JP2016199541A - Improving or therapeutic agent of zoster keratitis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a useful agent in the improvement or treatment of zoster keratitis.SOLUTION: The present invention relates to novel pharmaceutical applications of a vaccinia virus inoculation inflammatory tissue extract, and relates to improving or therapeutic agents of zoster keratitis which contain the extract as an active ingredient. The agent containing the extract as an active ingredient is highly effective and safe as well as extremely useful, as an improving or therapeutic agent of zoster keratitis.SELECTED DRAWING: None

Description

  The present invention relates to a novel pharmaceutical use of an extract of inflamed tissue inoculated with vaccinia virus (hereinafter sometimes referred to as “the present extract”). More specifically, the present invention relates to an agent for improving or treating herpes zoster keratitis containing the present extract as an active ingredient.

  Shingles is caused by infection with varicella-zoster virus (VZV). The virus lies in dorsal root ganglia and trigeminal ganglia after varicella disease. The trigeminal nerve is a nerve on the face that reduces the immune system due to illness or fatigue, or when the virus reactivates due to other triggers, causing shingles in the first or second branch area of the trigeminal nerve, causing pain in the eyelids. In addition to accompanying rashes and edema, various eye symptoms may occur. In addition to pain symptoms, various ocular symptoms include pseudo-dendritic keratitis, diffuse corneal edema / endotheliitis, multiple subepithelial infiltrates, discoid keratitis, etc. (In general, it is referred to as “zoster keratitis”) (see “Infectious keratitis clinical practice guideline (2nd edition)” on page 489, Table 5). In severe cases, iridocyclitis, secondary glaucoma, acute retinal necrosis, and sometimes ocular muscle paralysis may occur. Although it may develop even in younger people, the onset frequency increases with age and tends to become more severe.

Herpes zoster keratitis is treated with systemic antiviral drugs from the early stages of the onset and appropriate steroid eye drops depending on the severity of ocular symptoms. Such treatment often produces a certain effect. . However, antiviral drugs have a lower antiviral effect against varicella-zoster virus than herpes simplex virus. Moreover, it is necessary to administer an appropriate amount of an antiviral drug in order to avoid side effects such as neuropsychiatric symptoms and acute renal failure in patients with impaired renal function. In addition, eye drops with steroids may cause side effects such as increased intraocular pressure, glaucoma, cataracts, and secondary infections.
From the above situation, there is a strong demand in the clinical field for new drugs effective against herpes zoster keratitis and having few side effects.

  About the extract of inflammatory tissue inoculated with vaccinia virus which is an active ingredient of an agent for improving or treating herpes zoster keratitis according to the present invention, analgesic action, sedative action, anti-stress action, anti-allergic action (see Patent Document 1), immune promotion Action, anticancer action, liver cirrhosis inhibitory action (see Patent Document 2), therapeutic effect on idiopathic thrombocytopenic purpura (see Patent Document 3), postherpetic neuralgia, cerebral edema, dementia, spinocerebellar degeneration etc. Therapeutic effect (see Patent Document 4), Raynaud's syndrome, diabetic neuropathy, therapeutic effect on SMON sequelae (see Patent Document 5), kallikrein production inhibitory action, peripheral circulation disorder improving action (see Patent Document 6), bone atrophy Improvement action (see Patent Document 7), Nitric oxide production inhibitory action (see Patent Document 8) effective for treatment of sepsis and endotoxin shock, therapeutic effect on osteoporosis Patent Document 9), AIDS treatment effect based on Nef action inhibitory action and chemokine production inhibitory action (see Patent Documents 10 and 11), therapeutic effect on ischemic diseases such as cerebral infarction (see Patent Document 12), fibromyalgia (See Patent Document 13), therapeutic effect on infectious diseases (see Patent Document 14), prevention or alleviation of peripheral neuropathy by anticancer agents (see Patent Document 15), chronic prostatitis, interstitial cystitis and / or In addition, the therapeutic effect of dysuria (see Patent Document 16), the action of promoting the production of neurotrophic factors such as BDNF (see Patent Document 17), and the action of promoting the synthesis of collagen and proteoglycan in chondrocytes (see Patent Document 18). Wide range of actions and effects are known. And it is also known that the formulation which uses this extract as an active ingredient has the therapeutic effect with respect to herpes zoster pain and postherpetic neuralgia (refer nonpatent literature 1, 2, 3). However, it has not been known so far that this extract is effective in improving or treating herpes zoster keratitis.

JP-A-53-101515 JP 55-87724 A Japanese Patent Laid-Open No. 1-265028 JP-A-1-319422 JP-A-2-28119 JP-A-7-97336 JP-A-8-291077 JP-A-10-194978 Japanese Patent Laid-Open No. 11-80005 JP-A-11-139777 JP 2000-336034 A Japanese Unexamined Patent Publication No. 2000-16694 International Publication WO 2004/039343 JP 2004-300146 A International Publication WO2009 / 028605 International Publication WO2011 / 111770 International Publication WO2011 / 162317 International Publication WO2012 / 051173

Basic and Clinical, Vol.17, No.5, p. 1187, 1983 The History of Medicine, 147, 7, 651, 1988 Clinical Medicine, Vol. 18, No. 11, 1255, 2002

  An object of the present invention is to provide a drug that is effective and effective in improving or treating herpes zoster keratitis.

  As a result of earnest research on drug treatment for shingles keratitis for which an effective treatment is sought, the present inventors have found that a preparation containing this extract as an active ingredient is superior to shingles keratitis The present invention was completed by finding that it shows an improvement or therapeutic effect.

  This extract has an excellent pharmacological action of improving or treating herpes zoster keratitis. Moreover, since the chemical | medical agent containing this extract as an active ingredient is a highly safe chemical | medical agent with few problems, such as a side effect, this invention is very useful.

  This extract is an extract containing a non-protein active substance extracted and separated from an inflamed tissue of an animal that has been inoculated with vaccinia virus. The extract is liquid in the extracted state, but can also be made solid by drying. A drug containing this extract as an active ingredient (hereinafter referred to as “the present preparation”) is very useful as a pharmaceutical product. In this case, since this extract is an active ingredient of this formulation, this extract is the drug substance of this formulation. A specific product manufactured and sold by the applicant in Japan as this preparation is “Vaccinia virus-inoculated rabbit inflammation skin extract-containing preparation” (trade name: Neurotropin / NEUROTROPIN (registered trademark)). This preparation includes injections and tablets, both of which are ethical drugs.

  The indications for injections of neurotropin are “back pain, neck-shoulder syndrome, symptomatic neuralgia, pruritus associated with skin diseases (eczema, dermatitis, urticaria), allergic rhinitis, cold feeling of SMON aftereffects. "Abnormal perception / pain". The indications for neurotropin tablets are “postherpetic neuralgia, low back pain, cervico-arm syndrome, peri-shoulderitis, osteoarthritis”. This formulation was created by the applicant and developed as a pharmaceutical product. Its superior efficacy and safety features have been evaluated, and it has been sold for many years, establishing a firm position in the Japanese pharmaceutical market. Is.

  The inflamed tissue extract inoculated with vaccinia virus in the present invention crushes inflamed tissue that has been inoculated with vaccinia virus, and after removing tissue fragments by adding an extraction solvent, the protein is removed and adsorbed by the adsorbent And then eluting the active ingredient. For example, inoculated vaccinia virus is inoculated into the skin of rabbits and collected inflamed skin tissue, crushed and treated by adding extraction solvent, then removed the tissue pieces, deproteinized and treated under acidic conditions Can be obtained by adsorbing to an adsorbent and then eluting the active ingredient in basic conditions.

  As animals for inoculating vaccinia virus to obtain inflamed tissues, various animals infected with vaccinia virus such as rabbits, cows, horses, sheep, goats, monkeys, rats and mice can be used. Inflamed skin tissue is preferred. Any rabbit may be used as long as it belongs to the order of rabbit eyes. Examples include rabbits, rabbits (rabbits made from rabbits), rabbits (Japanese rabbits), rabbits, snow rabbits, and the like. Of these, chira rabbits are suitable for use. In Japan, there is a so-called rabbit that has been bred from the past and used widely as domestic animals or experimental animals. There are many varieties (breeds) of the rabbit, but varieties such as Japanese white varieties and New Zealand white varieties (New Zealand white) can be suitably used.

  The vaccinia virus may be of any strain. Examples include Lister strains, Daren strains, Ikeda strains, EM-63 strains, New York City Board of Health strains, and the like.

As a basic extraction process of the present extract, for example, the following processes are used.
Step (A) Inflammated skin tissue obtained by intradermal inoculation of vaccinia virus into the skin of rabbits is collected. The collected skin tissue is washed and disinfected with a phenol solution. This inflamed skin tissue is crushed and 1 to 5 times the amount of extraction solvent is added. Here, crushing means crushing finely into a mince using a mincing machine or the like. In addition, as extraction solvents, distilled water, physiological saline, weakly acidic to weakly basic buffer solutions, and the like can be used. Sterilizers and preservatives such as phenol, stabilizers such as glycerin, sodium chloride, potassium chloride Further, salts such as magnesium chloride may be appropriately added. At this time, extraction can be facilitated by disrupting the cell tissue by treatment with freeze-thaw, ultrasound, cell membrane lytic enzyme, surfactant or the like. The resulting suspension is left for 5 to 12 days. Meanwhile, the mixture may be heated to 30 to 45 ° C. with or without stirring as appropriate. The obtained liquid is subjected to solid-liquid separation (filtration, centrifugation, etc.) to remove the tissue piece to obtain a crude extract (filtrate or supernatant).

About a process (B) A protein removal process is performed about the crude extract obtained at the process (A). Deproteinization can be carried out by known methods commonly used, such as heat treatment, treatment with a protein denaturant (for example, an organic solvent such as acid, base, urea, guanidine, acetone, etc.), isoelectric precipitation, salting out. Etc. can be applied. Subsequently, the insoluble protein that has been precipitated by a usual method for removing insoluble matters, for example, filtration using filter paper (cellulose, nitrocellulose, etc.), glass filter, celite, zeit filtration plate, etc., ultrafiltration, centrifugation, etc. A removed filtrate or supernatant is obtained.

About Step (C) The filtrate or supernatant obtained in Step (B) is adjusted to acidic, preferably pH 3.5 to 5.5, and the adsorption operation to the adsorbent is performed. Examples of usable adsorbents include activated carbon, kaolin, and the like. Add the adsorbent to the extract and stir, or pass the extract through an adsorbent-filled column to add the active ingredient to the adsorbent. Can be adsorbed. When an adsorbent is added to the extract, the adsorbent can be obtained by adsorbing the active ingredient by removing the solution by filtration or centrifugation.

About step (D) In order to elute (desorb) the active ingredient from the adsorbent obtained in step (C), an elution solvent is added to the adsorbent and adjusted to basic, preferably pH 9-12, Alternatively, it is eluted by heating or stirring as appropriate, and the adsorbent is removed by a usual method such as filtration or centrifugation. As an elution solvent to be used, a basic solvent, for example, water adjusted to a basic pH, methanol, ethanol, isopropanol or the like, or an appropriate mixed solution thereof can be used, preferably water adjusted to pH 9 to 12. Can be used. The amount of the elution solvent can be appropriately set. In order to use the eluate thus obtained as a drug substance, the pH is appropriately adjusted to near neutral, etc. to finally obtain a vaccinia virus-inoculated rabbit inflammation skin extract (this extract). Can do.

  Since this extract is liquid at the time of completion, it can be made to have a desired concentration by appropriately concentrating and diluting. When manufacturing a formulation from this extract, it is preferable to heat-sterilize. In order to obtain an injection, for example, sodium chloride or the like can be added to prepare a solution that is isotonic with physiological saline. Moreover, oral solid preparations, such as a tablet, can also be manufactured by performing operation, such as concentration and drying suitable for this extract in a liquid state. Specific methods for producing such an oral solid preparation from this extract are described in the specifications of Japanese Patent Nos. 3818657 and 4883798. This preparation is an injection or a solid preparation for oral use thus obtained.

Examples of methods for administering a pharmaceutically effective amount to a patient in need of treatment include subcutaneous, intramuscular and intravenous administration in addition to oral administration, and the dosage depends on the type of inflammatory tissue extract inoculated with vaccinia virus. It can be set appropriately. The dose allowed for commercially available formulations is basically indicated as a medicinal product to administer 16 NU per day for internal use and 3.6 to 7.2 NU per day for injections. It can be appropriately increased or decreased depending on the degree of serious injury, patient individual differences, administration method, administration period, etc. Tested according to the modified Randall-Selitto method and defined by the ED ₅₀ value of analgesic potency, 1NU is the activity showing 1 mg of the analgesic activity-containing component of the neurotropin preparation when the ED ₅₀ value is 100 mg / kg. )

  The following is an example of the method for producing the extract, and the pharmacological test results relating to the novel pharmacological action of the extract and herpes zoster keratitis, but the present invention is not limited in any way by the description of these examples. Absent.

Example 1 (Production of the present extract)
The skin of healthy mature rabbits was inoculated intradermally with vaccinia virus, and the cut skin was cut out and collected. The collected skin is washed and disinfected with a phenol solution, then the excess phenol solution is removed, crushed, the phenol solution is added and mixed, left to stand for 3 to 7 days, and then stirred for 3 to 4 days. Warmed to 35-40 ° C. Thereafter, the extract obtained by solid-liquid separation was adjusted to pH 4.5 to 5.2 with hydrochloric acid, heat-treated at 90 to 100 ° C. for 30 minutes, and then filtered to deproteinize. Further, the filtrate was adjusted to pH 9.0 to 9.5 with sodium hydroxide, heated at 90 to 100 ° C. for 15 minutes, and then separated into solid and liquid.

  The obtained deproteinized solution was adjusted to pH 4.0 to 4.3 with hydrochloric acid, activated carbon in an amount of 2% of the deproteinized solution mass was added and stirred for 2 hours, followed by solid-liquid separation. Water was added to the collected activated carbon, adjusted to pH 9.5 to 10 with sodium hydroxide, stirred at 60 ° C. for 90 to 100 minutes, and then centrifuged to obtain a supernatant. Water was added again to the activated carbon precipitated by centrifugation, and then adjusted to pH 10.5 to 11 with sodium hydroxide, stirred at 60 ° C. for 90 to 100 minutes, and then centrifuged to obtain a supernatant. Both supernatants were combined and neutralized with hydrochloric acid to obtain the present extract.

Example 2 (Test method)
Next, an example of the test result about the effect | action (therapeutic effect) with respect to the herpes zoster keratitis of the formulation (this formulation) containing this extract obtained in the said Example 1 as an active ingredient is shown.

  In order to examine the effect of this preparation on herpes zoster keratitis, a test was conducted in humans as follows.

(1) Test 1 (Test period: June 2010 to June 2013)
Thirty patients diagnosed with herpes zoster keratitis were randomly divided into two groups, a treatment group and a control group. These two groups were treated with systemic administration of acyclovir, topical chloramphenicol, acyclovir ophthalmic solution and levofloxacin ophthalmic solution. Acyclovir is an antiviral drug, and chloramphenicol and levofloxacin are antibacterial drugs. The treatment group was treated in the same manner as the control group, and then “Neurotropin injection solution 3.6 units” (trade name of the injection in this preparation) was administered by infusion for 20 days (1 tube, 1 tube) Once a day). Basically, no other drugs were used. The therapeutic effect was determined after the completion of 20 days of treatment.

(2) Test 2 (Test period: April 2012 to April 2014)
Forty patients diagnosed with herpes zoster keratitis were randomly divided into two groups: a treatment group and a control group. A test similar to Test 1 was performed on these two sets.

(3) Determination of therapeutic effect The following diagnostic criteria were used to determine the therapeutic effect.
“Healing” is the disappearance of pain and irritation of the eye, complete recovery of keratitis, clear cornea, fluorescent staining (negative), conjunctival hyperemia with ciliary hyperemia, The shingles are pulled and the scab is formed.
“Improved” reduced conjunctival hyperemia with ciliary hyperemia and irritation symptoms, almost recovered keratitis, reduced fluorescence, partially eliminated herpes on the forehead, and reduced local pain and discomfort State.
“Invalid” is a condition in which the corneal inflammation is not improved or worsened, and complications such as glaucoma and ocular muscular palsy develop.
The therapeutic effect was determined using the above diagnostic criteria, and the cure rate, the reversal rate, and the total effective rate of the total number of cases in each group were calculated. The results of Test 1 are shown in Table 1, and the results of Test 2 are shown in Table 2.

(4) Statistical analysis
The two groups were compared using the chi-square test. The case of p <0.05 was regarded as “significant”.

  The test results in Table 1 and Table 2 were statistically analyzed. As a result, administration of this preparation to patients with shingles keratitis significantly increased the cure rate and the overall effective rate compared with the control group. From this, it was shown that this preparation is an effective drug for generally improving and treating symptoms of herpes zoster keratitis.

  In Tests 1 and 2, this preparation is used in combination with an antiviral agent and an antibacterial agent. However, it does not indicate that these two drugs are essential for the effect of this preparation on herpes zoster keratitis. Since herpes zoster keratitis is caused by a virus (VZV), it is not particularly necessary to use an antibacterial agent in combination. Further, even when used in combination, the antiviral drug is not limited to acyclovir used in Tests 1 and 2. For example, penciclovir, valacyclovir hydrochloride, famciclovir, and the like, which are antiviral agents used for herpes zoster keratitis, can also be mentioned as suitable antiviral agents. Similarly, antibacterial drugs (external preparations and eye drops) are not limited to chloramphenicol and levofloxacin used in Tests 1 and 2. For example, gentamicin sulfate, chloramphenicol / fradiomycin sulfate combination agent, bacitracin / fradiomycin sulfate combination agent etc. as external preparations, gentamicin sulfate, tobramycin, dibekacin, sodium colistin methanesulfonate as eye drops , Vancomycin hydrochloride, norfloxacin, ofloxacin, lomefloxacin hydrochloride, gatifloxacin hydrate, tosufloxacin tosylate hydrate, moxifloxacin hydrochloride, cefmenoxime hydrochloride and the like can be used, respectively.

  As described above, this preparation was found to have an excellent improvement / treatment effect on symptoms of herpes zoster keratitis. In addition, this preparation has been used for many years and is recognized as a very safe drug. Therefore, this preparation is extremely useful as an agent for improving or treating herpes zoster keratitis.

Claims (12)

  An agent for improving or treating herpes zoster keratitis containing an extract of inflamed tissue inoculated with vaccinia virus as an active ingredient.   The improvement or treatment agent according to claim 1, which is used in combination with an antiviral agent and / or an antibacterial agent.   The improvement or therapeutic agent of Claim 1 or 2 with respect to the pain of the eye part by the shingles keratitis, the irritation | stimulation symptom of the eye part, turbidity of the cornea, or conjunctivitis.   The improvement or treatment agent according to any one of claims 1 to 3, wherein the inflamed tissue is an inflamed rabbit skin tissue.   The improvement or treatment agent according to any one of claims 1 to 4, which is an injection.   The improvement or treatment agent according to any one of claims 1 to 4, which is an oral agent.   Use of an extract of inflamed tissue inoculated with vaccinia virus for improvement or treatment of shingles keratitis.   The use according to claim 7, wherein the agent for improving or treating herpes zoster keratitis is used in combination with an antiviral agent and / or an antibacterial agent.   The use according to claim 7 or 8 for the improvement of a pain in the eye due to herpes zoster keratitis, eye irritation, corneal turbidity or conjunctivitis, or the manufacture of a therapeutic agent.   The use according to any one of claims 7 to 9, wherein the inflamed tissue is a rabbit inflamed skin tissue.   The use according to any one of claims 7 to 10, wherein the agent for improving or treating herpes zoster keratitis is an injection.   The use according to any one of claims 7 to 10, wherein the agent for improving or treating herpes zoster keratitis is an oral agent.