RU2238709C1 - Method for introducing drugs in subscleral way - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves displacing eyeball upward and inward, making a 1mm deep pierce with injection needle in inferoexterior segment closer to posterior pole of the eyeball in perpendicular to its surface through conjunctiva, external and internal leaflet of Tenon's capsule under episcleral flap. The preparation is introduced. Disk restrictor from thickened fabric is mounted on the needle end 1 mm far from needle tip.

EFFECT: enhanced effectiveness of treatment; avoided eye structures damage; reduced risk of traumatic complications.

2 cl, 2 dwg, 1 tbl

Description

The invention relates to medicine, namely to ophthalmology, and can be used in the development of effective methods of treating eye diseases.

Features of the anatomical structure of the eye provide great opportunities for topical use of drugs. Various concentrations of drugs are used, as well as different methods of their application: instillation of eye drop solutions, ointments, ophthalmic films into the conjunctival sac, injections under the conjunctiva, parabulbar, retrobulbar, into the anterior chamber of the eye, into the vitreous. The pharmacotherapy of eye diseases is based on local therapy, which is often the only treatment. General treatment is added according to indications. The concentration of drugs in the tissues and environments of the eye largely depends on how they are administered. A significant obstacle to penetration into the inner membranes of the eye is the so-called blood-brain barrier [1].

The question of the blood-ophthalmic barrier is one of the most confusing questions in ophthalmology. Different authors in this concept include ambiguous meaning. Some include elements of the eye drainage system as structures of the blood-ophthalmic barrier. Others include the ciliary epithelium of the ciliary body or the retinal pigment epithelium [2, 3].

The concept of a blood-ophthalmic barrier can only be applied to retinal neurons, which determine the function of the organ of vision. There are blood vessels in the retina; there is a system of protection for retinal neurons corresponding to the blood-ophthalmic barrier. Photoreceptor cells, due to trophic features, have a defense system different from other neurons. The drainage system of the eye provides an outflow of intraocular fluid and is not directly involved in the trophic provision of retinal neurons, contributing to the maintenance of ophthalmotonus and the removal of metabolites [4].

Therefore, a clear definition of the blood-ophthalmic barrier is necessary. To the blood-ophthalmic barrier we include: 1. nuclear-free sections of the capillary endothelial cytoplasm; 2. unfenestrated basement membrane of the endothelium; 3. neuroglia; 4. fluid pericellular space; 5. The membrane of the nerve cell. Photoreceptor cells have an enhanced defense system, which consists of: 1. fenestrated endothelium of the capillaries of the choriocapillary layer; 2. all elements of the Bruch membrane; 3. The basement membrane of the pigment epithelium; 4. cytoplasm of the pigment epithelium; 5. the apical part of the basement membrane of the pigment epithelium [4].

The idea of bringing drugs closer to the lesion site to create their high concentration is widely discussed in domestic and foreign publications. Subconjunctival, endolymphatic, para- and retrobulbar injections, the introduction of drugs into the anterior chamber, vitreous humor, summing them using drains, special devices, medicinal films, the use of electric current (electrophoresis), ultrasound, and magnetotherapy are widely used in ophthalmology. But each of these methods has its own characteristics and disadvantages.

In modern conditions, in ophthalmic practice, various methods of drug administration are used. The instillation of medications into the conjunctival sac is one of the most accessible, often used and widely used methods of administration for various ophthalmopathology. However, the therapeutic effect of some potent drugs in the form of instillations in the conjunctival sac may be accompanied to one degree or another by side (undesirable) manifestations. Medicinal substances introduced into the conjunctival sac quite quickly (after 10-15 minutes) penetrate through the cornea into the eye, and are absorbed through the conjunctival membrane and penetrate into the bloodstream of the body. The cavity of the conjunctival sac is quite significant over its surface area, so the absorption of drugs occurs quickly. Moreover, some medicinal substances with a pronounced pharmacotherapeutic effect, even in small concentrations, can affect various tissues, organs and systems of the body. These substances include: atropine, scopolamine, clonidine (clonidine), α- and β-blockers, latanoprost (xalatan), and some other substances. In addition, medicinal substances introduced into the conjunctival sac in the form of solutions, emulsions, suspensions, gels and ointments have an effect mainly on the tissues of the anterior part of the eye, lacrimal organs and eyelids. Their effect on the retina, choroid, and optic nerve is significantly limited [1].

It has been established that repeated instillations into the conjunctival sac - up to 6-8 times per hour, are equivalent in effectiveness to a single subconjunctival injection of 0.2-0.3 ml of the drug [11]. Subconjunctival injection is performed using an insulin syringe. The needle is inserted between the conjunctiva and tenon capsule, and the needle can be injected under the conjunctiva of transitional folds [5], as well as under the conjunctiva of the sclera. Previously, before the injection, it is necessary to anesthetize the conjunctiva, instilling 1-2 drops of a 0.5-1% solution of dicain [6, 7]. This method of administration is also available and widely used in ophthalmology for the treatment of mainly diseases of the sclera and the anterior part of the eye, since with subconjunctival administration the drug partially enters the conjunctival cavity (by diffusion and through the injection hole) and penetrates into the eye through the cornea from lacrimal fluid . However, the bulk of the drug diffuses into the liquid medium of the eye through its limbal zone and the deep sections of the sclera [1, 8]. With this method of administration, the highest concentration of drugs is noted in the sclera and their insignificant concentration in other structures of the eye [1].

For diseases of the choroid, retina and optic nerve, retrobulbar administration of drugs is used [1], since this method of administration provides more pronounced absorption and drug delivery through the hematophthalmic barrier collectors, and therefore, the highest content of drugs is observed in the choroid and retina , as well as in the vitreous body [6]. Retrobulbar injection is one of the most complex manipulations performed by a doctor only in a hospital setting. To carry out this injection, it is necessary to lay the patient in a horizontal position. The patient is asked to look up and inside, in order to divert the eyeball from the needle injection zone and provide tension to the inferior temporal intramuscular fascia. A 4-4.5 cm long needle is inserted through the skin of the lower eyelid in the region of the outer corner of the eye directly above the lower edge of the orbit. Next, the needle is advanced strictly posteriorly approximately in the middle between the lower and external rectus muscles. When the end of the needle passes the equator of the eye, it should be slightly turned to the eyeball until you feel resistance when passing the tip of the needle in the muscle fascia. After a fascia puncture, the needle is held for another 5-8 mm tangentially to the surface of the eyeball. After that, the syringe plunger is slightly pushed back to make sure that the end of the needle does not pierce the vessel, after which the solution is introduced. Recently, ophthalmologists have become less likely to use retrobulbar injections due to the possibility of various complications (hemorrhages in the orbit, wounding with a sclera and optic nerve needle, penetration by the tip of the needle into the lower orbit). Most often, retrobulbar injection is used during surgical procedures on the eyeball to perform retrobulbar anesthesia [9, 10].

The retrobulbar method of administering drugs is close to parabulbar in the effectiveness of the therapeutic effect. Orbital fiber is very loose and tender, therefore, the administered drug spreads quite quickly in it [1].

Parabulbar injections, unlike retrobulbar injections, are easier to perform and can be performed not only by a doctor, but also by specially trained paramedical staff of the ophthalmological department both in a hospital and in a polyclinic. An insulin syringe is used to perform parabulbar injection. The needle is injected in the same area of the outer corner of the eye directly above the lower edge of the orbit. Next, the needle is advanced strictly posteriorly approximately in the middle between the lower and external rectus muscles, after which the solution is injected.

In diseases of the cornea and iris, the method of introducing drugs into the anterior chamber of the eye can be used, since this method creates the maximum concentration of the drug in these structures of the eye [6]. The introduction of drugs into the anterior chamber is performed through a puncture of the cornea in the limb or through a section of the cornea. This method is more often used during surgical interventions on the eyeball [9, 10].

Intravitreal administration of drugs is most often used for opacities of the vitreous body of various etiologies. They are injected through the sclera in the projection area of the flat part of the ciliary body or through an ophthalmic injection device (ophthalmic nipple), as well as together with irrigation fluid during vitrectomy [6, 11]. With intravitreal injections, the maximum accumulation of drugs is noted not only in the vitreous, but also in the lens, ciliary body, choroid and retina proper. But at the same time, this method of drug administration is available only in the operating room, requires additional to the generally accepted methods for examining patients, preoperative preparation of the patient, akinesia, retrobulbar anesthesia. The introduction of drugs into the vitreous body can be associated with the possibility of various complications: subluxation of the lens, damage to its posterior capsule, hypopion, formation of posterior synechia, increased diffuse opacification of the vitreous, reactive ophthalmic hypertension and retinal detachment [12].

Thus, the listed methods of drug administration do not have the proper effect on the photoreceptor layer of the retina, on the avascular structures of the eye (vitreous body, lens, internal corneal epithelium), which are often damaged in case of eye disease.

A significant part of the drug does not pass through the hematoretinal barrier or spreads against the fluid flow in the eyeball, which does not directly affect the desired target structures and requires an increased dosage of the drug.

As shown by the analysis of the available scientific and patent information, information related to the subscleral method of administration into the eyeball was not found. In the analysis of the known information, it was not possible to identify decisions regarding the subscleral method of administering drugs, taking into account the direction of movement of the intraocular fluid and the targeted effect on the desired eye structures. It is to solve this problem that the invention is directed.

Thus, the objective of the invention is the development of a universal method of administration of drugs to increase the effectiveness of the treatment of eye diseases.

The problem is solved by subscleral administration, taking into account the direction of movement of the intraocular fluid.

It is generally accepted that intraocular fluid (HPW) is formed due to secretion of the ciliary epithelium [13] and enters the eye through the intershell cerebrospinal fluid spaces of the brain, then the optic nerve, passing into the subscleral intershell cracks. From there, it passes through the channels into the retina and further into the vitreous body, providing also its physiological regeneration. VGZH washes a surface of a crystalline lens, serves as a source of its trophic support. Partially HPV is absorbed by the ciliary epithelium. The ultrastructure of the microvilli of the ciliary epithelium, similar to the microvilli of the small intestine and the epithelium of the proximal tubule of the nephron [13], in our opinion, indicates the absorption of not only proteins but also water (figure 2). The remainder of the IHC comes from the posterior chamber of the eye through the Sonderman canals, through the Barkan membrane, the trabeculae, covered with the endothelium, into the Schlemm canal, then through the venous collectors into the water veins and the venous system of the sclera, the orbital vein, and then into the orbicular-stony sinus and anterior interventricular sinus . Thus, retinal neurons, like brain neurons, receive part of the trophic support due to the circulation of cerebrospinal fluid [4].

Our data on the hydrodynamics of the eye allow us to substantiate the introduction of drugs taking into account the direction of movement of the intraocular fluid and the targeted effect on certain eye structures, i.e. subscleral.

Cerebrospinal fluid, produced mainly by the vascular plexuses of the lateral ventricles of the brain, circulates in the 3rd and 4th ventricles, and then into the spinal canal; according to the corresponding structures, it communicates with the subdural space of the brain, as well as with the tanks: cisterna anterior - in front of the chiasm, cisterna inferior - between the pons Varolii and the inner edges of the temporal lobes, communicating with each other and with the cistern of the sylvian groove. The cerebellar vein large cistern communicates with the third and lateral ventricles, as well as the lower cistern. The largest cistern is located between the lower surface of the cerebellum and the posterior surface of the medulla oblongata, communicates with the cistern of the cerebellar vein and with the 4th ventricle through foramen Magndii and Lushka, passing into the subarachnoid space of the brain and spinal cord [14]. In this way, a constant circulation of cerebrospinal fluid through all the cisterns, the intershell spaces of the brain and the optic nerve, and the connection of these spaces with the cerebral ventricles are established. The volume of circulating fluid is 90-150 ml, is exchanged at least five times a day.

Pericillular fluid is one of the essential factors of the internal environment of the retina, its composition and properties affect the function of neurons. However, the issue of fluid intake in the eyeball has not yet been resolved and has not been considered.

It is known that cerebrospinal fluid circulation occurs not only in the brain and spinal cord, but also extends to the optic nerve membrane [4, 15]. The retina, being a derivative of the brain brought to the periphery, requires the same cerebrospinal fluid supply as the neurons of the central nervous system. However, information on the morphological substrate that ensures the transport of cerebrospinal fluid in the eyeball to the retina is not available in the available literature.

The membranes of the optic nerve are an extension of the membranes of the brain, therefore, the intershell neural cracks containing cerebrospinal fluid communicate with the subarachnoid and subdural spaces of the brain. The membranes of the optic nerve continue sequentially to the eyeball. The episclera is a continuation of the dura mater, and the sclera’s own plate is a continuation of the arachnoid [16]. It has been established that the episclera and the sclera proper are not tightly fused, and spaces filled with liquor remain between them.

To confirm the data on the hydrodynamics of the eye and the effectiveness of the subscleral method of administration, we conducted a series of experimental studies on animals. For the experiment, 15 laboratory sexually mature albino rats (30 eyes) were used. Apply intravital coloration of the structures of the eyes of mammals with trypan blue according to the Spatz method. A 1% trypan blue dye solution is administered 2 times every other day, 0.2 ml subsclerally. In ocular practice, insulin syringes are used to administer drugs. For control, drugs are administered under a microscope and, nevertheless, eye damage is not ruled out. We propose to install a stopper at the end of the needle at a distance of 1 mm, made in the form of a disk with a diameter of 0.3-0.5 mm from a densified fabric, such as silicone, so as not to damage the surface of the eye in contact with the disk. Using the limiter eliminates the possibility of damage to other structures of the eye.

It is most convenient and technically feasible when the eyeball is brought up and inside, an injection needle is punctured to a depth of 1 mm in the lower outer segment, closer to the posterior pole of the eyeball and perpendicular to its surface through the conjunctiva, the outer and inner sheet of the tenon capsule, under the episcleral flap and administer the drug. The needle is injected taking into account the anatomical features of the sclera, falling into the part that has the greatest thickness and the most pronounced subscleral space, without affecting the sclera’s own and pigmented leaf. On average, the sclera has the largest thickness of 1.1 mm. Given the puncture to a depth of 1.0 mm of the conjunctiva, the outer and inner leaf of the tenon capsule, we fall under the episcleral flap of the sclera, without affecting its other layers in order to avoid damage to the eye.

The control group was injected with 0.9% NaCl solution, and the main group with 1% trypan blue solution (see table).

Slaughter of animals is carried out under ether anesthesia. After taking biopsy samples of the eyes, they are poured into paraffin and sections are prepared with a thickness of 5-7 microns, then dewaxed according to the classical method. If it is necessary to obtain greater contrast, the sections are stained with eosin. They study eye structures using a Nicon microscope (Japan).

An analysis of the experimental data on the subscleral administration of trypan blue dye showed that the dye from the subscleral region spreads uniformly from the posterior pole to the anterior pole and sequentially stains the retina, vitreous body, pigmentless ciliary epithelium, crystalline lens, and then the drainage system in the region of the iris-corneal angle (Fig. .1 a, b, c, 2).

Thus, the subscleral method of administering drugs is most effective for treating patients for whom traditional methods of drug administration have no effect. These are diseases such as purulent processes, unstable glaucoma, recurrent hemorrhages, acute circulatory disorders in the retina and optic nerve, etc.

The subscleral method of drug administration was used by us in the Regional Clinical Hospital No. 2 of Vladivostok.

Example 1. Patient O., 54 years old. Diagnosis: Hemophthalmus. Within 2 weeks, hormonal drugs and antibiotics were administered retrobulbarly. No effect was observed. Hormones and antibiotics were introduced by the proposed method subsclerally under a microscope. For this purpose, the prescribed hormones and antibiotics were introduced into the retracted eyeball up and inside, into the lower external segment closer to the posterior pole of the eyeball and perpendicular to its surface, through the conjunctiva, the outer and inner leaf of the tenon capsule, under the episcleral flap with an injection needle to a depth of 1 mm. The next day, the patient showed improvement - according to ultrasound, hemophthalmus decreased, visual functions improved, treatment continued.

Example 2. Patient N., 56 years old. Diagnosis: Glaucoma. He was treated for several years. No effect noted. Stably increased intraocular pressure, lacrimation, pain in the eyeball, decreased visual function.

Held the treatment of the proposed method. Under the microscope, antioxidants and nootropics (piracytes and histochrome) were introduced subsclerally. Two days later, an improvement was noted in all of the above indicators, and against the background of improvement, treatment was continued with repeated subscleral administration of drugs to a persistent improvement in visual function and the cessation of pain.

Thus, the proposed subscleral method of drug administration has significant advantages. The method is physiological, because when used, its dosage level of drugs can be reduced by 50%, because they spread in the structures of the eye, bypassing the blood-brain barrier, and have a direct effect on the desired target structures, moreover, they guarantee the protection of eye structures from damage due to the presence of a disk limiter on the injection needle.

List of references

1. Morozov V.I., Yakovlev A.A. Pharmacotherapy of eye diseases. - M .: Medicine, 2001 .-- 472 p.

2. Castilio A., Dias D., Sayaques O. et al. Analisis of the Blood Retinal Barrier Its Relation to Clinical and Metabolic Factors and Progression to Retinopathy in Juvenile Diabetic A 4 Year Follow Up Study // Greafes Arch. for Clinical and Exp. Ophthalmol. 1996. V.234. Iss 4. Pp. 246-250.

3. Yoshida A., Ishiko S., Kojima M. Inward and Outword Permeability of the Blood Retinal Barrier in Experimental Myopia // Greafes Arch. for Clinical and Exp. Ophthalmol. 1996. V.234. Iss 1. Pp. 5239-5242.

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8. Somov E.E., Vorontsova T.N. and others. The content of antibiotics in the lacrimal fluid and liquid media of the eye with various methods of administration. // Vestn. ophthalmol. - 1991. No. 4. - p. 56-59.

9. Gorban A.I., Dzhaliashvili O.A. Eye microsurgery, errors and complications. - St. Petersburg: Hippocrates, 1993 .-- 272 p.

10. Krasnov M.L., Belyaev B.C. Guide to eye surgery. - M .: Medicine, 1988 .-- 624 p.

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12. Krasnov M.M., Laryukhina G.M. et al. Intravitreal enzymatic treatment of vitreous opacities. // Vestn. ophthalmol. - 1996. No. 4. - p.31-37.

13. Nesterov A.P. Glaucoma. - M .: Medicine, 1995 .-- 256 p.

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16. Raspanty M., Marchini M., Delia P. et al. Sclera. // J. Anat. 1992. V.181 No. 2. p. 181-187.

Claims (2)

1. The method of subscleral administration of drugs, which consists in taking the eyeball up and inside, puncture with an injection needle to a depth of 1 mm in the lower outer segment, closer to the posterior pole of the eyeball and perpendicular to its surface, through the conjunctiva, the outer and inner leaf tenon capsule, under the episcleral flap, and the drug is administered. 2. The method according to claim 1, characterized in that at the end of the injection needle, a stop is made, made in the form of a disk with a diameter of up to 0.3-0.5 mm from a compacted fabric.

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