000, cylindrical matrices (diameter = 1.5 mm: length = 2 cm) with various drug loadings. (Extrusion temp = 120-150 C, pressure 300Kpa);
Figure 2 shows the cumulative in vitro release of homidium bromide (HBr) from reservoir systems: 1.85 mm diameter core (length = 1 cm) consisting of poly(c-caprolactone-co-L-lactide) 80/20, MW 48,000, 40% homidium bromide loading (extrusion temp = 1500C, pressure 300Kpa) and a coating membrane of poly(c-caprolactone), MW 50,000;
Figure 3 shows the cumulative in vitro release (average of 2 replicates) of homidium bromide (HBr) from poly(E-caprolactone-co-l-lactide) cylinder matrices (diameter = 1.7 mm; length = 1 cm; extrusion temp = 1900C, pressure 1379 Kpa; HBr content = 25%;
Figure 4 shows the cumulative in vitro release (average of 2 replicates) of homidium bromide (HBr) from cylinder matrices comprising D,L-lactide homoplymer and copolymer with c-caprolactone (diameter = 1.7 mm; length = 1 cm; extrusion temp = 1900C, pressure 1379 Kpa;HBr content = 25%); Figure 5 shows the cumulative in vitro release of homidium bromide (HBr) from reservoir systems, 1.85 mm diameter core and length = 2 cm, consisting of poly(c-caprolactone, MW = 50000, (extrusion temp = 1500C, pressure 300Kpa) and a coating membrane of poly(c-caprolactone); 25% homidium bromide content: and
Figure 6 shows the in vitro release of homidium bromide (HBr) from poly(c-caprolactone-co-lactides) cylinder matrices (diameter = 1.7 mm; length = 1 cm; extrusion temp = 1500C, HBr content = 25%).
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.
4 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.
Example 7
Evaluation of the therapeutic effectiveness of the delivery system against pre-established T. congolense infection.
The method described in Example 6 is used. At days 28, 91 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 28 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 proving that the observed prophylactic effect is not an 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 |
---|---|
GB8904597D0 GB8904597D0 (en) | 1989-04-12 |
GB2216411A true GB2216411A (en) | 1989-10-11 |
Family
ID=10632911
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB888805286A Pending GB8805286D0 (en) | 1988-03-05 | 1988-03-05 | Trypanocides |
GB8904597A Withdrawn GB2216411A (en) | 1988-03-05 | 1989-03-01 | Sustained-release trypanocide compositions |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB888805286A Pending GB8805286D0 (en) | 1988-03-05 | 1988-03-05 | Trypanocides |
Country Status (3)
Country | Link |
---|---|
AP (1) | AP86A (en) |
GB (2) | GB8805286D0 (en) |
OA (1) | OA09237A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991011176A1 (en) * | 1990-01-30 | 1991-08-08 | 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 |
US5444113A (en) * | 1988-08-08 | 1995-08-22 | Ecopol, Llc | End use applications of biodegradable polymers |
ES2416004A1 (en) * | 2012-01-24 | 2013-07-29 | Investigaciones Farmaceuticas Y Veterinarias, S.L. | Pharmaceutical composition comprising isometamidium chloride in solution for the treatment of trypanosomiasis in animals |
Citations (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 |
GB1521938A (en) * | 1975-08-25 | 1978-08-16 | Shell Int Research | Parasite control compositions |
GB1573459A (en) * | 1977-05-20 | 1980-08-20 | Ethicon Inc | Absorbable polymer drug compositions |
EP0025697A1 (en) * | 1979-09-12 | 1981-03-25 | Eli Lilly And Company | Growth promotant controlled release formulations and method of treatment |
EP0025696A2 (en) * | 1979-09-12 | 1981-03-25 | Eli Lilly And Company | Controlled release parasiticidal formulations |
EP0130935A1 (en) * | 1983-07-01 | 1985-01-09 | Battelle Memorial Institute | Biodegradable polypeptide and its use in the sustained release of medicaments |
EP0134318A2 (en) * | 1983-06-10 | 1985-03-20 | Connaught Laboratories Limited | Controlled release of injectable and implantable insulin compositions |
EP0147335A2 (en) * | 1984-01-02 | 1985-07-03 | LABORATOIRES D'HYGIENE ET DE DIETETIQUE L.H.D. Société Anonyme dite: | Pharmaceutical inert matrix made of polycaprolactone, and method of preparing an oral galenic form |
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 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4495934A (en) * | 1978-07-25 | 1985-01-29 | Shaw Jr Seth T | 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 |
-
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 (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 |
GB1521938A (en) * | 1975-08-25 | 1978-08-16 | Shell Int Research | Parasite control compositions |
GB1573459A (en) * | 1977-05-20 | 1980-08-20 | Ethicon Inc | Absorbable polymer drug compositions |
EP0025697A1 (en) * | 1979-09-12 | 1981-03-25 | Eli Lilly And Company | Growth promotant controlled release formulations and method of treatment |
EP0025696A2 (en) * | 1979-09-12 | 1981-03-25 | Eli Lilly And Company | Controlled release parasiticidal formulations |
EP0134318A2 (en) * | 1983-06-10 | 1985-03-20 | Connaught Laboratories Limited | Controlled release of injectable and implantable insulin compositions |
EP0130935A1 (en) * | 1983-07-01 | 1985-01-09 | Battelle Memorial Institute | Biodegradable polypeptide and its use in the sustained release of medicaments |
EP0147335A2 (en) * | 1984-01-02 | 1985-07-03 | LABORATOIRES D'HYGIENE ET DE DIETETIQUE L.H.D. Société Anonyme dite: | Pharmaceutical inert matrix made of polycaprolactone, and method of preparing an oral galenic form |
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 |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5444113A (en) * | 1988-08-08 | 1995-08-22 | Ecopol, Llc | End use applications of biodegradable polymers |
US5760118A (en) * | 1988-08-08 | 1998-06-02 | Chronopol, Inc. | End use applications of biodegradable polymers |
WO1991011176A1 (en) * | 1990-01-30 | 1991-08-08 | 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 |
US5496557A (en) * | 1990-01-30 | 1996-03-05 | 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 |
ES2416004A1 (en) * | 2012-01-24 | 2013-07-29 | Investigaciones Farmaceuticas Y Veterinarias, S.L. | Pharmaceutical composition comprising isometamidium chloride in solution for the treatment of trypanosomiasis in animals |
Also Published As
Publication number | Publication date |
---|---|
AP8900117A0 (en) | 1989-04-30 |
OA09237A (en) | 1992-06-30 |
AP86A (en) | 1990-05-28 |
GB8805286D0 (en) | 1988-04-07 |
GB8904597D0 (en) | 1989-04-12 |
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WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |