This invention relates to a biodegradable, implantable device for the in situ delivery of a pharmaceutical composition and to a method of manufacturing such a device.
The development of soluble or biodegradable polymers has revolutionized the administration of sustained release formulations or dosage forms of pharmaceutical compositions in treating humans or animals. Briefly, a polymer having a desired biodegradability coefficient for a particular region of the human or animal body is mixed with a pharmaceutical composition and formed, usually by an extrusion process, into a delivery form which is an elongate, oval or circular tablet or disk. When implanted in a human or animal body or ingested, the polymer biodegrades or dissolves slowly depending on its biodegradability coefficient. This results in a sustained release of the pharmaceutical over a predetermined period of time.
The above-described drug delivery device works well for orally ingestable pharmaceuticals. There are, however, situations where the pharmaceuticals are applied to another part of the body and the period over which the pharmaceuticals are released is measured in months rather than minutes or hours. An example of such an application is contraceptive pellet which is injected into the gluteus maximus muscle and releases an oestrogen or similar compound over a period of between three and six months.
The above-described implant is suitable for use in body regions where the pellet can be retained in place by surrounding tissue. There are, however, situations where a drug must be administered over a period of time in an area where some form of securement of the pellet is necessary. Such regions include the intraocular regions, within blood or lymphatic vessels and intraperitoneally.
An intraocular implant known to the applicant is the Vitrasert® implant which is produced by Chiron Vision Incorporated of the United States of America. This implant consists of a pellet of a semi-permeable polymer containing a drug to be delivered to the eye. The pellet is attached to a suturing strip made of a strip of polyvinyl alcohol which is not biodegradable. The suturing strip has a bore therethrough for suturing the implant in the intraocular space. The disadvantage of such an implant is that a second surgical procedure is required to remove the non-biodegradable portion of the implant after the drug supply is exhausted. This doubles the risk of infection and possible damage to the eye.
In this specification the terms “biodegradability coefficient” when used to refer to a biodegradable polymer is to be interpreted as providing a rough indication of the speed with which the polymer will degrade in the human or animal body. Thus, a polymer with a high biodegradability coefficient will take a longer time to biodegrade than a polymer with a low biodegradability coefficient situated in the same region of the body.
It is an object of this invention to provide a biodegradable and implantable device for the sustained in situ delivery of a pharmaceutical composition to the human or animal body, to provide a method of manufacturing such a device and to provide a method of treating the human or animal body using said device.
In accordance with this invention there is provided a biodegradable and implantable device for the in situ delivery of a desired pharmaceutical composition to a human or animal body said device comprising a generally discoid body formed from a biodegradable polymeric composition, the body having at least one aperture therethrough whereby said body is anchorable, in use, within a human or animal body by a suture.
There is also provided for the body to contain a desired pharmaceutical composition and for said body to release the pharmaceutical composition as the body biodegrades.
There is further provided for the body to have a single, alternatively a plurality, preferably two or three, of apertures therethrough and, in addition to said aperture or apertures, for the circumferential periphery of the body to have a number of surface area increasing slots.
There is also provided for the body to have biodegradable polymeric sheets on each of the planar surfaces thereof, the planar polymeric sheets having a greater biodegradability coefficient than the polymer forming the body as thus, in use, permitting the body forming polymer to biodegrade before the sheets.
There is further provided for the aperture, apertures or slots to be shaped such that, when the body forming polymer degrades, the surface area of the biodegradable portion of the body remains relatively constant.
The invention also provides for a method of manufacturing a device for the sustained, in situ, delivery of a desired pharmaceutical composition to a human or animal body, said method comprising the steps of:
There is also provided for the method to include forming a plurality, preferably two or three apertures through the body and, optionally, a number of surface area increasing slots in the circumferential periphery of the body.
There is also provided for the method to include applying biodegradable polymer sheets to each of the generally planar surfaces of the body, the sheets having a higher biodegradability coefficient than the body forming polymer thus permitting the body to degrade, in use, before the sheets.
The invention also extends to a method of treating a human or animal comprising inserting a device as described above into a body cavity of said human or animal and suturing the body in place to prevent movement of the body within said body cavity.
The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.
Embodiments of the invention will be described below by way of example only and with reference to the accompanying drawings in which:
Referring to
The discoid body (2) is formed from a biodegradable polymeric composition which is selected from a range of similar compositions according to the locality in the human or animal body in which the device (1) is to be inserted or implanted and the period over which the pharmaceutical composition is to be released which can vary from one or two hours to several months.
The device (1) is made by mixing a pharmaceutical composition with a suitable biodegradable polymer and then forming the device (1) using a pill or tablet press fitted with a suitably shaped die which forms the means (3) whereby the body (2) of the device (1) is sutured into place.
Referring specifically to
Referring to
Referring especially to
Referring now to
In general, it is envisaged that the release of a pharmaceutical composition mixed with the biodegradable polymer is directly proportioned to the surface area of polymer and pharmaceutical exposed. It is also envisaged that as the circumferential periphery of the device reduces in size and, consequently, surface area, the inner wall of the aperture or apertures and, where present, arcuate slots, increases in size and, consequently, in surface area. By correctly dimensioning the radii of the aperture or apertures and slots it is envisaged that the surface area of the device will remain relatively consistent as the polymer degrades and that the release of the pharmaceutical composition will be consistent.
In addition, by correctly dimensioning and positioning the aperture or apertures and slots it is envisaged that a variable release of the pharmaceutical composition can be achieved. Thus, for example, if a plurality of relatively shallow slots are formed in the periphery of the device the initial release of pharmaceutical will be greater than when the polymer has degraded such that the slots disappeared. Conversely, if a plurality of small apertures are formed through the device then as the polymer degrades the surface area will increase and a greater concentration of pharmaceutical will be released towards the end of the devices lifetime.
Referring now to
Accordingly, if it is desired to have an initial, fast release of a particular pharmaceutical followed by a sustained, slower release of another pharmaceutical or indeed of the same pharmaceutical, a polymer having a low biodegradability coefficient is selected as the secondary polymer (6) and it is laminated as shown in
In
Embodiments of the invention will be described below by way of the exemplification within and with reference to
1. Materials and Methods
Resomer® grades RG502, RG503, RG504, and RG756 consisting of poly(lactideco-glycolide) (PLGA) with a 50% lactide content, were purchased from Boehringer Ingelheim (Ingelheim, Germany). These polymers are all biodegradable and have inherent viscosities ranging from 0.16-8.2 dl/g. All polymers were ground in a mortar and the fraction passing through a sieve with an aperture size of 125 μm (Endcotts Test Sieves, Ltd., London, United Kingdom) was used. Phosphonoformic acid (Foscarnet) was obtained from Sigma-Aldrich Co. (Aldrich, Germany). Ganciclovir was purchased from Roche Products (Pty) Ltd. (Isando, South Africa). The antiviral bioactives were used as supplied.
1.1 Preparation of the Device
Referring to
Referring specifically to
All blending of drug and polymer was performed using an Erweka AR 400 Cube Blender (Erweka, Germany), and a Manesty F3 eccentric (single punch) tableting press (Manesty Machines, United Kingdom) was used for directly compressing the powder blends into the doughnut-shaped mini-tablet (DSMT) device. A model TR 104 mass balance supplied by the Denver Instrument Company (Denver, USA.), was used for all gravimetrical analysis.
The directly compressed formulations consisted of two principal components, namely, the antiviral bioactives and the various biodegradable polymers. With the appropriate choice of polymer, compression of the mixture led to the formation of a matrix tablet. To study the influence of different variables on the release rate of the device, formulations containing various concentrations of bioactive material were produced, and at the same time, the polymer grades were varied to produce different implants.
Devices were produced consisting of 30% w/w, 40% w/w, 50% w/w, 60% w/w, and 70% w/w foscarnet and 10% w/w, 15% w/w, and 20% w/w ganciclovir, in each of the three Resomer® grades chosen in fabricating the device. These concentrations were selected on the basis of the dose required for each bioactive in treating cytomegalovirus retinitis (CMV-R) over a sustained period of time. The various formulations were individually pre-weighed and blended for 10 minutes and then manually fed into the die cavity. The press was set to compress the devices to a thickness of 2 mm.
The variation in compression forces were accomplished by firstly adjusting the upper punch to its lowest position in order to ensure a maximum stable compression force exerted from above, while adjusting the lower punch accordingly by elevating the punch for higher compression forces, or alternatively lowering it for lower compression forces. The adjustments on the lower punch were executed using inherent calibration marks positioned on the adjustment bearing of the tableting press. The flywheel of the tablet press was then twisted backward as far as possible (to the limit where the lower punch started to rise again). This was done to ensure that the tablet press would have enough time to speed up to a relatively constant velocity during compression. The powder blends were then compressed at room temperature.
1.2 Textural Analysis
Textural analysis was employed to characterize the compressibility of the polymers used in fabricating the DSMT device, employing the TA.XTplus Texture Analyzer (Stable Micro Systems, England) fitted with a probe having a spherical indenter of 3.125 mm in diameter and a 5 kg load cell. The indentation hardness was represented by a conversion to the Brinell Hardness Number (BHN). The textural settings used to calculate the BHN values are depicted in Table 2 where:
1.3 Erosion Studies
Mass loss of the DSMT matrix was evaluated by gravimetrical analysis. Individual DSMT devices were initially weighed, after which degradation was allowed to progress in 4 ml of SVH (pH 7.4, 37′C) in an oscillating laboratory incubator (Labcon® FSIE-SPO 8-35, California, USA) set to oscillate at 50 r.p.m. At predetermined intervals the DSMTs were removed from the vials incubated and gently rinsed with deionised water to remove any superficial particles resulting from undissolved buffer salts. The hydrated matrices were then vacuum-dried and weighed accordingly to assess any gravimetric changes. All experiments were performed in triplicate. The initial and final masses were used to calculate the percentage mass loss (ML %) using the following equation:
ML %=100(W0Wr/W0
1.4 Scanning Electron Microscopy
Samples were prepared for photomicrographs by applying a thin layer of colloidal graphite on aluminum stubs and mounting the DSMT devices on the graphite to hold them in place during microscopic examination. The devices were then coated with a thin layer of gold-platinum using a sputter coater under an electrical potential of 15 kV. Several photomicrographs were produced by scanning fields, selected at different magnifications using a Jeol JSM-840 scanning electron microscope (Tokyo, Japan).
1.5 In Vitro Drug Release Studies
A modified closed-compartment USP XXV dissolution testing apparatus was utilized in performing all the release studies. At time zero, the DSMT devices were immersed in 4 ml of SVH, (pH 7.4, 37° C.) in closed vials and placed in an oscillating laboratory incubator (Labcon© FSIE-SPO 8-35, California, USA) set to at 50 r.p.m. At predetermined intervals, 2 ml of the release medium was sampled and 2 ml of fresh SVH was replaced to the sampled vial to maintain sink conditions.
1.6 Analysis of the Antiviral Bioactives
Analyses of foscarnet and ganciclovir were performed on a System Gold (Beckman, San Ramon, Calif.) high performance liquid chromatograph (HPLC) equipped with a 20 μl loop, and array detector. The system was fitted with a Discovery C18 (particle size 5 μm, 4.6 mm id., 150 mm) analytical column (Supelco, USA). Samples of 20 μl were injected using a microlitre syringe (705 NR 50 μl, Hamilton Bonaduz AG, Switzerland).
The mobile phase for analysing foscarnet samples was composed of 0.005 M sulphuric acid/methanol (95:5% v/v) and approximately 0.09% w/v of tetrahexylammonium hydrogensulphate (THAHSO4) as an ion pairing reagent. A solvent flow rate of 1.5 ml/min was maintained. In the case of ganciclovir, the mobile phase was composed of 0.05 M ammonium acetate (pH 6.5)/acetonitrile (96:4% v/v), and a solvent flow rate of 1.0 ml/min was maintained. Prior to use, the column was equilibrated by passing 45 ml of solvent through the system. The eluant was monitored at an analytical wavelength set at 254 nm. The entire assay procedure was performed at room temperature. Ascorbic acid and acyclovir were used as the respective internal standards for foscarnet and ganciclovir analysis.
2. Results and Discussion
2.1 Compressibility of the PLGA Polymers Employing Textural Analysis
Table 3 lists the force values (N) generated from indentation of the PLGA compacts, as well as the BHN values. The compressibility profiles for each polymer investigated are shown in
tForce produced on indentation of compacts
This observation highlights the important differences in the mechanical properties of amorphous pharmaceutical material, which is temperature and pressure dependant in their response to applied mechanical stress. Firstly, the copolymer PLGA is an amorphous type material. Amorphous materials do not have melting points but rather go through a glass transition temperature (T9). PLGA 50:50 has a Tg value of 39.85° C.
Secondly, poly(lactide) (PLA) is thermally unstable (Zhang et al., 1992). Hence, the presence of this monomer randomly distributed within the copolymer backbone structure tends to increase chain flexibility and therefore, at elevated temperatures during the direct compression technique, it's inclined to contribute to the opening of the polymer structure and widening in the copolymer molecular weight distribution and a decrease in yield pressure. The yield pressure indicates the point where forces involved in consolidation have essentially been ‘broken’.
The yield pressure for PLGA is well below the lowest pressure used in the compressibility of the DSMT's and its value has been significantly surpassed. In most cases the Manesty tabletting press used cannot exceed a compression force of 1200 pounds (1 ton=2000 pounds) when employing PLGA as a directly compressible excipient.
Compression of the PLGA powders generates significant heat within the internal structure of the tablet. The excess heat is dissipated and escapes gradually through the surface of the tablet matrix. Since it would have required significant modification of the current testing equipment to permit data to be collected in order to monitor these in situ elevated temperatures, this phenomenon could not be explored in detail as part of the current work.
At temperatures above the Tg value, amorphous material would show a transformation in its behaviour with an increase in ductility. Subsequently what is occurring is that the material is transitioning into a more rubbery state. It is well-known that above the Tg value molecular motions are very rapid which may lead to a decrease in the extent of polymer chain entanglement and an increased mobility of the polymer chain segments, whereas below the Tg value these motions are restricted and are regarded as almost ‘frozen’.
With regard to the DSMT device, the study commenced employing 1 ton of uniaxial compression force, which has already exceeded the yield pressure (>1200 pounds), resulting in increased heat generation and dissipation, that is well above the stated Tg value. This excess heat induces structural changes at a molecular level and causes a deformation of the matrix that leads to stress relief at heterogeneous stress loci distributed within the tablet matrix. Consequently stress relaxation and surface disruption occur on a micro-level. This is consistent with the broader expectation that amorphous type materials have a higher free energy. Essentially, the greater the compression force, more heat is generated when above the yield value, which results In exceeding the Tg value. The DSMT consequently turns into a more rubbery state and therefore the higher compression force produces a ‘softer’ matrix
2.2 Erodibility of the DSMT Device
Table 4 lists the residual masses obtained for the DSMT devices investigated. The effect of the various polymer grades used in fabricating the DSMTs on mass loss profiles are shown in
tcalculated using the % mass loss equation
2.3 Scanning Electron Microscopy
The morphological characteristics of the DSMT devices undergoing erosion at various predetermined time intervals are shown in
Before storage in SVH at 37° C., the surface of the DSMT device appeared smooth without many cracks and pores visible within the matrix (
2.4 In Vitro Release Studies
In general, the release profiles of both antiviral bioactives from the biodegradable polymer matrices have a biphasic release pattern: an initial burst and a second phase that is derived from diffusional release before the onset of polymer erosion. The initial burst may have resulted from the rapid release of the drugs deposited on the surface of the matrix. During the diffusion phase, the bioactives were released slowly, and possibly was controlled by the degradation rate of the polymer and the drug loading. The rate of release in the diffusion phase tended to be more prolonged in the DSMT's consisting of the polymer with the higher inherent viscosities. An increase in the drug load of the device may also increase the release rate and an overload of drug may result in the release of a large amount of drug as an initial burst.
The release kinetics during the second phase was fairly consistent at the various drug loading concentrations. The devices have a biphasic pattern and in the higher viscosity polymer, the duration of drug release tends to be more prolonged (
3. Conclusion
PLGA can be regarded as suitably compressible for designing implantable devices such as the DSMT using relatively low compression forces which aid in trouble-free manufacturing with regard to wear on major tableting equipment such as punches and dies. The veracity of the compact structure of the DSMT device was retained even after 24 weeks of Incubation during the erosion studies, indicating that the device is suitable as a biodegradable drug delivery system.
The DSMT device generally has a biphasic release pattern: an initial burst and a diffusional phase. The inherent viscosity of the polymers employed and the drug loading characteristics affects the duration and rate of bioactive release. These factors are able to regulate the release profile from the DSMT device in order to achieve the desired release kinetics of the drug delivery system. The DSMT with a superior load of bioactive had a larger quantity of bioactive released during the initial phase.
The DSMT has proved to be a flexible and versatile biodegradable intraocular drug delivery system that provides rate-modulated release of antiviral bioactives to the posterior segment of the eye and may be suitable for the treatment of CMV-R.
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.
This application is a continuation of U.S. application Ser. No. 11/288,035, filed Nov. 28, 2005. The entire teachings of the above application is incorporated herein by reference.
Number | Date | Country | |
---|---|---|---|
Parent | 11288035 | Nov 2005 | US |
Child | 13020943 | US |