RU2621553C1 - Method for treatment of heavy forms of dry keratoconjunctivitis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: silicone-hydrogel soft contact lens (SCL) saturated with 0.05% Cyclosporin A (CyaA) is used. Ciclosporin A is used in the form of an emulsion and used to saturade an SCL with non-blind depots in the form of a hemisphere with microscopic incisions on the inner surface located on the external or internal surface of the lens. Drug substance saturation is carried out under vacuum conditions at a pressure of 2600 Pa, until the depots are fully filled up under the control of an electron scanning microscope. The lens is used around the clock for 7-14 days against the background of installations of a non-conservative douche in the conjunctival cavity up to 6 times a day. The course of treatment is repeated after re-saturation of the same SCL.

EFFECT: method provides a prolonged, persistent anti-inflammatory and immunosuppressive effect with accelerated epithelialization of corneal defects in the absence of side effects of Ciclosporin A.

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Description

The present invention relates to ophthalmology and is intended for the treatment of severe forms of dry keratoconjunctivitis (CCM).

Dry keratoconjunctivitis (CCM) is a multifactorial disease of the ocular surface, accompanied by an increase in osmolarity of the tear and inflammation of the ocular surface, leading to symptoms of discomfort, visual impairment and destabilization of the tear film [1]. The use of tear substitutes, epithelizing and anti-inflammatory drugs for a long time does not have a significant positive clinical effect in the treatment of severe forms of CCM (filamentous and bullous-filamentous keratitis, recurrent corneal microerosion).

Currently, a local immunosuppressant Cyclosporin A (CIA) is used to treat CCM. The mechanism of action of QiA is based on the suppression of dephosphorylation of calcineurin in the cell cytoplasm, and the prevention of translocation of the nuclear T-cell activation factor in the nucleus, which reduces the production of pro-inflammatory cytokines. By inhibiting the migration of new lymphocytes into the conjunctiva, TsiA contributes to the attenuation of the inflammatory process [Sall K., Stevenson O.D., Mundorf T.K. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 2000; 107 (4): 630-639]. A significant decrease in the level of 11-6 in conjunctival biopsies, a decrease in the number of cells expressing CD11a and HLA-DR lymphocyte activation markers, was observed in the experiment after applying 0.05% Cyclosporin A for 6 months [Ankita S. Bhavsar, Samir G. Bhavsar , Sunita M. Jain. A review on recent advances in dry eye: Pathogenesis and management. Oman J Ophthalmol. 2011; 4 (2): 50-56]. Long-term systematic installations of QiA reduce the intensity of apoptosis of epithelial cells and increase the density of goblet cells in the bulbar conjunctiva. There was a significant decrease in the severity of subjective sensations, assessed by the index of damage to the ocular surface (OSDI), and objective symptoms of CCM against the background of increased stability of the tear film and increased volume of tear production [Gladkova OV, Safonova TN Treatment of severe forms of dry keratoconjunctivitis. Bulletin of Ophthalmology. 2015; 131 (6): 99-105]. Due to the low solubility in water (27.67 g / ml at 25 ° C), OA in ophthalmology is used in the form of an oil-water emulsion with a concentration of 0.05% (Restasis, manufactured by Allergan inc, USA) [Sail K., Stevenson OD, Mundorf T.K. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group.Ophthalmology. 2000; 107 (4): 630-639]. The recommended regimen for drug installations in the conjunctival cavity is twice a day. It corresponds to a daily dose of TsiA of 0.057 mg [Sall K., Stevenson O.D., Mundorf T.K. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 2000; 107 (4): 630-639]. When the QiA emulsion is instilled into the conjunctival sac, more than 95% of the drug enters the systemic circulation by transnasal or transconjunctival absorption [Peng C. C., Kim J., Chauhan A. Extended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing vitamin E diffusion barriers . Biomaterials. 2010; 31 (14): 4032-4047]. The bioavailability of 0.05% QiA in the form of drops is low, therefore, when local corneal immunosuppressive therapy is involved in the corneal pathology, it is ineffective. According to the literature, the clinical effect with regular twofold use of 0.05% of TsiA develops only after 3-6 months [4, 5]. With a positive effect, attempts were made to use QiA with a higher concentration: 0.5%, 1% and 2%. However, due to the high concentration of QiA and prolonged use of oil-based drops, a number of side effects arose, such as delayed corneal epithelization, epithelialopathy, allergic and toxic reactions, and conjunctivitis. The liposomal preparation TsiA developed in Russia (Cyclolip, SSCA production, Russia) has not received wide clinical use due to problems in the domestic pharmaceutical industry [6, 7].

To eliminate the disadvantages of using QA in the form of eye drops, a large number of studies have been conducted aimed at creating a convenient form of release. Davis J.L. et al. [Davis J.L., Gilger B.C., Robinson M.R., Novel approaches to ocular drug delivery, Curr. Opin. Mol. Ther. 2004; 6 (2): 195-205] developed silicone-based ophthalmic implants capable of continuously releasing ChiA for several years. Preclinical animal studies have shown that implants are highly effective for the lifelong treatment of ocular transplant rejection reactions and severe dry eye syndrome [Kim N., Csaky K.G., Gilger B.C., Dunn J.P., et al. Preclinical evaluation of a novel episcleral cyclosporine implant for ocular graft-versus-host disease, Investig. Ophthalmol. Vis Sci. 2005; 46 (2): 655-662]. The placement of implants required surgical intervention, so they are not widely used. Gupta et al. [Gupta C, Chauhan A., Ophthalmic delivery of cyclosporine A by punctal plugs, J. Control. Release 2011; 150 (1): 70-76] suggested a combination therapy of CVH lasting about 3 months, based on the use of occluders of the lacrimal openings from pHEMA, which are a reservoir for QiA. This therapy was used only with severe hypolacrimia. Maychuk D.Yu. et al. [Patent RU 2285511, 10/13/2004] developed ophthalmic drug films from a polyacrylamide copolymer saturated with a 0.2% solution of CIA. The production of such a film caused discomfort in the patient for up to 5 minutes. After 30-60 minutes, the film was dissolved. The resulting polymer solution containing ChiA was distributed over the ocular surface. Ophthalmic drug films were introduced into the lower conjunctival arch once a day. The main disadvantage of this method is the toxicity of acrylamide.

Currently, in clinical ophthalmology, therapeutic MCLs are widely used, which are used to accelerate the epithelization of corneal defects and as a new dosage form for prolonging the action of medicines. The purpose of using MKL in CCM is to protect the cornea from external factors, stabilize the tear film, create conditions for the repair of corneal epithelium. According to the researchers, wearing MKL in patients with tear deficiency helps to restore the epithelium and improve the optical properties of the cornea [Sail K., Stevenson O.D., Mundorf T.K. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 2000; 107 (4): 630-639. Peng C.C., Kim J., Chauhan A. Extended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing vitamin E diffusion barriers. Biomaterials. 2010; 31 (14): 4032-4047].

In our previous studies, the use of therapeutic MKL on the background of installations of 0.05% CiA in patients with a severe degree of CCM allowed us to achieve complete epithelialization of the cornea within 1-3 months [O. Gladkova, T. Safonova, V. I. Boev The use of therapeutic MKL against the background of local immunosuppressive therapy in patients with dry keratoconjunctivitis of autoimmune origin. X Congress of Ophthalmologists of Russia. Sat scientific tr - M .: 2015. - S. 51]. Due to its special design, therapeutic MKL was well tolerated by patients and created optimal conditions for corneal repair. A high degree of oxygen permeability and moisture saturation of silicone-hydrogel MKL against the background of tear replacement therapy allowed them to be used for a long period without replacement and the threat of complications. Curative MKL, additionally protecting the cornea from external irritating factors, prolonged the effect of drugs on the ocular surface. After 3 months all patients noted an increase in visual acuity, an increase in ocular aperture, a decrease in osmolarity, a decrease in the OSDI index and the degree of staining of the cornea and conjunctiva with vital dyes according to the Oxford scale.

The closest analogue of the proposed invention is a method for the treatment of dry keratoconjunctivitis with the help of MKL, saturated with QiA. Peng S.S. et al. [Peng S. S., Kim J., Chauhan A. Extended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing vitamin E diffusion barriers. Biomaterials. 2010; 31 (14): 4032-4047] suggested saturating the silicone hydrogel QiA lenses by soaking the MCL in a drug solution diluted in saline. QiA diffused from therapeutic MCL according to the concentration gradient. Theoretically, a prolonged (within 1 month) release of TsiA from MKL, suppressing the inflammatory process, can alleviate the symptoms of SSC, accelerate the restoration of the epithelium of the ocular surface. This model of MCL has not been studied in humans and animals due to a number of disadvantages associated with the method of saturation of the lens. In this model of MCL, the effect of eyelid pressure on the lens surface during blinking was not taken into account, which has a significant effect on the rate of release of the therapeutic substance from the MCL and the total concentration of the substance on the ocular surface [Galante R, Paradiso P, Moutinho MG, Fernandes AI et al. About the effect of eye blinking on drug release from pHEMA-based hydrogels: an in vitro study. J Biomater Sci Polym Ed. 2015; 26 (4): 235-251]. Possible loss of part of the drug substance from MKL due to mechanical and chemical effects during sterilization. Also, the issue of storing the lens is not resolved, because upon soaking such MCLs in buffer solutions, QiA will diffuse from the lens into the solution.

The task of the invention is the further development and improvement of a method for the treatment of CCM with the help of MKL and TsiA.

The technical result of the invention consists in obtaining a prolonged persistent anti-inflammatory and immunosuppressive effect with an acceleration of the time for epithelialization of corneal defects in the absence of side effects of ChiA.

The technical result is achieved due to the combined effect, which consists in the effect of therapeutic MKL, providing a uniform exit of Cyclosporin A to the ocular surface against the background of installations of a tear substitute without preservatives.

An additional technical result is the possibility of sterilization and reuse of MCL saturated with TsiA.

The method uses MKL made of silicone-hydrogel material with an individual optical power MKL, depending on the refraction of the patient’s eye. The MKL curvature radius corresponds to the data obtained using keratometry (Full auto ref-keratometer RK-F1 "Canon", USA). The lens contains a non-through depot to fill 0.05% of ChiA. Depots are located on the outer or inner surface of the lens. The localization of the depot on the outer or inner surface of the MCL depends on the degree of involvement in the pathological process of the eyelids or cornea. Depots have the shape of a hemisphere, on the inner surface of the hemisphere there are micro notches. Microscallions due to the surface tension of the solution prevent the diffusion of the drug substance from the lens. TsiA under the influence of vacuum is loaded into the depot MKL until the latter are completely filled. To do this, sterile MKL with empty depots is placed in a 0.05% solution of TsiA and sent to the bell of a vacuum installation. Then, for two cycles (main and control) lasting 20 seconds, vacuum pressure is pumped up to 2600 Ra. After that, MCL with filled QiA depots are washed from the residues of the QiA solution. Saturated MKL is sterilized and placed in a buffer solution on demand. Due to the design of the lens — the presence of a depot and the lipophilicity of the drug substance, the latter does not diffuse from the lens into the buffer solution, which makes it possible to store saturated MKL for a long time.

Studies have been conducted to study the dynamics of the release of the drug from the lens. MKL, saturated 0.05% of QiA was removed from the patient’s eye after 24 hours from the 2nd to 14th day from the beginning of wearing therapeutic MKL. Depot fill level in the MCL was monitored by scanning electron microscopy. After determining the amount of drug in the depot, the same lens was sterilized and worn on the patient. As a result, it was found that the medicinal substance completely leaves the MCL on days 7-10 when the depot is localized on the inner surface of the lens and on day 10-14 when the depot is localized on the outer surface of the lens, depending on the number of blinks. Using liquid spectroscopy of buffer solutions in which saturated MCLs were soaked, it was proved that CuA does not diffuse from MCL during storage.

The use of therapeutic MCL saturated with QiA allows one to achieve complete corneal epithelization in a short time (2 weeks - 1 month) and significantly reduce the treatment time for severe forms of CCM. MKL, by virtue of its design, gradually releases TsiA on the ocular surface, which has pronounced anti-inflammatory, immunosuppressive and immunomodulating effects. The gradual release of QiA from the MKL depot over 7-14 days ensures the creation of a constant effective concentration of the drug substance in the affected tissue. Curative MKL is well tolerated by patients and creates optimal conditions for corneal repair, protecting the cornea from external irritating factors. Installations of a tear substitute without preservatives, in particular, based on hyaluronic acid, provide a sufficient level of hydration of the eye surface, make it safe to wear MCL with hypolacrimia, additionally feeding the cornea. As a result of the combination of MKL and QiA, the prolonged effect of QiA with the simultaneous bandage action of MKL in combination with tear replacement is achieved. After putting saturated QiA MKL on the patient’s eye, the drug leaves the lens under the action of eyelid pressure during blinking, which is 3-20 mm Hg. The concentration of QiA on the ocular surface depends on the amount of depot MKL and the frequency of blinking. This allows you to effectively use therapeutic MKL for 7-14 days until the depot is completely emptied.

The method is as follows.

The patient is put on a therapeutic MCL saturated with ChiA, with a radius of curvature and a diameter corresponding to keratometry data, for continuous wear for the entire treatment period. A non-preservative tear substitute, for example, based on hyaluronic acid, is installed in the conjunctival cavity up to 6 times a day against the background of wearing a contact lens. The treatment period is 7-14 days. If necessary, prolongation of therapy may re-saturation of the same MKL with a drug substance. The total treatment time is determined individually - until the corneal epithelization is complete.

Example 1

Patient N., born in 1967, first contacted the Research Institute of Eye Diseases in 2014. She was diagnosed with OU - Dry keratoconjunctivitis of severe severity, hypolacrimia 3 tbsp. She suffers from Sjögren’s disease for 12 years, is observed at the Research Institute of Rheumatology of the Russian Academy of Medical Sciences, receives general therapy: inside Prednisalon 4 mg per day, i / m Cyclophosphamum 200 ml once every 2 weeks. Clinical symptoms of CCM in the patient manifested in the form of keratopathy, filamentous keratitis, conjunctival hyperemia and photophobia. For 2 years, in the form of installations, I used various tear substitutes, reparative agents, non-steroidal anti-inflammatory drugs and corticosteroids. The process was characterized by a slowly progressing course with periodic exacerbations and short remissions.

The patient complained of pain, a foreign body sensation in the eyes, dryness, decreased vision, photophobia and severe blepharospasm. The examination revealed the following. Visual acuity was 0.7 with correction. According to the Schirmer test, basal secretion was 2 mm on both sides, a decrease in the reflex component to 2 mm was noted. The Norn test was 3 seconds on both sides. Tests with vital dyes demonstrated staining of the cornea with fluorescein over the entire surface, staining of many small epithelial filaments, and lissamine green staining of the bulbar conjunctiva on the nasal and temporal sides. Tear osmolarity was 336 mOsmol / L.

The patient was wearing MKL saturated with QiA. The diameter of the lenses was 14.5 mm, the base curvature was 8.4 mm, and the diameter of the pupil zone was 5 mm. Depot with the drug was localized on the inner surface of the lens. As a tear substitute, a hyaluronic acid-based preparation was used without a preservative, which was instilled 3-6 times a day with dry eyes. Medical lenses against the background of tear replacement therapy were well tolerated by the patient, did not cause a feeling of discomfort and irritation in the eyes. Wearing MCL saturated with TsiA allowed improving the patient's condition from the first days of treatment: complaints significantly decreased, blepharospasm and photophobia were stopped. MKL, saturated with QiA, was well tolerated by the patient, did not cause discomfort. After 7 days, the lenses were removed. On examination, the cornea became smoother, there were no epithelial filaments, and a decrease in corneal staining with fluorescein was noted. Visual acuity increased to 0.9. The tear salinity was 280 mOsmol / L. To continue therapy, the same MCLs were sterilized and saturated with QiA. The special design of MKL allowed to leave saturated QiA MKL in the buffer solution until the next visit of the patient. Therapeutic MKL were again worn on the patient for another 7 days. After removal of the MCL during examination, complete corneal epithelization was noted; there was no staining of the cornea with fluorescein. Visual acuity increased to 1.0. The positive dynamics of the data of functional tests was recorded: basal secretion according to the Schirmer test increased to 3 mm, the Norn test increased to 5 seconds on both sides.

Example 2

Patient L., born in 1981, turned to the Research Institute of Eye Diseases with complaints of redness of the eyes, swelling of the eyelids, a feeling of dryness, discomfort and itching in the eyes. From the anamnesis it is known that these complaints worry for more than 1 year. Wore MKL in order to correct refraction for more than 10 years. It was observed at the local therapist with a diagnosis of OU - conjunctivitis, dry eye syndrome, mild myopia. Instilled disinfectant, anti-inflammatory drugs and tear substitutes without a pronounced positive effect.

On examination, it was revealed: the edges of the eyelids are thickened, hyperemic, the expansion of the intercostal space, stagnation of the secretion in the mouth of the meibomian glands, conjunctival hyperemia, decreased lacrimal meniscus, unevenness of the epithelium of the lower half of the cornea. Visual acuity was 0.9 with correction. According to the Schirmer test, basal secretion was 5 mm on both sides. The Norn test was 6 seconds on both sides, the tear osmolarity was 318 mOsmol / l. Carrying out tests with vital dyes demonstrated staining of the cornea with fluorescein in the lower half of the surface. The diagnosis was made: OU - CCM (epithelial dystrophy of the cornea 2 degrees), chronic blepharoconjunctivitis, hypolacrimia 3 tbsp. The patient was offered MCLs saturated with Cyclosporin A. Due to the fact that the clinical picture of the patient was dominated by eyelid lesions and palpebral conjunctiva, she was wearing therapeutic MKL with a depot on the outer surface of the lens. The diameter of the lenses was 14.3 mm, the base curvature was 8.6 mm, and the diameter of the pupil zone was 5 mm. As a tear substitute, a hyaluronic acid-based preparation was used without a preservative, which was instilled 3-6 times a day. Medical lenses against the background of tear replacement therapy were well tolerated by the patient. Immediately after putting on the MCL saturated with the drug, the patient noted a decrease in eye discomfort, an improvement in vision. After 13 days, the lenses were removed. On examination, complete corneal epithelization was noted (there was no staining of the cornea with fluorescein), a decrease in conjunctival hyperemia and edema of the eyelids. Visual acuity increased to 1.0 with correction. Tear osmolarity was 275 mOsmol / L. Positive dynamics was noted according to functional tests: basal secretion according to the Schirmer test increased to 8 mm, the Norn test increased to 10 seconds on both sides. To maintain the clinical effect, the patient was transferred to instillation of a tear substitute based on hyaluronic acid.

Thus, the proposed method provides a prolonged, persistent anti-inflammatory and immunosuppressive effect with an accelerated timeline for epithelialization of corneal defects in the absence of side effects of ChiA.

Claims (4)

1. A method of treating severe forms of dry keratoconjunctivitis, including the use of silicone-hydrogel soft contact lenses (MKL), saturated with 0.05% Cyclosporin A preparation, characterized in that Cyclosporin A is used as an emulsion and saturates it with MKL, on the outer or inner surface which has non-through depots in the form of a hemisphere with micro notches on the surface, and drug saturation is carried out under vacuum under a pressure of 2600 Ra until the depot is completely filled under the control of an electron scanning microscope ii, using the lens around the clock for 7-14 days against the background of installations in the conjunctival cavity of the non-preservative tear substitute. 2. The method according to p. 1, characterized in that the treatment is repeated after re-saturation with the drug Cyclosporin A of the same MKL. 3. The method according to p. 1, characterized in that as a non-preservative tear substitute, a tear substitute based on hyaluronic acid is used.  4. The method according to p. 1, characterized in that the tear substitute is installed up to 6 times a day.