CN112569224B - Use of arteether amine maleate for preparing ophthalmic preparation - Google Patents
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- CN112569224B CN112569224B CN201910937864.9A CN201910937864A CN112569224B CN 112569224 B CN112569224 B CN 112569224B CN 201910937864 A CN201910937864 A CN 201910937864A CN 112569224 B CN112569224 B CN 112569224B
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 28
- HPGHCIXRRLNXRN-XQLAAWPRSA-N beta-aminoarteether Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](OCCN)[C@@H]4C HPGHCIXRRLNXRN-XQLAAWPRSA-N 0.000 title claims description 15
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- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 description 1
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- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to the use of arteether maleate (Aminoarteether Maleate, SM 934) for the preparation of an ophthalmic formulation, and more particularly to the use of arteether maleate for the preparation of an ophthalmic formulation for the prevention or treatment of ocular inflammatory lesions caused by hypolacrimation.
Description
Technical Field
The invention relates to a new application of arteether maleate, in particular to an application of arteether maleate in preparing an ophthalmic preparation for treating ocular inflammation injury caused by lacrimal secretion deficiency.
Background
Dry eye, also known as keratoconjunctivitis sicca, refers to a general term for a class of diseases that result from abnormalities in the quality or quantity of tears or abnormalities in tear fluid dynamics, which are associated with ocular discomfort and damage to the surface of the eye. The clinical manifestations include dry feeling, burning feeling, foreign body feeling, itching feeling, photophobia, eye redness, blurred vision, vision fluctuation, asthenopia and the like. Severe dry eye can also cause keratitis, corneal angiogenesis, corneal ulcers, and the like. Dry eye is mainly divided into tear deficiency and evaporation excess, and meibomian gland dysfunction, xerophthalmia, vitamin a deficiency, allergy, pregnancy, and drug treatment can all cause occurrence of dry eye. With the development of socioeconomic performance and the improvement of the living standard of people, the incidence of dry eye is increased and the affected population tends to be younger.
At present, medicines for treating xerophthalmia clinically are classified into antibacterial medicines, hormones, artificial tears and the like, but the curative effect on xerophthalmia is very limited because eye tissues are sensitive and drug resistance and the like are easy to generate.
Scopolamine hydrobromide is an anticholinergic agent with strong peripheral effect, and can block M cholinergic receptor and inhibit gland secretion [1] . The stable and durable tear deficiency type xerophthalmia can be established by inducing the reduction of tear secretion of rats through subcutaneous injection of scopolamine, and is a recognized animal model of the tear deficiency type xerophthalmia [2-3] 。
Artemisinin is an antimalarial active ingredient extracted from the traditional Chinese medicine Artemisia annua (plant Artemisia annua l.), a rare sesquiterpene lactone containing peroxy groups. It has not only excellent antimalarial effect, but also good anti-inflammatory immunosuppressive activity. The artemisinin compound has immunosuppressive activity, but the problems of poor solubility, low oral bioavailability and the like of the existing artemisinin drugs (artemether, dihydroartemisinin, artesunate and the like) limit the application, popularization and research of the drugs in the field of immune system disease treatment. The arteether maleate amine (Aminoarteether Maleate, SM 934) is a novel water-soluble artemisinin derivative, and compared with the artemisinin medicines for resisting malaria, the arteether maleate amine has the advantages of good water solubility, high patentability, convenient preparation, easy oral administration and absorption, high bioavailability, strong immunosuppressive activity and good safety.
The arteether maleate has excellent in vivo and in vitro inhibitory activity, and can inhibit mitogen and allogenic antigen induced proliferation of mouse or human lymphocyte and inhibit production of inflammation-related cytokines by in vitro administration; in vivo administration can significantly inhibit cell-mediated immune response of mice, namely delayed hypersensitivity (DTH) of mice induced by DNFB or SRBC; inhibiting the humoral immune response of mice, namely SRBC-induced sheep erythrocyte hemolysis (QHS); the oral administration has good therapeutic effect on a doxorubicin-induced rat kidney disease model; and its therapeutic effectiveness was further verified on two classical internationally recognized idiopathic lupus erythematosus mouse disease models (female NZB/W F1 mice and female MRL/lpr mice). The arteether maleate has the following structural formula:
there are no applications and reports of arteether maleate amine in treating ocular inflammatory injury caused by insufficient tear secretion.
Disclosure of Invention
The present inventors have found for the first time the therapeutic effect of arteether amine maleate on ocular inflammatory injury caused by hypolacrimation, and have thus completed the present invention.
Accordingly, an object of the present invention is to provide the use of arteether amine maleate in the preparation of an ophthalmic preparation (particularly an ophthalmic external preparation) for preventing or treating ocular inflammatory injury caused by hypolacrimation.
The inventor finds that the curative effect and convenience of the arteether maleate can be improved by the mode of local administration.
Thus, according to one aspect, the present invention provides the use of arteether maleate in the manufacture of an ophthalmic formulation (particularly an ophthalmic external formulation) for the prevention or treatment of ocular inflammatory lesions caused by hypolacrimation.
In the present invention, the ocular inflammatory injury caused by insufficient lacrimal secretion includes, but is not limited to, ophthalmic diseases such as corneal and conjunctival inflammatory injury caused by insufficient lacrimal secretion due to diseases or excessive ocular use. Preferably, the ocular inflammatory injury caused by insufficient lacrimal secretion is dry eye, in particular, tear-deficient dry eye.
In the present invention, preferably, the ophthalmic formulation may be in various dosage forms known in the art, including, but not limited to, eye drops, ophthalmic gels, ophthalmic ointments, and the like.
The ophthalmic formulation may include a therapeutically effective amount of arteether amine maleate and one or more pharmaceutically acceptable conventional excipients. The pharmaceutically acceptable conventional auxiliary materials can be excipient, filler, diluent and the like.
As used herein, the term "therapeutically effective amount" means that amount that has a therapeutic effect and is useful for preventing or treating a particular disease, disorder, or condition described herein. For example, a "therapeutically effective amount" may refer to an amount required to provide a therapeutic or desired effect on the individual receiving treatment. As known to those skilled in the art, the therapeutically effective amount will vary depending on the route of administration, the use of excipients, and the likelihood of co-usage with other therapies.
According to the invention, a scopolamine hydrobromide is used for inducing a xerophthalmia model with insufficient tear secretion of rats, and researches show that the ophthalmic external preparation containing arteether amine maleate can increase tear secretion, reduce corneal inflammation injury, increase conjunctival goblet cell number, increase mucin secretion, maintain conjunctival barrier function and the like, so that the eye disease caused by insufficient tear secretion of rats is treated, and the eye external preparation has good clinical application prospect.
Drawings
FIG. 1 shows the results of treatment with arteether amine maleate in example 2 to increase scopolamine-induced tear secretion in rats. Wherein, FIG. 1A is a graph showing the lacrimal secretion amount of each group of rats in the treatment period; FIG. 1B is a graph showing the amount of tear secretion in groups of rats treated on day 0; FIG. 1C is a graph showing tear secretion in groups of rats treated on day 3; FIG. 1D is a graph showing tear secretion in groups of rats treated on day 5; fig. 1E is a graph showing the amount of tear secretion in each group of rats on day 7 of treatment. Wherein each group compares to model groups with P <0.05, =p <0.01, =p <0.001.
FIG. 2 shows the results of arteether amine maleate in example 2 to alleviate scopolamine induced corneal damage in rats. Wherein, fig. 2A is a graph showing the corneal fluorescein sodium staining injury score for each group of rats treated on day 3; FIG. 2B is a graph showing the scoring of damage by corneal sodium fluorescein staining for each group of rats on day 5; fig. 2C is a graph showing corneal fluorescein sodium staining injury scores for each group of rats treated on day 7. Wherein each group compares to model groups with P <0.05, =p <0.01, =p <0.001.
FIG. 3 shows a representative graph of arteether amine maleate in example 2 to alleviate scopolamine induced corneal damage in rats. Wherein, fig. 3A is an image of rat corneal fluorescein sodium staining observed under the treatment day 3 slit lamp; FIG. 3B is an image of rat corneal fluorescein sodium staining observed under a treatment day 5 slit lamp; fig. 3C is an image of rat corneal fluorescein sodium staining observed under a treatment day 7 slit lamp.
FIG. 4 is a graph showing the results of staining rat conjunctival tissue with periodic acid Schiff (periodic acid Schiff, PAS) and counting goblet cells after 7 days of treatment in example 2. Each group was compared to model group =p <0.05, =p <0.01, =p <0.001.
FIG. 5 is a graph showing the result of periodic acid Schiff (periodic acid Schiff, PAS) staining of conjunctival tissue of a rat 7 days after the treatment in example 2.
Detailed Description
The invention is further illustrated by the following detailed description. The examples provided herein are merely illustrative or explanatory of embodiments of the invention and are not intended to limit the scope of the invention.
Unless otherwise indicated, reagents and methods employed in the present application are those conventional in the art.
Example 1 preparation of arteether amine maleate eye drops
For a specific preparation of arteetheramine maleate (SM 934), reference may be made to the applicant's previous patent (ZL 93112454.9) and published paper J.Med. Chem,2000,43:1635-1640.
SM934：
Salifying with maleic acid. White crystals. Melting point: 139-141 DEG C
Elemental analysis (C) 21 H 33 NO 9 )：
Calculated values: C56.87H 7.50N 3.16
Actual measurement value: C56.84H 7.59N 3.10
The ophthalmic preparation of this example was an eye drop, and based on 100ml, it contained arteether maleate 0.5g or 0.1g, sodium chloride 0.8g, potassium chloride 0.02g, disodium hydrogen phosphate dodecahydrate 0.2924g, potassium dihydrogen phosphate 0.02g, and pH 7.37.
The preparation method comprises the following steps: 8g of sodium chloride, 0.2g of potassium chloride, 2.924g of disodium hydrogen phosphate dodecahydrate and 0.2g of potassium dihydrogen phosphate are taken and dissolved in 1L of distilled water, and the mixture is fully and uniformly mixed at room temperature to prepare a solution of pH7.39, which is solution A.
Adding 0.5g or 0.1g of arteether maleate amine into 100ml of solution A, standing at room temperature, dissolving completely, and filtering with sterile filter membrane to obtain arteether maleate amine eye drops with content of 0.5w/v% and 0.1w/v% respectively, and pH of 5.91 or 6.89.
EXAMPLE 2 therapeutic Effect of arteether amine maleate eye drops prepared in example 1 on eye inflammatory injury caused by scopolamine-induced insufficient tear secretion in rats
1. Main experimental materials and sources
(1) Animals: SPF-grade SD rats, females, weighing 120-150g, supplied by Shanghai Jieshijie laboratory animal Co., ltd., eligibility number: 20180004006541.
(2) Main experiment medicine and reagent
Arteetheramine maleate, trait: an eye drop (arteether maleate amine eye drop, pH 5.91; arteether maleate amine eye drop, pH 6.89) was prepared as in example 1 as a white powder.
Reagent: scopolamine hydrobromide, available from national pharmaceutical chemicals, inc., CAS:6533-68-2, lot number: #f1713061. 1.5w/v% and 1.75w/v% concentration were formulated in sterile water. Sodium hyaluronate eye drops are produced by the company Santa Classification of Tenceae, inc., division package of Tenceae pharmaceutical (China), small package license number of imported medicine registration license: h20130583, import drug registration certificate large package certificate number: h20130584, packet approval document: chinese medicine standard J20130150. Tear detection phenol red cotton thread, produced by Tianjin Crystal Ming New technology development Co., ltd., production license number: production of jin food and medicine monitoring instrument is No. 20100040, registration certificate number: body fluid food medicine monitoring instrument (quasi) word 2014, 2410002, production lot number: 20171002. sodium fluorescein injection, produced by Guangzhou white cloud mountain Mingxing pharmaceutical Co., ltd., national drug standard H44023401, product batch No. 170303.
(3) Main instrument
KOWA hand-held slit lamp, model SL-17, available from Shanghai Youshen Tree biotechnology Co. A fluorescence scanner (model: nanoZoomer 2.0 HT) for pathological sections of Pinus maritima.
2. The experimental method comprises the following steps:
(1) Experimental grouping: all rats were tested for tear secretion using phenol red cotton prior to molding and equally grouped according to tear secretion levels, with 10 rats per group, each: normal control, model control, sodium hyaluronate control, (0.5%, 0.1%) eye drop treatment.
(2) Model construction
Each rat except the normal control group was subcutaneously injected at 9:00, 12:00, 15:00 points with 1.5w/v% scopolamine injection 0.2ml,18:00 points with 1.75w/v% scopolamine injection 0.2ml daily for 7 days.
(3) Therapeutic method
Normal control group and model control group rats do not interfere with each other, the sodium hyaluronate control group rats adopt 0.1% sodium hyaluronate eye drops (20 μl/eye/time) 4 times a day, and the eye drops treatment group rats adopt 0.5% arteether maleate amine eye drops (20 μl/eye/time) prepared in example 14 times a day respectively. The eye drop time was about 9:30, 12:30, 15:30, 18:30 daily for 7 consecutive days.
1) Tear secretion amount detection: the tear secretion of each group of rats was measured with phenol red cotton thread on treatment day 0, day 3, day 5 and day 7, respectively;
2) Cornea damage score: scoring lesions by sodium fluorescein staining of cornea on treatment days 3, 5, and 7, respectively, and observing the area of cornea staining with slit lamp;
3) Conjunctival goblet cell count: at the end of the experiment, namely, taking left eye conjunctiva tissue of a rat on the 7 th day of treatment, placing the left eye conjunctiva tissue in 4% formaldehyde for room temperature fixation, performing periodic acid Schiff (periodic acid Schiff, PAS) staining on paraffin sections, taking 3 fields of view in a 40-time amplification range of each specimen for positive staining cup cell counting, wherein the average value of the 3 field of view counts is the conjunctival cup counting result of the sample;
(4) Experimental results
1) As shown in figure 1, the arteether maleate amine eye drops with the concentration of 0.5 percent and 0.1 percent can obviously improve the tear secretion of rats and have better effect than sodium hyaluronate eye drops;
2) As shown in fig. 2 and 3, the results of staining the bilateral cornea of the rat with sodium fluorescein show that the arteether maleate amine eye drops with 0.5% and 0.1% can significantly improve the corneal injury of the rat, and the alleviation effect is superior to that of the sodium hyaluronate eye drops;
3) As shown in fig. 4 and 5, the table of the rat conjunctival goblet cell count shows that the arteether maleate amine eye drops with the concentration of 0.5% and 0.1% can maintain the normal number of goblet cells of the rat conjunctiva, and the protection effect on goblet cells is better than that of the sodium hyaluronate eye drops.
The results show that the arteether maleate has remarkable treatment effect on the ocular injury caused by the lacrimal hyposecretion of rats, can improve the lacrimal secretion amount, improve the corneal inflammatory injury and maintain the conjunctival goblet cell number, has better effect than that of sodium hyaluronate eye drops, and can be developed into a medicament for treating the ocular inflammatory injury caused by the lacrimal hyposecretion.
Reference to the literature
[1]Viau S，Maire MA，Pasquis B，et al.Time course of ocular surface annd lacrimal gland changes in a new scopolamine-induced dry eye model[J].Graefes Arch Clin Exp Ophthalmol，2008.246:857-867.
[2] Liu Huijuan, huang Yue, zhang, etc. establishment of a rat dry eye model and modification of corneal nerve [ J ]. New ophthalmic progression, 2014, 34 (5): 422-427.
[3] Liu Xue, xu, gao Weiping injection of atropine sulfate eye drops and scopolamine hydrobromide subcutaneously to make dry eye rabbit model experimental study of water deficiency [ J ], journal of clinical ophthalmology, 2015 (3): 263-266.
Claims (7)
1. Use of arteether amine maleate in the manufacture of an ophthalmic formulation for the prevention or treatment of ocular inflammatory lesions caused by hypolacrimation.
2. The use according to claim 1, wherein the ocular inflammatory injury caused by hypolacrimation comprises an ocular disease of corneal, conjunctival inflammatory injury caused by hypolacrimation due to disease or ocular overuse.
3. The use according to claim 1, wherein the ocular inflammatory injury caused by hypolacrimation is dry eye.
4. The use according to claim 1, wherein the ocular inflammatory injury caused by hypolacrimation is hypolacrimation dry eye.
5. The use of claim 1, wherein the ophthalmic formulation comprises an eye drop, an ophthalmic gel, or an ophthalmic ointment.
6. The use according to claim 1, wherein the ophthalmic formulation comprises arteether amine maleate and one or more pharmaceutically acceptable excipients.
7. The use according to claim 6, wherein the pharmaceutically acceptable excipients are selected from one or more of excipients, fillers and diluents.
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