TW202202168A - Composition for improving vitreous opacities and uses thereof - Google Patents

Abstract

This invention discloses that a composition comprising fruit bromelain, papain and ficin can be used for improving vitreous opacities.

Description

Composition for improving vitreous opacity and application thereof

The present invention relates to a composition for improving vitreous opacities (VO) and its application.

The vitreous body (also known as vitreous humor) of the human eye contains a highly hydrated network consisting primarily of an elongated network of collagen fibrils and interspersed hyaluronan The transparent jelly-like structure, and a layer of vitreous membrane covering it. The vitreous fills the cavity between the lens and the retina, supports the lens and maintains the shape of the posterior cavity and the vitreous.

As the human body grows and ages, collagen fibers aggregate and redistribute, resulting in the formation of liquid pockets between colloids, a process called syneresis. These aggregated collagen aggregates are suspended in the vitreous, and their shadows cast on the retina to form linear, dotted, circular, or cloudy opacities in the line of sight, known as vitreous opacity (VO). or floaters. In most cases, small VO will disappear within three months, or the patient will adjust to its presence because it will not interfere with vision, and choose not to treat; however, some patients may see mesh, large or Multiple VOs persisting for more than three months and requiring treatment due to severe interference with vision are referred to as pathological vitreous opacity (SVO).

In addition to vitreous liquefaction, other ocular diseases have been found to cause VO or SVO production, including posterior vitreous detachment (PVD), retinal tears (retinal detachment, RD), astrology Asteroid hyalosis, vitreous heamorrhage, uveitis, vitritis, etc.

Approaches that have been used clinically to treat VO (especially SVO) include: (i) invasive treatments, mainly by vitrectomy to remove part or all of the cloudy vitreous, or by intravitreal Intravitreal protease (eg, ocriplasmin) to dissolve VO pharmacological vitreolysis; and (ii) non-invasive treatment, mainly by neodymium doping Neodymium-doped yttrium aluminum garnet (Nd:YAG) laser vitreolysis (also known as Nd:YAG laser surgery) is used to directly vaporize VO in the vitreous.

However, with the exception of vitrectomy, other treatments have not been proven to be completely effective, and all of these treatments have the potential to develop side effects such as cataracts, glaucoma, macular degeneration, and intraocular inflammation within a few years after surgery (side effects), which may even lead to blindness in severe cases. Therefore, relevant researchers in the field try to find active components that can be used for the treatment of VO from natural sources.

The applicant found in a previous study that after SVO patients ingested 100-300 g of pineapple per day for 3 months, up to 74.2% of the patients had significant improvement in the symptoms of vitreous opacity, or even completely recovered, and the Therapeutic efficacy is in a dose-dependent manner.

Notwithstanding the above, there is still a need in the art for drugs that can effectively improve VO, especially SVO.

Summary of Invention

Thus, in a first aspect, the present invention provides a composition for improving vitreous opacities (VO), comprising fruit bromelain, papain and ficin.

In a second aspect, the present invention provides the use of a composition as described above for the preparation of a medicament for treating vitreous opacity.

In a third aspect, the present invention provides the use of the above-mentioned composition for preparing a health food for improving vitreous opacity.

In a fourth aspect, the present invention provides a method for treating an individual having or suspected of having vitreous opacity, comprising administering to the individual a composition as described above.

Detailed description of the invention

It is to be understood that if any antecedent publication is cited herein, that antecedent publication does not constitute an admission that, in Taiwan or any other country, the antecedent publication forms a common general practice in the art part of knowledge.

For the purposes of this specification, it will be clearly understood that the word "comprising" means "including but not limited to" and that the word "comprises" has a corresponding meaning.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Of course, the present invention is in no way limited by the methods and materials described.

In the development of drugs that can be used to treat vitreous opacities, the applicant has found through experiments that a composition comprising ficin, papain and fruit bromelain can be effective It can effectively improve the symptoms of pathological vitreous opacities (SVO), so it is expected to have the potential to treat vitreous opacities.

Therefore, the present invention provides a composition for improving vitreous opacity, which comprises bromelain protease, papain and ficin.

Preferably, ficin, papain and bromelain are in a ratio ranging from 1:1:1.5 (w/w/w) to 1:2:5 (w/w/w). In a preferred embodiment of the present invention, ficin, papain and pineapple fruit protease are in a ratio of 1:1:2 (w/w/w).

According to the present invention, the pineapple protease, papain and ficin may be commercially available products, or may be products prepared by techniques well known and used by those skilled in the art, such as , natural products isolated from plant materials or recombinant proteins obtained through genetic engineering.

According to the present invention, the bromelain fruit protease can be prepared by extracting the fruit of a plant of the family Bromeliaceae with water.

According to the present invention, the papain [also known as papaya proteinase I] can be obtained by extracting latex from a papaya ( Carica papaya ) or a mountain papaya ( Vasconcellea pubescens ) fruit with water. was made.

According to the present invention, the ficin can be prepared by extracting with water the latex, fruit or leaves of a Ficus (also known as Ficus) plant.

According to the present invention, the above-mentioned water extraction method can be carried out using techniques well known and commonly used by those skilled in the art. For example, the bromelain, papain, and ficin were prepared by extracting the fruits of these plants with water at 40-50°C, followed by addition of dichloromethane to Partitioning was performed, and then the dichloromethane separated fraction was recovered and concentrated, dried, and recrystallized.

It can be understood that the operating conditions of the above-mentioned extraction method will be further changed according to the treatment method of the plant used and the dosage ratio of the plant, so as to achieve the best extraction effect. The selection of these operating conditions is routinely determined by those skilled in the art.

The present invention also provides the use of the above-mentioned composition for preparing a medicine for treating vitreous opacity.

As used herein, "treating" or "treatment" means preventing, reducing, alleviating, ameliorating, relieving, or controlling ( controlling one or more clinical signs of a disease or disorder, and lowering, stopping or reversing a condition being treated or The progression of the severity of the symptoms.

As used herein, the terms "vitreous opacity", "vitreous opacities", "vitreous floaters" and "floaters" are used interchangeably, And means the opacity formed in the vitreous due to degenerative changes (such as dehydration and coagulation of collagen, and depolymerization of hyaluronic acids) in the vitreous Opacities that cast shadows on the retina and form plaques in the field of vision. In addition, vitreous opacity can also be caused by other diseases or conditions, including, but not limited to: posterior vitreous detachment, retinal tears or retinal detachment (RD), proliferative retinopathy Proliferative retinopathy (such as diabetic retinopathy, sickle cell retinopathy, and retinal vein occlusion) caused by vitreous hemorrhage, Eales disease 'disease), myopia, intraocular inflammation [such as uveitis and vitritis], asteroid hyalosis, non-Hodgkin's lymph non-Hodgkin's lymphoma, amyloidosis, trauma, and cataract surgery.

As used herein, the terms "symptomatic vitreous opacity (SVO)" and "myodesopsia" are used interchangeably and mean that an individual has a vitreous opacity for a longer period of time (for example, lasting more than 3 months) and seriously interfere with the patient's vision.

In a preferred embodiment of the present invention, the vitreous opacity is floaters.

According to the present invention, the composition or the medicinal product can be manufactured into a composition suitable for parenteral administration, oral administration or topical administration using techniques well known to those skilled in the art. ) dosage form.

According to the present invention, the composition or the pharmaceutical product may further comprise a pharmaceutically acceptable carrier which is widely used in pharmaceutical manufacturing technology. For example, the pharmaceutically acceptable carrier may comprise one or more agents selected from the group consisting of: solvent, buffer, emulsifier, suspending agent, decomposer ), disintegrating agent, dispersing agent, binding agent, excipient, stabilizing agent, chelating agent, diluent , gelling agents, preservatives, wetting agents, lubricants, absorption delaying agents, liposomes, and the like. The selection and quantity of these reagents are within the scope of the expertise and routine skills of those skilled in the art.

According to the present invention, the composition or the medicinal product may be administered by a parenteral route selected from the group consisting of: intraperitoneal injection, intrapleural injection, intramuscular injection Intramuscular injection, intravenous injection, intraarticular injection, intrasynovial injection, intrathecal injection, intracranial injection, epidermis Intraepidermal injection, subcutaneous injection, intradermal injection, intralesional injection, intravitreal injection, and sublingual administration. Preferably, the composition or the medicinal product is manufactured in a dosage form suitable for administration by intravitreal injection.

According to the present invention, the composition or the medicinal product can also be manufactured into a dosage form suitable for oral administration using techniques well known to those skilled in the art, including, but not limited to: sterile powder, lozenge (tablet) , troche, lozenge, pellet, capsule, dispersible powder or granule, solution, suspension, emulsion , syrup (syrup), elixir (elixir), thick syrup (slurry) and the like.

According to the present invention, the composition or the medicinal product may also be manufactured into an external preparation suitable for topical application to the skin using techniques well known to those skilled in the art, including, but not limited to: Emulsion, gel, ointment, cream, patch, liniment, powder, aerosol, spray, Lotion, serum, paste, foam, drop, suspension, salve and bandage.

The present invention also provides the use of the above-mentioned composition for preparing a health food for improving vitreous opacity.

The present invention also provides a method for treating an individual having or suspected of having vitreous opacity, comprising administering to the individual a composition as described above.

In accordance with the present invention, the dosage and frequency of administration of the composition will vary depending on the severity of the disease to be treated, the route of administration, and the age, physical condition and response of the individual to be treated. In general, the pharmaceutical products according to the present invention may be administered orally or parenterally in a single dose or in divided doses. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention will be further described with respect to the following embodiments, but it should be understood that these embodiments are only for illustration purposes and should not be construed as limitations on the implementation of the present invention. Examples General experimental methods: 1. Non-mydriatic fundus photography examination:

In the following example, a non-mydriatic retinal camera (brand KOWA, model nonmyd 8) was used to perform fundus photography on the subject and take pictures to obtain SVO images to preliminarily test whether the subject has a vitreous Large blood clots or clearly visible SVO. 2. B-scan ultrasonography:

In the following examples, an ocular ultrasound imaging system (Alcon ^® Ultrascan ^® Imaging System, Alcon Laboratories, Ltd.) was used to perform B-mode ultrasound scan examinations on subjects and to obtain ultrasound scan images for the purpose of To confirm the number of SVO and whether there is retinopathy. 3. Optical coherence tomography (OCT):

In the following examples, subjects were subjected to OCT and tomographic images were obtained using an ocular optical coherence tomograph (ZEISS, model Cirrus HD-OCT 5000, available from Clinico Instrument Co., Ltd.). , to confirm the number of SVO and the presence of retinopathy. 4. Statistical analysis:

The experimental data obtained in the following examples were statistically analyzed using SAS 9.0 statistical software (SAS Inst., Cary, NC, USA). All data were analyzed by paired Student's t-test, Williams' test, and Scheffé's test to evaluate each set of experiments discrepancies between data. Statistical significance was indicated if the result of the statistical analysis obtained was p < 0.05. Experimental subject:

The following experiments were performed in accordance with procedures approved by the Institutional Review Board (IRB) of the National Army Kaohsiung General Hospital and in accordance with the current revised version of the Declaration of Helsinki. Written informed consent in compliance with IRB specifications was obtained after full experimental instructions were given to participants.

Subjects for this study included 280 patients diagnosed with ocular symptomatic vitreous opacities (SVOs) [also known as myodesopsia] between April and December 2017. All subjects were between 20 and 60 years old, with a mean age of 48±3 years.

Inclusion criteria included: the presence of one or more ophthalmic examinations (including non-mydriatic fundus photography, B-mode ultrasonography, and OCT) in the subjects' eyes within 3 months prior to the trial. Vitreous opacities (ie, an SVO number greater than 1), and confirm that the measured objective evidence matches the subject's subjective complaints. Subjects were allowed to have vitreous hemorrhage due to diabetic retinopathy, hypertensive retinopathy or trauma.

Exclusion criteria included: any treatment for intraocular hemorrhage, ophthalmic surgery within 6 months, posterior uveitis, posterior lymphoma, endophthalmitis Or intraocular tumors, or have had an intravitreal injection that resulted in emulsified oil droplets in the vitreous. Example 1. Preparation of the enzyme composition of the present invention

The pineapple fruit protease (fruit bromelain) used in this example was purchased from Xi'an Sgonek Biologic Technology. Co., Ltd., China; papain was purchased from from Shaanxi Hongda Phytochemistry. Co., Ltd., China; and ficin was purchased from HK. Gotopharm Co., Ltd., Taiwan.

The enzyme composition of the present invention is prepared by mixing 190 mg of pineapple fruit protease, 95 mg of papain and 95 mg of ficin, followed by a mixture of hydroxypropyl methylcellulose (HPMC) and Sustained-release capsules composed of pectin (purchased from Yongxin Pharmaceutical Industry Co., Ltd.) (which are not easily decomposed by gastric acid, but are slowly decomposed in the intestine) are coated and prepared. Embodiment 2. Efficacy evaluation experimental method of the enzyme composition of the present invention in the treatment of SVO : A , administration of the enzyme composition of the present invention and symptom evaluation:

Before the start of the experiment, the subjects' eyes were checked for larger SVO by non-mydriatic fundus photography, and the number of SVOs in each subject was observed and recorded by OCT. Then, 120 subjects were divided into 2 groups according to the OCT examination results, including the single SVO group (n=80) and the multiple SVO group (n=40). Afterwards, subjects in these groups were given the enzyme composition of the present invention, 2 capsules per day, for a total of 3 months.

During the trial, subjects underwent monthly best-corrected visual acuity (BCVA) measurements, non-mydriatic fundus photography, B-mode ultrasonography, and OCT to observe clinical signs and SVO Quantitative changes were used to assess the efficacy of the treatment and the presence or absence of side effects. In the single-SVO group, subjects were considered to have improved if the number of SVOs decreased to 0; in the multiple-SVO group, subjects were considered to be improved if the number of SVOs decreased to 1 or 0 is improved.

Afterwards, the obtained experimental data were analyzed according to the paired Student's t-test described in item 4 "Statistical Analysis" of "General Experimental Methods" above. Results: A. Evaluation of therapeutic efficacy:

Table 1 below shows the change in the number of subjects diagnosed with SVO in each group before and after administration. Table 1. Number of subjects with SVO and cure rate by group group Before administration Dosing for 1 month Dosing for 2 months Dosing for 3 months improvement rate Single SVO group 80 78 68 twenty four* 70.0% Multiple SVO groups 40 37 30 11* 72.5% *: p < 0.05 compared to before administration.

It can be seen from Table 1 that after the start of administration, the number of subjects with SVO in each group decreased significantly, and it became more obvious with the increase of administration time. In particular, after 3 months of administration, the improvement rate in each group was as high as 70 to 72.5%.

For example, in the ultrasound scan image and OCT image of Figure 1, it can be clearly observed that SVO disappears after 3 months of administration; and in the non-mydriatic fundus photography image, a large number of lumps and The cobweb-like cloudiness completely disappeared 3 months after administration.

In addition, vision improved significantly in all subjects (data not shown).

The experimental results show that the enzyme composition of the present invention can effectively improve the pathological vitreous opacity. B. Assessment of side effects:

Throughout the trial period, all subjects had normal angle of anterior chamber, lens status, cornea and zonular fiber, and no retinal damage occurred. or ocular inflammation, and no other significant side effects or discomfort. In addition, intraocular pressure (intraocular pressure), blood sugar (blood sugar) and blood pressure (blood pressure) were also within the normal range.

This result shows that the enzyme composition of the present invention has no negative effect on the human body [especially the normal collagen fibrils in the ocular tissue]. Example 3. Experimental method for evaluating the efficacy of different doses of enzyme compositions in the treatment of SVO :

First, the number of SVOs for each subject was observed and recorded as described in Example 2 above. Next, 160 subjects were randomly divided into 4 groups (n=40 in each group), including a low-dose group, a middle-dose group, a high-dose group and a control group. The subjects in the low-dose group, the middle-dose group and the high-dose group took 1 tablet, 2 tablets and 3 tablets of the enzyme composition of the present invention, respectively, for 3 months; as for the subjects in the control group, they did not take any drugs .

During the test, the number of SVOs for each subject was observed and recorded as described in Example 2 above. Afterwards, the obtained experimental data were analyzed using the Sheffield's test described in Item 4 "Statistical Analysis" of the "General Experimental Methods" above, and the difference in results between the groups was assessed using the Williams test. result:

Table 2 below shows the change in the number of subjects diagnosed with SVO in each group before and after administration. Table 2. Number of subjects with SVO in each group group Before administration Dosing for 1 month Dosing for 2 months Dosing for 3 months improvement rate control group 40 40 40 38 ^* 5.0% low dose group 40 38 33 14 ^*# 65.0% medium dose group 40 35 32 12 ^*# 70.0% high dose group 40 34 30 10 ^*# 75.0% ^* : p < 0.05 compared with before administration. ^# : compared with the control group, p < 0.05.

It can be seen from Table 2 that after the start of the test, the number of subjects with SVO in each group decreased significantly, and it became more obvious with the increase of medication time and dose. In particular, after 3 months of administration, the improvement rate in each group was as high as 65 to 75%.

Based on the above experimental results, it can be known that the enzyme composition of the present invention can improve pathological vitreous opacity in a dose-dependent manner.

All patents and documents cited in this specification are incorporated by reference in their entirety. In the event of conflict, the detailed description of the case (including definitions) will prevail.

Although the present invention has been described with reference to the specific embodiments above, it will be apparent that many modifications and changes can be made without departing from the scope and spirit of the invention. It is therefore intended that the present invention be limited only as indicated by the scope of the appended claims.

The above and other objects, features and advantages of the present invention will become apparent with reference to the following detailed description and preferred embodiments and accompanying drawings, wherein: Figure 1 shows the vitreous of a subject in various SVO groups by non-mydriatic fundus photography and B-scan before dosing and 3 months after dosing Ultrasonography) and the subsequent images of the posterior vitreous by optical coherence tomography (OCT).

Claims (10)

A composition for improving vitreous opacity, comprising bromelain fruit protease, papain and ficin. The composition of claim 1, wherein the ficin, papain and bromelain are in a range from 1:1:1.5 (w/w/w) to 1:2:5 (w/w/w) proportion. The composition of claim 2, wherein the ficin, papain and bromelain are in a ratio of 1:1:2 (w/w/w). The composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier. The composition of claim 1, wherein the composition is in a dosage form for oral administration. A composition as claimed in any one of claims 1 to 5 provides use for the manufacture of a medicament for the treatment of vitreous opacities. As in the use of claim 6, the vitreous opacity is floaters. The use of claim 6, wherein the medicinal product further comprises a pharmaceutically acceptable carrier. The use of claim 6, wherein the medicinal product is in a dosage form for oral administration. A composition according to any one of claims 1 to 5 is provided for use in preparing a health food for improving vitreous opacity.

Images