JPH0930966A - New pharmaceutical preparation for eye - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical preparation for eye containing the first immunosuppressant in the world as an active ingredient. SOLUTION: Mycophenolic acid and its derivative are prepared as an eye drop or an eye ointment and mycophenolic acid as an active ingredient is passed through ectocornea and absorbed into cornea. As a result, the preparation suppresses immunological rejection in corneal transplantation or exhibits excellent treating effect on inflammatory eye diseases and allergic conjunctivitis derived from autoimmunization and difficult to treat.

Description

Description: The present invention relates to a process for the production of new eye drops. More specifically, it relates to a method for producing eye drops and an eye ointment for treating or preventing immune-related inflammatory eye diseases such as corneal transplant rejection, autoimmune or allergy. BACKGROUND OF THE INVENTION In recent years, inflammatory eye diseases considered to be involved in autoimmunity or allergies have been on the increase due to artificial aging and changes in living environment. The eye is said to be the most difficult tissue in the body for the immune system to recognize foreign substances,
It has long been known that allogeneic cancer tissue, which is immunologically easily rejected when transplanted into a tissue other than the eye, can be engrafted and proliferated by transplanting into the eye chamber. Therefore, human corneal transplantation has a very high success rate of about 70% even if intensive immunosuppressive drug administration is not required unlike renal transplantation which is an allograft. On the other hand, 80% of the remaining 30% rejected may be engrafted by suppressing the rejection reaction by using an appropriate immunosuppressive agent, but the immunosuppressive agent that can be used is limited. In addition, these drugs, which exhibit an excellent immunosuppressive effect for renal transplantation, are difficult to reach the cornea, which is an allograft transplanted into the eyeball. As will be described later, mycophenolic acid is absorbed from the corneal epithelial cells when it is instilled and easily migrates into the cornea, so that the immune reaction in the eye can be effectively suppressed. Therefore, one of the fields in which the novel eye drops according to the present invention can be clinically applied is corneal transplantation. Further, intractable diseases such as Behcet's disease and Sjogren's symptom, which are regarded as autoimmune diseases, often cause inflammation of the uveal membrane of the eye and eventually blind the patient. Since these intractable diseases are inflammations induced by the attack of autologous lymphocytes on the uveal membrane, immunosuppressive therapy that controls lymphocytes systemically or locally is essential. Since mycophenolic acid is known to suppress the action of lymphocytes that attack self-antigens, another field in which the preparation of the present invention is involved is to treat or prevent the above-mentioned blindness-refractory eye diseases. It is to provide a new eye drop and an eye ointment. Fifty years after the war, the Japanese living environment changed dramatically. With the improvement of nutrition and the spread of hygiene, the number of infectious diseases decreased significantly, and the body position improved remarkably. Is a series of diseases that involve immune system. Since mycophenolic acid suppresses the above-mentioned allergies, one of the objects of the present invention is to provide a novel eye drop and an eye ointment for treating / preventing allergic conjunctivitis, which is an inflammatory eye disease involving allergies. is there. [0006] Drugs that have been put into practical use for suppressing the inflammatory reaction in the eyeball are classified into steroidal and nonsteroidal anti-inflammatory drugs, but both have serious problems. Steroid eye drops have a very strong anti-inflammatory effect, but have the drawback of causing many serious side effects.As a side effect, exacerbation of infection, induction of infection, delayed wound healing, cataract, glaucoma, pituitary gland, Suppression of adrenal function occurs.
Also. A major drawback is that when the drug is discontinued, the rebound phenomenon occurs in which inflammation becomes worse than before the drug administration. Non-steroidal anti-inflammatory agents are more versatile and have less serious side effects than steroids, but have a major drawback that their efficacy is insufficient. These exert an anti-inflammatory effect by suppressing the production of prostaglandins. Therefore, since it does not suppress the action of lymphocytes that trigger inflammatory diseases, it is also a drawback that it is limited to symptomatic treatment and does not lead to a fundamental treatment. The therapeutic agent for eye diseases expected to be developed from now on is a preparation containing an immunosuppressive agent such as cyclosporin A and tacrolimus which specifically suppresses T lymphocyte function as an active ingredient. However, ophthalmic drugs containing these immunosuppressive agents as active ingredients have many difficulties that must be overcome in terms of formulation, pharmacokinetics, and clinical efficacy. From the viewpoint of formulation, both do not dissolve in water, and the dosage form that can be put to practical use seems to be limited to eye ointment. Furthermore, taking cyclosporin A as an example, since the organic solvents that can be dissolved are limited to low molecular weight, low boiling point ethanol, acetone, etc., precipitation of cyclosporin A due to volatilization of the dissolving agent is inevitable during storage, and it is stable. It is very difficult to prescribe eye drops or eye ointments. In addition, after clearing the formulation-related difficulties, these are large molecules with a molecular weight exceeding 1,000, and the active substance contained in the formulation penetrates the mucosal epithelial cells of the cornea to reach the inflammatory site and exerts an anti-inflammatory effect. There is no guarantee that you can do it. Furthermore, from the viewpoint of efficacy, these drugs only suppress the appearance of T lymphocytes that recognize self-antigens as foreign substances, so that chronic inflammatory properties after T lymphocytes that attack self-antigens as foreign substances divide and proliferate. It is estimated that the effect on eye diseases may be poor. DISCLOSURE OF INVENTION Problems to be Solved by the Invention The present inventors have detailed the physicochemical properties, biological activity, clinical efficacy, etc. of this substance before 1968, when it first published a paper on mycophenolic acid. I've been studying. One end of them is, for example, as described in Merck Index Eleventh Edition, page 998. On the other hand, in the field of eye drops, immunosuppressants other than steroids have long been requested by clinicians.
From these findings, the present inventors were convinced that mycophenolic acid has excellent attributes as an immunosuppressive agent for eye drops, studied the formulation of the formulation, and conducted a series of animal experiments using the completed formulation. I went. Means for Solving the Problems The object of the present inventor is to prevent corneal transplantation, intractable autoimmune eye diseases leading to blindness and frequent allergic symptoms in atopic patients without serious side effects unlike steroids. It is intended to invent a water-soluble eye drop and a long-acting eye ointment which are highly effective in treating conjunctivitis and have a stable dosage form. The following is a description of how good mycophenolic acid is for this purpose. The first thing to mention about mycophenolic acid is its convenience in terms of formulation. This substance has a molecular weight of 3
It has 20 small molecules and is very chemically stable. Moreover, the free acid is insoluble in water and soluble in an organic solvent, and its alkali metal salt, alkaline earth metal salt and organic amine salt are conversely soluble in water and insoluble in an organic solvent. An aqueous solution or a liquid solubilized with an organic solvent is stable even when formulated. For example, gel cream formulations of free mycophenolic acid are very stable. Mycophenolic acid is almost insoluble in water in the free acid state, but alkali metal ions,
Salts with alkaline earth metal ions or organic amines
It becomes soluble in water. For example, if you suspend free mycophenolic acid in water and add 5% caustic soda in small portions,
Soluble in water up to about 6% at pH 7.4. Even when triethanolamine and diethylaminoethanol are added for neutralization, 5% or more is dissolved in water at around pH 8.0. Such properties are suitable for eye drops or eye ointments. Eye drops and eye ointments are a type of drug delivery system in which the drug is directly applied to the lesion.
It is clear that it has great advantages in terms of efficacy and side effects compared to systemically administered drugs. Although any drug cannot avoid side effects, topical application is relatively easy to avoid the negative effects of the drug. In addition, the topical agent has the great advantage that it is easier to control the amount of the drug to be delivered to the lesion than it is to be administered systemically, and that it is easy to exert the effect continuously. As a prerequisite for topical administration to be effective, it must be absorbed from the mucosa or skin to which the drug is applied and reach the lesion. When mycophenolic acid is not dissociated as ions, it is a fat-soluble low molecular weight substance, and therefore can be easily absorbed from the outer surface such as mucous membrane or skin. That is, it is qualified as a topical application agent because it can be absorbed from the outer surface of the body. The strong inhibition of mouse antibody production by mycophenolic acid was already reported in 1969 by Suzuki et al., A collaborator of the present inventor (Mitsu).
i Aand Suzuki S: J. Antibio
tics 22: 358-363, 1969). on the other hand,
The suppression of cell-mediated immunity by mycophenolic acid was also reported by Osugi, who is also one of the collaborators (Osugi Yoshimasa et al .: Transplantation 7: 257-259, 1972).
Its mechanism of action has also been shown to be the specific inhibition of inosinate dehydrogenase, which is induced when lymphocytes are stimulated to start proliferation. Therefore, mycophenolic acid not only suppresses the immune reaction involving T lymphocytes such as cyclosporin A and tacrolimus, which have been put into practical use as immunosuppressants for organ transplantation, but also B
A major feature is that it strongly suppresses antibody production involving lymphocytes. Furthermore, suppression of T and B lymphocyte activity by mycophenolic acid seems to suppress reactions that are relatively late in the immune reaction chain in any case. In other words, in the case of allogeneic transplantation, it is better to administer after the T cells that recognize the alloantigen as a foreign substance proliferate and start the rejection reaction to the graft than to administer it before the rejection reaction does not start. The effect of lengthening clothes is great,
Even in the case of suppressing antibody production, it is more effective to administer the antibody after B cells have started to produce antibody. For detailed immunosuppressive action of mycophenolic acid, its derivative RS
A review of Allison, who developed -61443 as an immunosuppressant for organ transplantation (Anales Off New York Academic Science: 696, pp. 11-20, 1
993). In the present invention, mycophenolic acid and its derivatives can be used as effective substances capable of suppressing the immune reaction of the eye. All the derivatives used in the present invention are compounds that regenerate mycophenolic acid when they are taken up by a living body, and from this point of view, all the derivatives are prodrugs. Unlike the cases such as penicillin and cephalosporin, the derivatives themselves including RS-61443 do not have immunosuppressive action. In the treatment of eye diseases involving immunity, the transfer of the active substance to the cornea is crucial for its efficacy. As is generally known, a low molecular weight compound such as mycophenolic acid is better absorbed from the skin or mucous membrane when it is present in a non-dissociated molecular form than when it is dissociated as an ion. The eye drop according to the present invention was applied to the eyes of a rabbit to measure the transfer into the cornea. As a result, it was found that even when a solution of pH 7.4 in which all the mycophenolic acid molecules were dissociated and ionized was instilled, it surely moved through the corneal epithelium and into the cornea. In addition, according to the Draize method, 0.1 ml of an aqueous solution having a pH of 7.0 containing 3% mycophenolic acid was instilled in a rabbit to observe symptoms, but as shown in Table 1, no abnormalities were observed for 188 hours. I was not able to admit. Therefore,
It is considered that mycophenolic acid does not have an action of acutely damaging the ocular mucosa. Table 1. Symptoms of Rabbits in which Mycophenolic Acid is Instilled The topical application agent according to the present invention can be manufactured into various dosage forms. The concentration of the active substance in the preparation is preferably in the range of 0.05 to 4.0% as mycophenolic acid. Not only can it be formulated as a liquid formulation, which is the most universal form of eye drops, but it can also be formulated as an eye ointment. The liquid agent is prepared by mixing a concentrated solution neutralized and dissolved in water or a concentrated solution solubilized with a solubilizing agent with a preservative, a buffering agent, a thickening agent and the like. The addition of preservatives is often undesirable because the ophthalmic formulations of the invention are often applied to chronic eye diseases. In that case, it is also possible to formulate as a single dose type unit dose type excluding preservatives. Further, in the case of an eye ointment, it can be formulated by a general eye ointment preparation method. Further, various antibiotics can be added to the eye drop of the present invention for the purpose of preventing and treating infectious diseases. The thus-prepared novel eye drops and eye ointment have excellent storage stability and are useful for suppressing rejection of transplanted cornea and for treating and preventing inflammatory eye diseases involving immunity. Examples will be shown below, but it goes without saying that the present invention is not limited to these examples. Example 1 2 g of mycophenolic acid was added to 25 cc. After suspending in 5% caustic soda little by little and completely dissolving it, sterilized purified water is used to obtain exactly 50 cc. And
The final pH at this time is adjusted to 6.0-8.0 (A
liquid). Meanwhile, 17.2 g of salt, 0.26 g of methyl paraoxybenzoate, and 0.14 of propyl paraoxybenzoate.
g of sterile purified water 1000 cc. To be dissolved (solution B). Liquid A 50 cc. And liquid B 50c
c. Are mixed to obtain an eye drop. Since this ophthalmic solution is an aqueous solution in which mycophenolic acid, which is a weak acid, is neutralized with caustic soda which is a strong base, it has a buffering action, and it is not particularly necessary to add a buffering agent. Example 2 19.11 g of borax was dissolved in sterile purified water, and the total amount was 500 cc. (Liquid A). On the other hand, as solution B, 12.4 g of boric acid was dissolved in sterile purified water, and the total amount was adjusted to 5
00cc. And Separately, 4 g of mycophenolic acid was suspended in sterilized purified water and 5% triethanolamine dissolved in sterilized purified water was added little by little to dissolve, and when completely dissolved, the pH was adjusted to 8.2 and the total amount was 100 cc. ．
(C liquid). Solution A 35 cc. , Solution B 65 cc. , C
Liquid 100 cc. Are further mixed, 0.52 g of sodium chloride and 0.01 g of benzalkonium chloride are added and dissolved, and bacteria are sterilized using a membrane filter having a pore size of 0.45 micron to give eye drops. The ophthalmic solution thus prepared contains 2% of mycophenolic acid and is stable at room temperature for a long period of time when stored in the dark. Example 3 A method for preparing eye ointment I is as follows. After 1.1 g of mycophenolic acid ethyl ester fine powder with an average particle size of 2.5 microns was well ground with a small amount of liquid paraffin to form a mud, a small amount of white ophthalmic petrolatum (trade name: propet) was used. One by one and kneaded to obtain a weight of 50 g. The ophthalmic ointment thus prepared contains 1% as free mycophenolic acid and is useful for treating patients who should avoid the use of preservatives. Example 4 A method for preparing eye ointment II is as follows. Solution A in Example 2 10 cc. After adding 10 g of purified lanolin to and kneading thoroughly, 80 g of white petrolatum as a base is added and ground to give an eye ointment. This formulation contains 0.4% free mycophenolic acid and is useful in treating patients who should avoid the use of preservatives. Example 5 A method for preparing eye ointment III is as follows.
ethyl O- {N- (p-carboxyphen
yl) -carbamyl} -mycophenola
After finely grinding 1.6 g of te fine powder with a small amount of liquid paraffin to form a mud, plastibase is added little by little and kneaded to a weight of 100 g. The ophthalmic ointment thus prepared contains 1% of free mycophenolic acid and is useful as a long-acting eye ointment. Sixth Embodiment [0023] Other components were added to the 5% mycophenolic acid aqueous solution (pH 6.5) prepared according to Example 1 to obtain a total amount of 1000.
cc. Was filtered through a Millipore filter having a pore size of 0.45 micron to obtain an eye drop. Example 7 An eye drop solution to which a thickening agent has been added has a characteristic that the effect lasts to some extent, though not as much as an eye ointment. Methylcellulose was selected as a thickening agent, and 3 g thereof was boiled in sterile purified water of about 200 cc. Soak in water and stir to disperse, then add 5.4 g of salt and 0.2 g of benzethonium chloride.
About 200 cc. Add and allow to cool for a while. After cooling to room temperature, add sterile purified water to obtain exactly 500 cc. (Liquid A). Separately, 20 g of mycophenolic acid was added to about 300 cc. Suspended in sterile purified water, add 5% caustic soda little by little to dissolve,
Adjust to 7.4

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 9/08 A61K 9/08 V 31/165 31/165 31/43 31/43 31/47 31 / 47 31/545 31/545 31/65 31/65 31/71 31/71 45/00 ADZ 45/00 ADZ 47/02 47/02 K Z 47/10 47/10 K 47/12 47/12 K Z 47/14 47/14 K 47/16 47/16 K 47/18 47/18 K 47/38 47/38 F C07D 307/88 C07D 307/88 // (A61K 31/365 45:00) (A61K 31/365 31:71)

Claims (1)

Claim: What is claimed is: 1. Mycophenolic acid or a derivative thereof is used as an essential active substance, and one or more selected from antibacterial agents, preservatives, buffers, thickeners and the like are constituted. A method for producing a novel eye drop and an eye ointment as a component, wherein the mycophenolic acid derivative in claim 1 is one of a phenolic hydroxyl group in the molecule and hydrogen of a side chain carboxylic acid, or Both refer to compounds substituted by other groups. 3. The antibacterial agent according to claim 1 is a β-lactam antibiotic, a tetracycline antibiotic, an aminoglycoside antibiotic, a macrolide antibiotic, chloramphenicol, a new quinolone antibacterial agent, etc. A method for producing a novel eye drop and eye ointment, which is one or more selected from 4. The preservative in claim 1 is benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, lower alcohol esters of paraoxybenzoic acid,
Chlorobutanol, phenethyl alcohol, sodium dehydroacetate, sorbic acid, boric acid, lactoferrin,
A method for producing a novel eye drop comprising one or more selected from lysozyme and the like. 5. A mycophenolate salt, a borate salt, a phosphate salt as a buffer in claim 1. A method for producing a novel eye drop, characterized by containing one or more selected from acetate, triethanolamine salt, diethylaminoethanol salt, etc. [Claim 6] As an agent, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, methylcellulose, carboxymethylcellulose,
A process for producing a novel eye drop comprising one or more selected from hydroxypropyl cellulose. 7. A mycophenolic acid or its derivative is ground with purified lanolin or liquid paraffin to obtain white petrolatum. Of a new eye ointment characterized by grinding with an ointment base such as