EP0652745A1 - Implants a liberation regulee - Google Patents

Implants a liberation regulee

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Publication number
EP0652745A1
EP0652745A1 EP93915569A EP93915569A EP0652745A1 EP 0652745 A1 EP0652745 A1 EP 0652745A1 EP 93915569 A EP93915569 A EP 93915569A EP 93915569 A EP93915569 A EP 93915569A EP 0652745 A1 EP0652745 A1 EP 0652745A1
Authority
EP
European Patent Office
Prior art keywords
coating
outer coating
pulse release
hydrogel
release implant
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Withdrawn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
EP93915569A
Other languages
German (de)
English (en)
Inventor
Richard Daratech Pty. Ltd. Yu
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.)
Agriculture Victoria Services Pty Ltd
Original Assignee
Daratech Pty Ltd
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 Daratech Pty Ltd filed Critical Daratech Pty Ltd
Publication of EP0652745A1 publication Critical patent/EP0652745A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K9/0012—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

Definitions

  • This invention relates to implants containing active ingredients, especially drugs or veterinary products suitable for administration to humans and animals in which the active ingredient is required to be administered in a pulsatile release profile.
  • Prior art implants are typically of the reservoir type and usually contain a single active ingredient and provide the continuous release of the active in a zero or first order mode of release kinetics.
  • a water insoluble excipient eg, calcium phosphate
  • a bioactive agent such as a protein or peptide in an amount sufficient to give the required dosage unit of active ingredient in the final product.
  • the bioactive agent is usually in the form of a solution or dispersion or powder to facilitate mixing.
  • a water soluble excipient eg, lactose
  • if used is then added, together with the other desired additives, eg, a lubricating agent such as magnesium stearate, and mixed to form a homogeneous dry powder.
  • the powder is then compressed into a tablet of the desired size and shape.
  • the compressed tablet is then coated in a pan coater by spraying with a solution or dispersion of the coating material in an amount sufficient to give implants with the required coating thickness.
  • the tablet is coated in a fluidized bed system.
  • ⁇ Melt Processing
  • Ivermectin implant for livestock pest control hy T Allan Miller.
  • Ivermectin in a melt of polyethylene glycol (PEG) (MW 15,000 - 20,000). The solution was then drawn by vacuum into a 3 mm internal diameter Teflon tube and allowed to cool. Upon cooling the resultant solid rod (3mm diameter) was removed and trimmed to the desired weight of 400 mg.
  • PEG polyethylene glycol
  • Implant products of this type are solid cylindrical rods of varying length and diameter and can have shapes ranging from flat discs to fine needles. This type of implant is useful where a prolonged continuous supply of the drug is required.
  • pan coating and Wurster coating methods involve substantial contact between the implants being coated. During the drying process, the coating gets sticky resulting in implants sticking together or "twinning". It has been attempted to overcome this problem by the addition of additives and modifiers in the coating.
  • additives and modifiers in the coating.
  • the additives which may be used are limited to those substances cleared for regulatory use. Polyester coatings, for example, have been cleared for regulatory use however these present a particular problem in the pan coating method due to adhesion of the particles during the drying process. In addition pinholes and other discontinuities can form in the outer coat during the drying process.
  • Vaccination has been used to protect humans and animals against bacterial and viral infectious diseases.
  • vaccines prepared in the form of killed suspensions of bacteria or viruses, or in the form of conjugated toxoids repeated injections at specific time intervals are required in order for the vaccination to effect adequate levels of immunological response. These intervals may typically range from a few weeks to several months. Due to prevailing epidemiological, social, economic accessibility, human temperamental, or simply convenience reasons, it is highly desirable that effective protection against diseases can be obtained with single injections.
  • the one shot vaccines have to release the actives at the required intervals, i.e. in a pulsatile mode, in the required profile, Le. a "dump".
  • a further application of the "one shot vaccine” approach is a 6 month or 12 month contraceptive implant or vaginal suppository which delivers the contraceptive hormones in a succession of pulses, the active ingredient in this application not being a vaccine.
  • a further non-vaccine example relates to the need for delivery of reaction mixtures to sites of action, specifically the delivery of the lactoperoxidase thiocyanate enzyme substrate reaction system to the hindguts of piglets in the control of diarrhoea.
  • Lactoperoxidase coupled with a peroxide generating oxidase (eg, xanthine and xanthine oxidase) converts SCN to SCNO, a very reactive and lethal ion for micro ⁇ organisms. Pulse release technology can be used to address the problem of reinfection.
  • a controlled release drug delivery device Although the most important attribute of a controlled release drug delivery device is its capability to maintain a therapeutically effective level of drug in an animal body over a scheduled period of time, its adoption ultimately depends on the cost, convenience, and ease of its fabrication and administration (1). In terms of the ease and convenience of administering these devices as implants, shapes like sheets, films or hemispheres are generally impractical. However rods, needles or cylinders are readily adapted for parenteral implantation using a conventional hypodermic needle.
  • the apphcant's copending Apphcation PCT/ AU93/ 00083 discloses a method of making implants which are suitable for continuous release of an active ingredient over a period of time which consist of a body member comprising a membrane forming a wall around a core matrix and comprising material which is substantially impervious to the active ingredient contained within the core matrix.
  • the cylinder is generally open ended, the active ingredient being released directly through the open ends of the cylinder.
  • one aspect of the present invention contemplates a pulse release implant comprising: an axial biodegradable core; a first concentric layer comprising dehydrated hydrogel containing an active ingredient; and an outer coating, said outer coating being removable by the environment in which the implant will reside after administration.
  • a process of preparing a pulse-release implant including the steps of: coating an axially disposed biodegradable core material with a hydrogel containing an active ingredient to form a concentric coating; separating the coating into discrete segments disposed along the core material; dehydrating the hydrogel; coating the discrete segments with an outer coating, said outer coating being removable by the environment in which the implant will reside after administration; and removing the exposed core material to obtain the pulse release implants.
  • the biodegradable core may be formed from any suitable material.
  • the core is biocompatible.
  • the core may be formed from a string, suture or rod.
  • hydrogel is used in its ordinary art recognised meaning of a water-based three dimensional nonflowable amorphous structure.
  • the gel maybe created by ionic or hydrogen bond interactions.
  • Hydrogels of particular interest consist of a solution of a polymer in water which under controllable conditions can be made to adopt either a fluid or semi-solid configuration. This allows the hydrogel to be applied as a fluid to the core member and retain its shape as a semi-solid form.
  • Methods to induce the transition include temperature control or the use of cross-linking agents such as calcium ions.
  • the temperature control method is suitable for gels such as agar and gelatine and the cross-linking method is suitable for hydrogels formed from substances such as alginate polymers.
  • a hydrogel in a fluid form is applied to the axial biodegradable core, a transition to a semi-solid state is induced and the hydrogel is thereby immobilised. In this state, the hydrogel may be cut and otherwise manipulated.
  • a dehydrated hydrogel is formed.
  • the dehydrated hydrogel forms a rigid solid which is suitable for storage and handling. Any suitable hydrogel may be used. Examples are gelatine, agar, alginates, carrageenan, gum gragacanth, acacia, or corn starch. It may also be desirable to include other components in the first concentric layer.
  • disintegrating agents such as corn starch, potato starch, alginic acid and the like and/or a lubricant such as magnesium stearate.
  • Osmotic modifiers such as sucrose and glucose may also be desirable. All such components, should be substantially pharmaceutically pure and non-toxic in the amounts employed and should be biocompatible and compatible with the active ingredient when used for human or animal use.
  • the active ingredient is typically a bioactive molecule and includes any native, synthetic or recombinant pharmaceutical agent or food additive or supplement including antigens, antibodies, cytokines, growth promotants, hormones, cancer cell inhibitory molecules or agents, immune stimulants or suppressants, anti-microbial agents including antibiotics, anti-viral agents, vitamins, minerals or inorganic or organic nutrients.
  • the active ingredient may comprise one type of bioactive molecule or may be a mixture of different bioactive molecules.
  • the active ingredient includes antigens from the clostridial family.
  • the outer coating may be formed of any suitable biocompatible substance.
  • the outer coating is generally membranous or polymeric and is substantially impervious to the active ingredient. The majority of the active material will be delivered or released as a result of the removal of the outer coating encasing the first concentric layer.
  • suitable coating materials include modified starches, sugars, poly anhydrides, polyorthoesters, bioerodible polyesters and the polylactic/polyglycolic acid family of polymers. Polylactic/polyglycolic acids are particularly suitable as they are widely commercially available with various degradation profiles and have regulatory clearance.
  • the coating may have a thickness of from typically 10pm to 1,000pm depending on the application of the implant, and the permeability or degradability of the coating. Sttdjng
  • the implant device may be in any suitable shape including elongate, oval, round, ball, capsule, rod, needle, or cylinder shape. Conveniently, the shape is an elongate cylindrical, rod or needle shape. In a most preferred embodiment, the implant device is elongate and generally cylindrical.
  • an axially disposed biodegradable core material is coated with a hydrogel containing an active ingredient to form a concentric coating.
  • Smaller discrete gel segments, which remain supported by the biodegradable core can be created by cutting the outer concentric hydrogel layer in such a way that the biodegradable core remains intact and sliding the cut segment along the axially disposed biodegradable core so as to form a space between the discrete gel segments. This operation will hereinafter be referred to as the "cut/slide operation”.
  • the cut/slide operation may be performed after the hydrogel has been dried and prior to coating however it is generally easier to perform the cut/slide operation on wet hydrogel. Therefore in the process of the present invention the separation and dehydration steps may take place in either order.
  • the hydrogel may be dehydrated before separation into discrete segments although it is preferred that the hydrogel is separated before dehydration.
  • the outer coating may be applied in any suitable manner.
  • the outer coating may be applied by means of a mould, dipping, spraying or by application via a "rod” or "wick".
  • the process of the present invention is readily adaptable for incorporation of heat labile active ingredients. It presents few constraints with respect to the choice of active ingredients; and it should be noted that by using a biodegradable structural support, such as surgical suture, the central core does not need to be removed from the final implant product.
  • the present device also provides the basis on which further refinement or sophistication of release can be effected.
  • the hydrogel layer bioerodible polyorthoester polymers prepared by the reaction between 3,9- bis(ethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane) and various ratios of trans- cyclohexanedimethanol and 1,6-hexandiol (2)
  • the production method can be readily adopted for mass production of needle injectable implants of antitumour agents such as 5-flurouracil for release in a time independent mode.
  • collagen poly (HEMA) hydrogel (1) as the incorporating matrix
  • needle injectable implants can be readily mass produced for a variety of hydrophilic or hydrophobic active substance with again a time independent release mode.
  • the recipient of the implant may be a human, livestock animal including a ruminant animal, e.g. a sheep, cow, horse, pig, goat or donkey, poultry, e.g. chicken, turkey, goose or game bird, a laboratory test animal, e.g. a rabbit, guinea pig or mouse, companion animal, e.g. dog or cat, or a wild animal in the captive or free state.
  • a ruminant animal e.g. a sheep, cow, horse, pig, goat or donkey
  • poultry e.g. chicken, turkey, goose or game bird
  • laboratory test animal e.g. a rabbit, guinea pig or mouse
  • companion animal e.g. dog or cat
  • a wild animal in the captive or free state e.g. a wild animal in the captive or free state.
  • Administration of the implant may be by any convenient means but is generally by injection via the intravenous, intraperitoneal, intramuscular, sub-cutaneous or intradermal route.
  • the device may also be surgically implanted or implanted by sub- surgical procedures such as during biopsy procedures. Devices such as these may also be administered by an oral route.
  • the amount of active ingredient used in a given implant will vary depending on the type of bioactive molecule, condition in the animal being treated and the presence or absence of agonists to the active ingredient or antagonists to the condition being treated. In general, an effective amount of active ingredient is employed meaning an amount effective to induce, stimulate, promote or otherwise initiate the immediately intended result.
  • the effective amount is that required to stimulate an immune response to the antigen.
  • the active ingredient will be present in amounts ranging from a few micrograms to gram quantities per implant.
  • Figure 1 is a part sectional, part schematic, cross section of an apparatus suitable for preparing implant cores by chemically induced gelling.
  • Figure 2 is a part sectional, part schematic, cross section of an apparatus suitable for preparing implant cores by temperature induced gelling.
  • Figure 3 is a schematic illustration of spray coating of hydrogel implants.
  • Figure 4 is a schematic illustration of rod coating solvent based polymer coating application.
  • Figures 5 and 6 are graphs of dye release from 35% (pLa i.v. 1) tolulene rod coated gelatine core implants; in vitro at PBS at pH 7.2, 37 ⁇ C.
  • FIGS 1 and 2 are part sectional, part schematic, cross sections of the apparatus for preparing implant cores.
  • the apparatus consists of a dialysis tube "1" fitted over an upper end portion "2" and a lower end portion "3" and located in sealing engagement by waterproof rubber sealants "4" and "5".
  • a supporting line formed of bioerodible core material "6” is maintained under tension by a spring steel bow “7”.
  • An inlet port "8” and bleeder hole “9” are provided respectively in the lower and upper end portions "2" and “3”.
  • An outer perforated mould “10” is provided to support the dialysis tube “1” and allow the ingress of gelling reagents to the dialysis tube. This outer perforated mould may be hinged to allow easy access to the dialysis tube.
  • the dialysis tube "1" is replaced with a teflon tube "11" which may be in two longitudinal halves and the outer perforated mould “10” is replaced with a jacketed temperature control member "12".
  • the gel structure is held on the support "6".
  • the support "6" is centred using the upper and lower end portions "2" and “3".
  • the support line "6" is kept taut using a device "7” made of spring steel resembling a bow. This device serves also as a handle to transport the gel structure for the convenience and security of subsequent gel processing, e.g. drying and coating.
  • a central support which forms the bioerodible core "6" e.g. a surgical suture, is positioned at the radial centre in a cylindrical mould "1" or “11" using appropriate positioning guides.
  • the inner surface of the mould should be lined with material such as teflon to facilitate cast removal.
  • a temperature sensitive implant hydrogel layer or core matrix on the central support may be prepared in the following manner:
  • the matrix active ingredient and the hydrogel material in the gelling mix is compounded according to the individual formulations used.
  • solutions of hydrogel and active materials are prepared separately and recombined in the proportion prescribed immediately prior to filling into the mould to minimise any possible denaturation or inactivation of the active during the preparation of the hydrogel solution.
  • the assembled mould, the gelling mix and the filling device eg a syringe
  • the filling device eg a syringe
  • Thermal prefilhng equilibration is desirable to prevent blockage during filling and deformities in the gel structure.
  • the preparation of the temperature induced gelling solution involves dissolution of a hydrogel, such as gelatine (270 mg), and, if required, an osmotic modifier such as sucrose (750 mg) in water (1.5 ml).
  • a hydrogel such as gelatine (270 mg)
  • an osmotic modifier such as sucrose (750 mg) in water (1.5 ml).
  • the stock hydrogel solution is prepared by heating the suspended solutes in a water bath at 100 ⁇ C. Subsequent to dissolution, fluidity of the hydrogel solution is best maintained by holding at 37 - 45 °C.
  • a stock *bioactive' solution is prepared by dissolution of the 'active' in water (0.5 ml). This solution is then held on ice. 2c If necessary, the requisite volume of the stock 'bioactive' solution is diluted to the requisite concentration by dissolution with water. This solution is also held on ice.
  • the gelling mix may be introduced to the mould by a syringe pump via the inlet "8" while the bleeding hole “9" provides an outflow for air and excess gel solution. Filling is preferably accomplished by one slow continuous action. By filling from bottom upward the process is made essentially trouble free and there is lesser likelihood of deformities in the gel structure due to occluded air bubbles especially in a clean teflon mould. Filling is completed when gelling mix appears to flow from the outlet bleeding hole in the top positioning guide.
  • the supporting string is centred by the positioning guides "2" and "3".
  • the support line "6" is kept taut using a device "7" within an appropriate dialysis tubing "1” which in turn is enclosed within a rigid perforated support "10" for the convenience of filling and subsequent induction of gelling.
  • Ion or chemically induced gelling is best achieved using the perforated mould assembly "10" with filled dialysis tube "1".
  • This assembly is filled preferably by one slow continuous action. By filling from bottom upward the process is made essentially trouble free and there is lesser likelihood of deformities in the gel structure due to occluded air bubbles adhering to the dialysis tubing.
  • 3b Filling is completed when gelling mix appears to flow from the outlet bleeding hole in the top positioning guide. 3c Following filling the complete assembly is maintained at the filling temperature for a short time and a check for proper filling is made.
  • the assembly is then transferred to a container of the inducer solution which may be held at any preferred temperature, for example, at zero degrees Celsius if denaturation of an active is a concern. Equilibration of the inducer across the semi-permeable membrane affords the gelling of the matrix active solution mix. 3e Extra time should be allowed to ensure proper gel formation and possible hardening of the gel structure for example, 240 minutes.
  • the moulded gel structure referred to above consists of an outer hydrogel layer which is supported by and concentric about an axial support line.
  • Smaller discrete gel segments which remain supported by the axial support line can be created by cutting the outer concentric hydrogel layer in such a way that the axial line remains intact and sliding the cut segment along the axial line so as to form a space between the discrete small gel segments.
  • the above cut/slide operation may be performed either before or after the concentric hydrogel layer has been dried and prior to coating. However, it is generally easier to perform the cut/slide operation on wet hydrogel.
  • the "long section” may be segmented into lengths, e.g. 10 mm, maintained on the support line "6". The supported segments may then be dried and processed as required for specific applications.
  • the core matrix may be sectioned subsequent to drying but prior to coating.
  • the water based gel structure may be air dried under ambient conditions or at low temperatures (e.g. at 2 °C) by flushing with dry nitrogen gas.
  • a gel structure containing about 10% total dry matter takes 8-10 hours to dry the gel to a constant weight at room temperature (21 °C).
  • the drying time will be appreciably longer at lower temperatures.
  • the drying times are gel composition dependent.
  • the gel structure mounted on the support may be reassembled with the 2 halves of the teflon mould of the same internal or different internal diameter to allow for the bioerodible outer coating to be applied to the core.
  • the dry cast may be coated with a water impermeable co- polymer such as polylactic acid (pLa)/polyglycolic acid (pGa) (85:15) co-polymer to form a coating.
  • the dried gel structure on the support "6" may be coated by repeated dipping into a polymeric solution and drying to achieve a thin layer of a substantially water impermeable coating with specific transport characteristics (refer to Example 3).
  • the dried gel structure on the support "6" may be coated by repeated spraying with a polymeric solution and drying to achieve a thin layer of a substantially water impermeable coating with specific transport characteristics (refer to Example 4).
  • the dried gel structure on the support "6" may be coated by repeated apphcation of a polymeric solution via a "rod” or “wick” and drying to achieve a thin layer of a substantially water impermeable coating with specific transport characteristics (refer to Example 5).
  • the release mode of the present device can also be modified by the concentration and composition of the matrix materials.
  • the concentration and composition of the matrix materials For example, when agar was used as the matrix material, the release was faster and the extent of release higher. This demonstrates the ability to affect the release rate by changes in matrix composition. Variations include replacement of the water based hydrogel matrix with hydrophobic materials such as glycerol monostearate.
  • This example is illustrative of temperature induced gelling and gives evidence of an immunological response to an incorporated antigen.
  • the inlets to the moulds were then stoppered and the moulds were allowed to equilibrate at 43 °C for 10-15 minutes before the temperature of the thermal jacket was slowly lowered to that of running cold tap water at about 20 °C over 20 minutes.
  • the gel was then solidified by cooling the mould assembly to 0 °C and maintaining it at that temperature for half an hour. After the mixture solidified the moulds were dismantled and the gel structure on a string stretched in a bow was removed carefully in a vertical orientation to avoid horizontal splitting of the gel structure by the stretched support while the gel structure was still fragile.
  • the gel structure supported by the string support in a bow were cut and separated in the cut/slide operation and air dried at room temperature overnight (about 18 hours).
  • Eudragit E 30D is an aqueous dispersion of poly(meth)acrylic acid esters supplied by Rohm Pharma GmbH Stamm Darmstadt, West Germany. When dry, the gel structures were dismounted from the bow and trimmed to segments of 1 cm length (diameter 3 mm). Each segment was estimated to contain 0.05 ml of the original HSA/human IgG antigen solution.
  • Placebo implants were made in exactly the same way as the antigen implants except that the HSA/human IgG solution was replaced by 0.9 ml of 0.1 M NaCl.
  • Sheep previously immunised with human serum were implanted subcutaneously on the inside surface of hindlegs using a mechanical implanter fitted with a 2.8 mm internal diameter needle. Two implant segments containing antigen or placebo were given to each sheep.
  • results of double immuno diffusion assay showed that there was an increase of antibody titre in recipients of the HSA/human IgG implants but not in those of the placebo.
  • the increase in antibody titre was comparable to that obtained when normal immunisation protocol with adjuvanted antigen suspension was used.
  • the response in general was maximal at day 9 of the four scheduled sampling days for both the specific anti-IgG and anti-HSA responses.
  • immunisation using antigen implants can afford a number of other advantages.
  • Immunisation with implants was very simple to perform and compared with the routine method far less time consuming. Apart from the pimcture mark caused by the implanter needle, no ulceration or swelling was evident at the implant site. This is in sharp contrast to the situation of routine practices when antigen suspensions, especially those using Freund's adjuvant, are used for immunisation.
  • This example is illustrative of chemical induced gelling and is preferred for heat labile active material.
  • the ion induced gelling mould was assembled as described above (refer to Figure 1) and equihbrated at room temperature. 7 ml of 3% w/w aqueous sodium alginate [Sigma Co. cat No. A-2033, alginic acid sodium salt medium viscosity, from Macrocvstis pyrifera (Kelp)] was mixed thoroughly with 7 ml of Clostridium novyi toxoid at room temperature. The active suspension was a concentrated solution of Clostridium novyi toxoid containing the toxoid produced by the bacteria and 5.3 mg/ml of hydrated aluminium hydroxide added as adjuvant.
  • the two suspensions may be held at lower temperatures (eg 4 ⁇ C) and mixed at lower temperatures.
  • the resultant mixture was transferred with a syringe via the inlet port in the mould assembly to fill the dialysis tube inside to a slight overflow from the outlet bleeder hole with about 7 ml per mould.
  • the two mould assemblies were transported into a bath of 500 ml aqueous A1C1 3 solution (0.5% w/w) at room temperature (or if desired at 1 °C) with continuous slow agitation using a magnetic stirrer. Gelling was usually effected within 2-3 hours of immersion but it is our normal practice to leave the gel structures to form for 4 hours.
  • the moulds were removed from the gels in a vertical position.
  • the resultant gel structures were allowed to dry at room temperature.
  • the gels may be surface coated with Eudragit E 30D as previously described and/or reloaded with another layer of toxin alginate gel structure.
  • sodium alginate may be directly substituted by K-carrageenan but the temperature during filling of the tube mould needs to be higher to prevent premature gelling of the K-carrageenan.
  • the gel inducing agent, A1C1 3 (e.g. 7 ml of 1.5% solution) can be added directly to the 14 ml of the alginate C. novyi mix and the resultant solution mixed thoroughly and quickly.
  • This example illustrates the technique of dip coating of hydrogel implants and provides evidence of pulsatile release in vitro evaluation.
  • Polylactic acid (cy-pLa) of inherent viscosity (i.v.) 1.0 dl/g (supplied by Boehringer Ingelheim) of mass 12 g was dissolved in 120 ml of dichloromethane.
  • hydrogel cores containing red food dye or antigen were manufactured according to the methodology described above using the cut/slide method.
  • This example Ulustrates spray coating of hydrogel implants and provides evidence of pulsatile release from an in vitro examination.
  • Polylactic acid (d ⁇ l-pLa) of inherent viscosity (i.v.) 1.0 dl/g (supplied by Boehringer Ingelheim) of mass 12 g was dissolved in 120 ml of dichloromethane.
  • Phosphate buffered saline (PBS), pH 7.2 was made according to the foUowing recipe: NaCl (80.00 g), KC1 (2.00 g), 2HP0 4 .12H 2 0 (15.36 g), KH 2 P0 4 (2.00 g) dissolved in 1000 ml of distiUed water.
  • hydrogel cores containing red food dye or antigen were manufactured according to the methodology described above using the cut/slide method.
  • An atomising spray nozzle connected to a compressed air cylinder and to a 250 ml separating funnel which contained the different polymer solutions was used to apply the polymer to the gelatine cores being rotated about the support line using a "rotisserie" mechanism (refer to Figure 3).
  • a polymer solution was sprayed onto the implant cores using air brush with a gas pressure of 200 kPa and a distance of 10-30 mm between the air brush outlet to the implant cores.
  • the implant core string was hand rotated during spraying in order to obtain uniform coating.
  • 65 ml of polymer solution was sprayed on a string of implant cores.
  • a method of coating gelatine cores was investigated to try to overcome the difficulty of covering the ends and edges of the core when spray coating.
  • dJ-pLa polylactic acid
  • Lv. inherent viscosity
  • a connected series of gelatine cores supported on an axial support was made using the cut/shde operation as described above. It was found that if one large viscous drop of material was spread along a slowly rotating gelatine core (approximately 120 rpm), the drop remained evenly dispersed and seemed to successfuUy surround the sharp edges and the end of the core (Fig. 4A).
  • Apphcation of the solvent based polymer was with a glass rod.
  • the rod is dipped into a viscous polymer solution to pick up a smaU amount of material (Fig. 4B).
  • the material is then applied to one end of the gelatine core and drawn to the other (Fig. 4C).
  • This example shows the use of implants to obtain pulsatile release in animals.
  • Implants were made as described in Example 4 except that 0.5 mg tetanus toxoid per implant was used as the active ingredient.
  • Antigens were used in implants with two coat compositions and the control group (3) received antigen in uncoated gelatine cores.
  • mice were implanted subcutaneously on the inside surface of hind legs using a mechanical implanter fitted with a 2.8 mm internal diameter needle. One implant segment containing antigen or placebo was given to each mouse.
  • ABTS 2,2'-azino-bis(s-ethylbenzthiazohne-6-sulphonic acid)

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Abstract

Implant à libération par pulsations comprenant: un noyau biodégradable axial; une première couche concentrique comprenant un hydrogel déshydraté contenant un principe actif; et un revêtement externe, ledit revêtement pouvant être résorbé par l'environnement dans lequel l'implant va résider après administration. L'invention se rapporte également à un procédé de préparation d'un implant à libération par pulsations, consistant à enrober un matériau central biodégradable, disposé axialement, d'un hydrogel contenant un principe actif pour former un revêtement concentrique; séparer le revêtement en segments discrets disposés le long du matériau central; déshydrater l'hydrogel; enrober les segments discrets d'un revêtement externe qui peut être résorbé par l'environnement dans lequel va résider l'implant après administration; et enlever le matériau central exposé pour obtenir les implants à libération par pulsations.
EP93915569A 1992-07-31 1993-08-02 Implants a liberation regulee Withdrawn EP0652745A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AUPL3879/92 1992-07-31
AUPL387992 1992-07-31
PCT/AU1993/000392 WO1994003159A1 (fr) 1992-07-31 1993-08-02 Implants a liberation regulee

Publications (1)

Publication Number Publication Date
EP0652745A1 true EP0652745A1 (fr) 1995-05-17

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EP93915569A Withdrawn EP0652745A1 (fr) 1992-07-31 1993-08-02 Implants a liberation regulee

Country Status (4)

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EP (1) EP0652745A1 (fr)
CA (1) CA2141459A1 (fr)
WO (1) WO1994003159A1 (fr)
ZA (1) ZA935569B (fr)

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CA2141459A1 (fr) 1994-02-17
WO1994003159A1 (fr) 1994-02-17
ZA935569B (en) 1994-04-12

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