KR100895840B1 - A method for manufacturing intrascleral implant for the sustained release of triamcinolone acetonide and intrascleral implant manufactured from this method - Google Patents

Abstract

The present invention relates to an intrascleral implantation apparatus for sustained release of triamcinolone acetonide (hereinafter referred to as TA), wherein a triamcinolone acetonide is released into the sclera using a biodegradable double membrane polymer matrix. It can compensate for the serious complications and repeated injections, which are disadvantages of intravitreal TA injection, and enhance the continuous release of drugs and drug delivery at the lesion site.

According to the present invention, the intraocular drug concentration was maintained at a constant level even after three months by being formed into a biodegradable double membrane polymer matrix, and thus, the concentration was expected to be maintained while the implantation device was absorbed. Not only can it be an alternative solution to repeated injections, which is a disadvantage of TA injection, but also help patients who have undergone rapid vitrectomy for removal of TA. It is expected.

Triamcinolone Acetide, Sustained Release, Implantation Device, poly (D, L-lactide)

Description

A method for manufacturing intrascleral implant for the sustained release of triamcinolone acetonide and intrascleral implant manufactured from this method}

Figure 1a is a model of the mold (frame) for making a disk-type scleral implant device manufactured for sustained release of triamcinolone acetonide according to an embodiment of the present invention,

FIG. 1B illustrates a biodegradable scleral implant device having a thickness of 0.8 mm and a diameter of 3 mm made using the mold of FIG. 1A,

FIG. 2 is a scanning electron microscope (SEM) photograph of the biodegradable polymer implantation device loaded with the triamcinolone of FIG. 1, wherein (a) is the sclera side (× 40) and (b) is the conjunctival coating (× 40). FIG. ), (c) is the convex side smooth coating (× 500), (d) is the side coating (× 500),

FIG. 3 is an SEM image of the biodegradable polymer implanter loaded with the triamcinolone of FIG. 2 after 8 weeks of insertion into the sclera, (a) the sclera side (× 40), and (b) the sclera side (× 10,000) Is the side coating (× 500), (d) is the conjunctival side (× 10,000),

FIG. 4 is a SEM photograph after 12 weeks of insertion into the sclera of the biodegradable polymer implanter loaded with the triamcinolone of FIG. 2, (a) the sclera side (× 40), and (b) the sclera side (× 10,000), (c) Is the side coating (× 500), (d) is the conjunctival side (× 10,000),

5 is in vitro of triamcinolone acetonide from a biodegradable membrane ball implant (In in vitro ) release graph,

Figure 6 (a) is a graph measuring the concentration of the triamcinolone acetonide in the anterior water, vitreous and retinal-choroid after the PLA implantation device loaded with triamcinolone acetonide loaded in the sclera,

Figure 6 (b) is a graph measuring the concentration of triamcinolone acetonide in a plurality of eye tissues after insertion of the PLA implantation device loaded with the triamcinolone acetonide in the sclera,

Figure 7 is a photograph taken the insertion place 1 week after the insertion,

FIG. 8 is a graph showing the change in b-wave amplitude and electrophysiological examination to determine retinal toxicity before and after intra- scleral insertion of PLA-implanted PLA implantation device (p> 0.05).

9 is a graph showing the change of intraocular pressure before and after intrascalation of the PLA implantation device loaded with triamcinolone (p> 0.05),

FIG. 10 is a photograph (a: × 400, b: × 400, c: × 200) of the retinal tissues observed by optical microscopy to identify retinal toxicity after 12 weeks of insertion of the TA-loaded PLA implantation apparatus.

The present invention relates to a scleral implant device for sustained release of triamcinolone acetonide, and more particularly, to compensate for the serious complications and repeated injections, which are disadvantages of intravitreal TA injection, and to sustained release of the drug and the drug at the lesion site. It relates to an intrascleral implantation device manufactured using a double-membrane biodegradable PLA (Poly (D, L-lactide)) to enhance the delivery effect.

In the past, steroids have been used in the treatment of inflammatory and proliferative diseases in the ophthalmology, among which triamcinolone acetonide has recently been associated with uveitis, secondary macular edema caused by retinal vascular disease, proliferative vitreoretinopathy, and age-related macular degeneration. It is widely used for the treatment of choroidal neovascularization.

In the use of such steroids, it is important to prevent systemic side effects and to maintain a certain concentration for a long time on specific areas with intraocular lesions. Difficult to treat There are many restrictions.

For eye drops, the drug must be absorbed through the sclera after passing through the conjunctiva for the drug to reach the posterior segment. Most of them are absorbed systemically by the conjunctiva or nasal mucosa through the conjunctiva and diluted by tears, so less than 5% of the drug is actually delivered to the eye.

Systemic dosing requires the administration of a significant amount of drug, which is a problem that can cause serious systemic side effects.

Intravitreal direct injection is the most direct method of delivering the drug to the posterior eye, and the therapeutic effect of the drug can be easily obtained. However, this method can cause complications such as glaucoma, cataracts, retinal detachment, vitreous hemorrhage, endophthalmitis, and often require repeated injections.

Recently, the drug delivery method through the sclera has been studied a lot, and the sclera has a surface area of 17 cm ² , which is very wider than 1 cm ² of the cornea and occupies 95% of the ocular surface area, which is advantageous for drug diffusion during drug delivery (Olsen TW, Aaberg SY, Geroski DH, Edelhauser HF.Human sclera: thickness and surface area.Am J Ophthalmol 1998; 125: 237-241).

In other words, subconjunctival injection, subtenon injection, and post-injection are also delivered through the sclera, and the drug is delivered to the posterior eye and is absorbed systemically. Low drug delivery levels can cause systemic side effects.

Inserting the drug in a specific area of the sclera has the advantage that the drug concentration is high in the vitreous at the site where the drug is inserted, so that it can be directly treated at the site of the lesion (Okabe K, Kimura H, Okabe J, Kato A). , Kunou N, Ogura Y. Intraocular tissue distribution of betamethasone after intrascleral administration using a non-biodegradable sustained drug delivery device.Invest Ophthalmol Vis Sci 2003; 44: 2702-2707).

Specifically, the scleral permeability is similar to that of the corneal parenchyma, and the drug delivery route through the sclera is through the perivascular space such as the arrhythmia vein, the aqueous route through the mucopolysaccharide, which is a component of the sclera, and By passive diffusion through the sclera parenchyma. Rabbit sclera can pass through 150kDa dextran or IgG and human sclera can pass 70kDa dextran, but it is known that the permeability decreases in inverse proportion to increasing molecular weight or molecular size.

Indeed, the scleral permeability of TA showed that the scleral permeability coefficient (PS) of TA for human sclera was 1.47 ± .17 × 10 ^-5 cm / s. A similar degree is compared with the (corneal permeability coefficient; Pc) 1.2-1.6 × 10 ^-5 cm / s. In general, the path through the sclera is less resistance than the cornea and its permeability is known to be similar to the cornea only if it is fat-soluble.

However, the most important part of drug delivery through the sclera may be the choroid and retinal pigment epithelium. The tight junction of the retinal pigment epithelium is a non-leaky type that forms the outer retinal blood-retinal barrier.In general, the water-soluble drug moves through the intercellular space. Transcellular diffusion is known to occur. TA is thought to pass through the retinal pigment epithelial layer, possibly by diffusion through cells.

In the experiments on the permeability of the retinal pigment epithelium and choroid, Pitkanen et al. Reported that the permeability of the retinal pigment epithelium and choroid decreased significantly as the molecular weight of the solute increased. In addition, the higher the molecular weight and the fat-soluble, the longer it takes to pass through the retinal pigment epithelial-choroid complex (lag time), and the water-soluble substance is difficult to pass about 10-100 times compared to the sclerotic permeability. It was. The molecular weight of TA used in this study is 434.5 Da, and it is thought that it will easily pass through the rabbit sclera and retinal pigment epithelial-choroid membrane by vitreous diffusion.

Recently, many studies on the intraocular drug delivery method and the development and experiment of the drug-sustained implant device through the sclera have been reported.

In addition, in the case of a polymer material used as a drug sustained release device, it is divided into biodegradable and biodegradable. In the case of non-biodegradable, EVA (ethylene vinyl acetate) copolymer, PVA / EVA (polyvinyl alcohol / Ethylene vinyl acetate) and the like, and biodegradability includes PLA (poly (D, L-lactide)), PLGA (poly (D, L-lactide- co- glycolide), chitosan and the like.

Biodegradable polymer materials are widely used in the method of eliminating the hassle of re-treatment by absorbing them in the body after the procedure. However, the drug is released by bulk erosion and is known to undergo three stages of change. Initially, a large amount of drug is released (initial burst), and then drug release is performed by diffusion (diffusion), and then the final burst process. In contrast, polymer materials that are not biodegradable release drugs relatively uniformly.

On the other hand, in the case of intravitreal TA injection, the duration of TA and intravitreal concentration vary greatly depending on the patient's lens condition or previous vitrectomy. Schindler et al. Reported that TA remained in the vitreous body for up to 6.5 days if the lens and vitreous were removed simultaneously, 16.8 days for vitrectomy alone and 41 days for normal eyes. The half-life after direct injection of TA was reported as 18.6 days in patients who had not previously had vitrectomy and 3.2 days in patients who had undergone vitrectomy, and it took 93 ± 23 days for TA to disappear completely in the vitreous. Scholes et al. Reported a half-life of 1.6 mg after intravitreal injection of 0.4 mg of TA in rabbits, and after 13 days, the intravitreal concentration was 66 ± 19 μg and was not found within 21 days after vitreous injection.

Therefore, the present inventors came to complete the present invention by focusing on a study using a biodegradable polymer material to compensate for serious complications and repeated injections, which are disadvantages of intravitreal TA injection.

In other words, an object of the present invention is to develop a new drug delivery method of triamcinolone acetonide (TA), which is widely used in the ophthalmology area, which is a disadvantage of intravitreal triamcinolone acetonide injection (IVTA). It is intended to complement repeated injections.

Another object of the present invention is to manufacture a TA drug sustained-release implantation device using PLA (poly (D, L-lactide)), a biodegradable polymer matrix, to compensate for serious complications and repeated injections, which are disadvantages of intravitreal TA injection, Sustained release and increased drug delivery effect at the lesion site.

According to the first aspect of the present invention,

A biodegradable scleral implant for sustained release of triamcinolone acetonide using a biopolymer is provided.

According to the second aspect of the present invention,

Mixing PLA (MW 120,000-125,000) and triamcinolone acetonide powder in a weight ratio of 1: 4 and dissolving in dichloromethane to prepare a solution;

Dropping distilled water into the solution to make an oil (emulsion) state and then rapidly freezing in liquid nitrogen;

Lyophilization to complete a homogeneous cake;

Pressure molding the homogeneous cake to obtain an implanter; And

Coating one surface of the obtained implantation device with PLA having a molecular weight of 250,000-300,000; Provided is a biodegradable scleral implant manufacturing method comprising a.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

In the present invention, PLA (poly (D, L-lactide)), a biodegradable polymer matrix, is used to compensate for the serious complications and repeated injections, which are disadvantages of intravitreal TA injection, and to enhance the continuous release of drugs and drug delivery effect at the lesion site. The TA drug sustained-release implantation device was used to measure the duration and drug release in vivo and ex vivo, and to confirm biocompatibility and changes in surrounding tissue.

In particular, the intraocular drug delivery route used in this study was via the sclera. The most important parts of drug delivery through the sclera are the choroid and the retinal pigment epithelium. The tight junction of the retinal pigment epithelium is a non-leaky type that forms the outer retinal blood-retinal barrier. In general, water-soluble drugs move through the intercellular space. Transcellular diffusion is known to occur. TA is thought to pass through the retinal pigment epithelial layer, possibly by diffusion through cells.

The molecular weight of TA used in the present invention can be reached within the vitreous body easily through the sclera of the rabbit and the retinal pigment epithelial-choroid membrane by diffusion to 434.5 Da.

Biodegradable polymer materials used as drug sustained release device in the present invention include PLA (poly (D, L-lactide)), PLGA (poly (D, L-lactide- co -glycolide), chitosan and the like.

As shown in the following examples, it was confirmed that a large amount of TA was released in the first 24 hours in the release experiment, but TA was released at a constant concentration after the initial burst, specifically, the total amount of TA released after 90 days had elapsed. The dose was about 8% of the total dose (6.4mg) of TA contained in about 513μg was released in 3 months.

Robinson and his colleagues measured the amount of intravitreal TA after subtenonal subcutaneous injection of TA in rabbits and reported that most of the TA injected through the lymphatic system and blood vessels of the conjunctiva were removed and absorbed. It is reported that a greater amount of TA should be injected than the clearance rate (8-13 μg / hour).

Therefore, in the present invention, it is more preferable to use PLA (poly (D, L-lactide)), which is a polymer material that has been clinically widely used and proven to be safe (MW 120,000-125,000), and in the case of such PLA, the higher the molecular weight Focusing on the slow degradation rate, the conjunctival and lateral parts of the implant can be coated with high molecular weight PLA (MW 250,000-300,000) to reduce the likelihood of systemic absorption through the conjunctiva or tenon membrane.

In addition, the present invention was not limited thereto, and the amount of TA contained was constant by manufacturing the implantation device using the TA in powder form.

Further, in the manufacture of the implantation apparatus of the present invention, but not limited to this, a self-made mold shown in FIG. 1A can be used. In the small hole of the lower frame part 2 of Figure 1a put the cake mixed with PLA and drug can be made by compressing from above using the upper bar 1 of Figure 1a (disk). 1B is a perspective view of the implantation device manufactured as described above, and once one disk is made as shown in FIG. 1B, it is preferable to cover the PLA of the thin film-like polymer on one side and to compress it again.

In this case, the material of the mold is not limited thereto, but stainless steel is used, and the pressurization condition is sufficient to be performed at about 100 ° C. for 1 hour. In addition, the compression conditions for PLA coating is enough to perform about 1 hour at about 120 ℃.

Although it is difficult to directly evaluate the systemic absorption of the drug in the present invention because it does not measure the blood TA concentration of the rabbit, the coating of the implantation device at 12 weeks after insertion shows that the coating is well maintained, indicating the usefulness of the coating indirectly. (See FIG. 4).

Meanwhile, in the implantation apparatus using PLA according to the present invention, lactic acid generated when PLA is decomposed may cause local burning or discomfort. However, most of the generated lactic acid can be removed without major problems depending on the pH buffer capacity of the tissue, PLA has already been used as a material such as absorbent suture in the clinical has proven its safety.

As shown in the following examples, TA was not detected after 8 weeks in the anterior chamber and TA was not detected after 12 weeks in the retina-choroid, whereas in the vitreous body, it was detected at a constant concentration up to 12 weeks. I could confirm that.

In each tissue, the concentration of TA was highest at 2 weeks and decreased from 4 weeks afterwards. The same result was obtained in the experiment of endothelium drug release using Betamethasone.

This is believed to be due to a decrease in drug release and diffusion through the sclera due to the thin coating around the implantation device observed in the histology. The film is formed by bioreaction over about 2-4 weeks, and the release rate of the drug seems to decrease from the 4th week, and the concentration of the drug is considered to be constant at 8 and 12 weeks.

For other reasons, as in Mora et al., TA delivery through the sclera is in equilibrium only four days later, and the lag time seen when the lipid-soluble substance reported by Pitkanen crosses the retinal pigment epithelium-choroid. This is a clue to explain the result.

In the present invention, TA was detected at a higher concentration than other tissues at 1-2 weeks and not at 8 weeks. This suggests that intraocular pressure or cataract may occur even when the implantation device is implanted. it means. This may be because the amount of TA contained in the implantation device was relatively high (6.4 mg), and bioabsorbable polymers such as PLA may initially release a large amount of drug (initial burst). It can be considered that it is inserted into the sclera of 3 mm posterior to the relatively close to.

However, in actual clinical practice, it may be solved to some extent by inserting into the sclera of the lesion site, the posterior pole or the equator of the eye, and the initial burst of drug may be balanced for a certain time before insertion. salt solution) may be used to immerse the implant device in the solution and then insert it into the sclera.

On the other hand, one-time intravitreal injection of TA requires repeated injections in order to maintain the therapeutic effect by decreasing the concentration of the drug and decreasing the therapeutic effect.

Jonas et al reported that the concentration of TA in the anterior water after direct injection of 25 mg of TA was 13 μg / L after 3.5 months and 3 μg / L after 6 months, and between 2-8 months with intraocular silicone oil filling. Reported at 3-61 μg / kg. Chin et al .: 0.3 mg of TA was injected into the vitreous body of rabbits. The half-life of TA was 1.57 days with vitrectomy, 2.89 days without vitrectomy, and intravitreal concentration 30 days after injection without vitrectomy. Was 0.92 ± 1.25μg / ml, and in 20 days after vitrectomy, the intravitreal concentration was 1.99 ± 2.35 μg / ml.

Also, Mason et al. Reported an intravitreal TA concentration of 48-380 ng / ml after 1.25-2.75 months after intravitreal TA injection in six patients.

In the following examples, the intravitreal concentration of TA was found to be 347-857 ng / ml up to 1-12 weeks, although the administration method was different, compared with the results of Mason and Chin et al. It was confirmed that the concentration of TA in the body was kept constant.

The present invention was able to confirm that the concentration of drug in the eye is maintained at a certain level even after three months, so that the concentration is expected to be maintained while the implantation device is absorbed.

Therefore, according to the above, it may not only be an alternative solution to the repeated injection, which is a disadvantage of intravitreal TA injection, but also may be helpful for patients who have undergone rapid vitrectomy to remove TA. It is expected to be an effective treatment method.

Hereinafter, the configuration and working effects of the present invention will be described in more detail with reference to Examples. Each example was repeated to confirm the reproducibility of the results.

Target and method

One. TA  contain Biodegradable  Fabrication of Implant Devices

A homogeneous cake of polymer and drug was first prepared to produce a disc-shaped implantation device in which polymer and drug were uniformly dissolved.

That is, PLA (MW 125,000, polysicence Co., USA) and triamcinolone acetonide (manufactured by DongKwang Pharmaceutical) in powder form were mixed in a ratio of 1: 4 and dissolved in 10% dichloromethane.

2 ml of distilled water was dropped into the solution to make it oily, and then rapidly frozen in liquid nitrogen. After drying for 24 hours in a freeze dryer to complete a homogeneous cake. The mold is a device made to press-form the implant in the form of a disc. It is made of stainless steel and weighed 8 mg (TA content of 6.4 mg) in the homogeneous cake, and put it in the second mold of the mold shown in FIG. By molding at 100 ℃ for 1 hour. The shape of the completed implantation device was in the form of a white disk with a diameter of 3 mm and a thickness of 800 μm (see FIG. 1).

PLA (polysicence Co., USA) having a molecular weight of 300,000 was used to coat one side of the completed implant device. PLA was first dissolved in 20% dichloromethane and poured onto slide glass. After completely drying in the hood, the PLA film was removed from the glass, the film was placed on a self-made mold, the implanter was raised, and compression molded at 120 ° C. for 1 hour.

The implantation device thus prepared was sterilized by irradiation twice with gamma radiation at 1390 rad / min and 600 sec.

2. Surface and cross section observation

The implantation device prepared by the above method was coated with gold at 8 weeks and 12 weeks before and after insertion, and then 40, 500 and 10000 times using Hitachi S-570 scanning electron microscope, respectively. The cross section and the surface were observed at the magnification of and the results are shown in FIGS. 2 to 4.

3. In vitro drug release test ( In Vitro Release Study )

The prepared implantation apparatus was immersed in 10 ml of PBS solution and left in a stirred tank at 37 ° C. for a certain time, and then the PBS solution containing the released TA was collected and replaced with a fresh PBS solution each time.

The collected solution was centrifuged at 3000 rpm for 15 minutes in a centrifuge, and then sterilized and disinfected using a syringe filter (0.20 μm) for bacteria removal and stored at 4 ° C.

The concentration of TA for each sample was measured using a liquid chromatography-mass spectrometer (Hewlett Packard, 1100 LC & MSD).

The column used was a C-18 reverse phase column (capcell Pak C18 UG120, 250mm x 4.6mm inner diameter; Shisheido Fine Chemicals), and the mobile phase was adjusted to pH 5.4 with acetonitrile and distilled water at a ratio of 45:55. The flow rate was 1.0 ml / min, the total operation time was 15 minutes, the injection volume was 100 μl, and the UV wavelength was fixed at 252 nm (Matysova L, Hajkova R, Sicha J, Solich P. Determination of methyl paraben, propylparaban, triamcinolone acetonide and its degradation product in a topical cream by HPLC.Anal Bioanal Chem 2003; 376: 440-443. and Brombacher S, Owen SJ, Volmer DA.Automated coupling of capillary-HPLC to matrix-assisted laser desorption / ionization mass spectrometry for the analysis of small molecules utilizing a respective matrix.Anal Bioanal Chem 2003; 376: 773-779).

4. Insertion into the sclera intrascleral implantation )

Twenty white rabbits weighing 2.5 to 3.0 kg were included.

The animals were divided into five groups of four, one week, two weeks, four weeks, eight weeks, and twelve weeks after the in vivo release test. Five animals were used for histology.

Anesthesia was performed by intramuscular injection of Xylazine hydrochloride (2mg / kg) and Ketamine hydrochloride (5mg / kg). 0.5% Proparacaine hydrochloride (Alcaine) was used for topical anesthesia.

An implantation device was inserted in the right eye and the left eye was used as a control. After the incision was made, the superior sclera of the right eye was exposed. Make an incision perpendicular to the sclera about 3 mm away from the limbal cornea, and then make a sclera bag on both sides with a crescent knife and insert the implant.The sclera is sealed with 8-0 monosof and the conjunctiva with 6-0 vicryl to prevent infection. Ofloxacin eye ointment (Ocuflox) was applied.

5. Biocompatibility Testing of Implant Devices

Shandong was performed with 1% tropicamide (Mydriacyl) and 2.5% phenylephrine (Mydfrin), and the retinal potential test was performed using UTAS E-2000 Electroretinography (LKC Technology, USA) and Tonopen (TonoPen XL, Mentor Co., USA). Intraocular pressure was measured by The anterior eye was observed with a mobile slit lamp, and the state of the retina was observed with an indirect ophthalmoscope.

Four eyes were taken at 1, 2, 4, 8, and 12 weeks after the procedure, and the eyes were extracted after slit lamp examination, fundus examination, intraocular pressure measurement and retinal potential test. The extracted eyeball was stored at -80 ° C rapidly frozen using liquid nitrogen. The stored tissues were separated into anterior water, vitreous, retinal-choroid, and the amount of TA was measured by HPLC for each.

The retinal potential test was performed after 1 week, 2 weeks, 4 weeks, 8 weeks, and 12 weeks after the operation of the animals for 30 minutes, after which the corneal electrode (ERG-jet electrode, Universo Co., Japan) was attached to both eyes. After attaching the irrigation electrode and the ground electrode to both ears, the photostimulation was performed using the Ganzfeld dome. As a light source, a Ganzfeld stimulator of 1.86 cd s / m ² was used, and the band pass was 0.3 to 500 Hz, and the average of waveforms obtained by measuring 10 times at 15 second intervals was recorded. The amplitude of b-wave was determined and the ratio between pre and post operation was obtained.

The histological examination was performed in 1 eye, fixed in neutral-buffered formalin and glutaraldehyde, and stained with hematoxylin-eosin.

Mann-Whitney U-test was used for statistical processing.

6. In vivo drug release test In Vivo Release Study )

Eye tissue from which the implantation device was removed was processed in the following manner to extract the drug in the tissue. After chopping each tissue isolated from the extracted eyeball, the mixture was placed in 1% HCl solution, reacted for 4 hours, and centrifuged to collect supernatant.

The supernatant was lyophilized, dissolved in 1 ml of acetonitrile, filtered again with a 0.2 μm syringe filter, and stored in an e-tube for refrigeration. The amount of drug dissolved in each tissue was measured by the same method as the ex vivo drug release test. However, the mobile phase measured acetonitrile and distilled water at an hourly rate of 30:70 up to 3 minutes, 45:55 within 5 to 15 minutes, and 30:70 after 15 minutes, and the flow rate was 1.0 ml / min, total. The running time was 25 minutes, the injection volume was 100μl and the UV wavelength was fixed at 252nm.

result

1. Cross-sectional and surface observation of the implant device

Figures 2 to 4 summarize the results obtained by observing the cross section of the implantation device before and after 8 weeks and 12 weeks after the insertion of the implantation device. However (FIG. 2A), however, the conjunctival side (FIGS. 2B and 2C) and the side (FIG. 2D) show an overall smooth cross-section and the PLA coating of the outer part of the implant device, which is a manufacturing feature, is well represented.

After 8 weeks, as the time went by, the disassembly of the implantation device progressed and a little more pores were found on the scleral side surface (FIGS. 3A, 3B), and the PLA coating on the side was well maintained (FIG. 3C). The conjunctival side of the implant device (FIG. 3D) remained smooth but had some cracking.

After 12 weeks, more pores and powders of TA were found on the scleral surface (FIGS. 4A, 4B), and the PLA coating on the sides remained relatively well but showed some cracking (FIG. 4C). On the conjunctival side of the implant (FIG. 4D), the surface remained smooth but there was some cracking and slight exposure of the TA powder under the surface.

2. In vitro emission testing (In Vitro Release)

As shown in FIG. 5, the concentration of TA accumulated over time in the in vitro release test shows that a large amount of TA is released in the first 24 hours and then released at a constant concentration, and after 90 days, the total amount of TA released The dose of about 513 μg of about 8% of the total dose of TA (6.4mg) was found to be released in 3 months.

3. The in vivo release tests (In Vivo Release)

As shown in FIG. 6, the average of the concentration and dose of TA detected in each eye tissue was 1016.37 ng / ml (7815.81 ng / g) at 1 week in the anterior chamber after implantation of the implanted device, and 1152.88 ng / ml (8865.58 ng at 2 weeks). / g), 406.72 ng / ml (3127.66 ng / g) at 4 weeks and were not detected in the anterior waters at 8 weeks.

On the other hand, in the retina-choroid, 135.8 ng / ml (2283.96 ng / g), 561.7 ng / ml (9446.69 ng / g), 278.58 ng / ml (4685.15 ng / g) at 1, 2, 4, and 8 weeks, It was 223.64 ng / ml (3388.77 ng / g) and was not detected at 12 weeks. On the other hand, in the vitreous, TA was detected in a constant amount up to 12 weeks, at 441.44 ng / ml (266.57 ng / g), 857.49 ng / ml (517.81 ng / g), and 655.95 ng at 1, 2, 4, 8, and 12 weeks, respectively. / ml (396.11 ng / g), 347.03 ng / ml (206.79 ng / g) and 510.46 ng / ml (357.40 ng / g).

4. Biocompatibility Testing of Polymer Matrix

Mobile slit lamp or indirect ophthalmoscope showed no specific inflammatory response in the cornea, anterior, lens and retina during the experimental period. As shown in FIG. 7, the conjunctiva and sclera of the implanted site did not show any inflammatory reaction, and the conjunctiva significantly decreased the degree of congestion after one week.

In addition, as shown in Figure 8, the amplitude ratio of the b-wave in the retinal potential test was 90.91 ± 11.82% at 1 week, 109.19 ± 21.33% at 2 weeks, 101.69 ± 11.45% at 4 weeks, 8 There was no difference between 103.57 ± 11.30% at week and 105.33 ± 3.39% at 12 weeks (p> 0.05).

Further, as shown in FIG. 9, the change in intraocular pressure was also 104.61 ± 19.6% at 1 week, 113.47 ± 43.56% at 2 weeks, 98.11 ± 24.06% at 4 weeks, 90.03 ± 9.61% at 8 weeks, and 12 weeks. At 92.62 ± 9.54%, there was no significant difference (p> 0.05).

Finally, as shown in FIG. 10A, the retina and choroid were not significantly changed in the biopsy performed at 12 weeks. However, neutrophil was found around the sclera where the implantation device is located, but it is thought to be a local inflammatory response due to sutures for fixing the implantation device (see FIGS. 10B and 10C).

Example: Application of Back Eye

Furthermore, the biodegradable polymer matrix (PLA (poly (D, L-lactide))) was inserted into the sclera for the treatment of inflammatory and proliferative diseases occurring in the posterior eye and thus sustained triamcinolone acetonide. To evaluate the release effect.

The biodegradable implant device containing 6.4mg of TA was prepared using a PLA (poly (D, L-lactide)) in the form of a disc of 0.8 × 3mm size, and the degree of ex vivo release was measured using a Liquid Chromatography-Mass Spectrometer. Measured.

In order to measure the release rate in vivo, the sclera was incised into 20 white rabbits and inserted into the sclera, and 4, 1, 2, 4, 8, and 12 weeks after surgery, respectively. The amount of TA extracted was measured by HPLC.

For biocompatibility, clinical observation, retinal potential test, and intraocular pressure were performed and histological examination was performed.

As a result, the drug was released continuously in proportion to time in the in vitro release experiment, and in vivo, TA was not detected at 8 weeks in the anterior water and 12 weeks in the retina-choroid, but was detected at a constant concentration up to 12 weeks in the vitreous body. It became. No abnormalities were found in clinical, retinal potential, IOP, and biopsy.

The TA-containing polymer matrix inserted into the sclera continuously released the drug to maintain a constant vitreous concentration and did not cause any special problems in the living body. Therefore, it can be used to treat inflammatory or proliferative diseases of the posterior eye. It is expected to be.

According to the above, it is believed that the implantation device obtained by the present invention not only maintains a constant level of intraocular drug even after three months, but also maintains a constant concentration while the implantation device is absorbed in the sclera. In addition, no abnormalities were found in clinical observations, retinal potential, IOP, and biopsy.

The TA-containing polymer matrix inserted into the sclera continuously released the drug to maintain a constant vitreous concentration and did not cause any special problems in the living body. Therefore, it can be used to treat inflammatory or proliferative diseases of the posterior eye. It is expected to be.

Therefore, this study may not only be an alternative solution to repetitive injection, which is a disadvantage of intravitreal TA injection, but may be helpful to patients who have undergone rapid vitrectomy for the removal of TA. It is expected to be an effective treatment.

Claims (9)

delete delete delete delete delete Mixing poly (D, L-Lactide) (PLA) having a molecular weight of 120,000-125,000 and triamcinolone acetonide powder in a weight ratio of 1: 4, dissolving in dichloromethane to prepare a solution; Dropping distilled water into the solution to make an oil (emulsion) state and then rapidly freezing in liquid nitrogen; Lyophilization to complete a homogeneous cake; Pressure molding the homogeneous cake to obtain an implanter; And Coating one surface of the obtained implantation device with PLA having a molecular weight of 250,000-300,000; Method for producing biodegradable scleral implant device for sustained release of triamcinolone acetonide comprising The method of claim 6, wherein the coating step Dissolving the PLA in dichloromethane and pouring it onto a slide glass; And Completely drying on the slide glass, and then peeling off the PLA film and attaching to an implantation device to perform compression molding; Biodegradable scleral implant device manufacturing method characterized in that performed through delete The triamcinolone acetonide produced by the method of claim 6 or 7, wherein the polymer and triamcinolone acetonide have a homogeneous dissolution disc form and are inserted into the sclera to continuously release the triamcinolone acetonide drug for at least 3 months. Biodegradable Scleral Implants for Sustained Release

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