CN111494647A - A pharmaceutical composition for treating cataract and its preparation method - Google Patents
A pharmaceutical composition for treating cataract and its preparation method Download PDFInfo
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- CN111494647A CN111494647A CN202010382772.1A CN202010382772A CN111494647A CN 111494647 A CN111494647 A CN 111494647A CN 202010382772 A CN202010382772 A CN 202010382772A CN 111494647 A CN111494647 A CN 111494647A
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- pharmaceutical composition
- farnesene
- cyclodextrin
- cataract
- eye
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- 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
- A61K31/01—Hydrocarbons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
- A61P27/12—Ophthalmic agents for cataracts
Abstract
The invention discloses a pharmaceutical composition for treating cataract, which comprises farnesene serving as an active ingredient, an inclusion material and other pharmaceutically acceptable ophthalmic excipients, wherein the farnesene and the inclusion material form an inclusion compound in a molar ratio of 1: 2. The invention also relates to a preparation method of the pharmaceutical composition and application of the pharmaceutical composition in preparing a medicinal preparation for treating cataract, in particular senile cataract.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a medicine composition for treating cataract and a preparation method thereof.
Background
Cataract is a process of degenerative change of crystalline lens of eye tissue and natural aging, which generally develops vertically, and finally leads to opacity and blindness of crystalline lens. Many factors, such as aging, genetics, metabolic abnormalities, trauma, radiation, poisoning, and local nutritional disturbances, can cause damage to the lens capsule, increase its permeability, lose barrier function, or cause metabolic disturbances of the lens, denature lens proteins, and create opacity.
It has been found that SOD and GSH-Px, which are antioxidant enzymes, have significantly reduced activity in the aqueous humor and crystalline lens of senile cataract patients. The reason for this is probably, on the one hand, that the activity of the enzymes synthesizing them in the aqueous humor and the crystalline lens gradually decreases with age, so that their synthesis decreases; another more important aspect may be the massive accumulation of active oxygen radicals in the aqueous humor and lens, leading to a massive consumption of SOD and GSH-Px. The significant decrease in both aqueous humor and lens results in the failure to promptly scavenge reactive oxygen free radicals, such as O2、H2O2OH, etc., which are accumulated in the above-mentioned sites, and the oxidation causes the most unsaturated fatty acid in the plasma membrane structure, and produces lipid peroxide (L PO) to damage the lens capsule epithelial cells, affecting the permeability and integrity of the membrane, and converting soluble protein in the lens into insoluble protein, so that the lens will finally turn from transparent to turbid, resulting in the occurrence of cataract.
For the drug treatment of cataract, the commonly used commercial drugs are mainly divided into western drugs and traditional Chinese medicines, the western drugs comprise ① aldose reductase inhibitors, such as cataline (cataline, best cataract, cataract), phacolysin, etc., ② antioxidant injury drugs, such as glutathione, taurine, aspirin, etc., ③ nutrient metabolism drugs, such as vitamins, carotenoids, etc.
Disclosure of Invention
One of the objects of the present invention is to provide a pharmaceutical composition for treating cataract, which comprises farnesene as an active ingredient, an inclusion material and other pharmaceutically acceptable ophthalmic excipients, wherein the farnesene and the inclusion material form an inclusion compound at a molar ratio of 1: 2.
Farnesene (farnesene) as an active ingredient is mainly contained in essential oil such as sweet orange oil, rose oil, cananga oil and orange oil, and has the following structural formula:
farnesene is colorless or pale yellow oily liquid in appearance and has a density of 0.795-0.850. Is insoluble in water, and is soluble in ethanol, diethyl ether, and chloroform. Can be obtained by dehydrating nerolidol under the action of various acidic catalysts. The inventor takes a selenium cataract rat model as a research object, and finds that farnesene serving as an active ingredient can effectively improve the contents of antioxidant enzymes SOD and GSH-Px in the cataract rat crystalline lens and can also reduce the content of Malondialdehyde (MDA). Research has shown that MDA is the end product of in vivo degradation of lipid peroxide generated by unsaturated fatty acid in biological membrane under the attack of free radical, so reducing the content of MDA reflects the role of farnesene in protecting lens and reducing the degree of oxidative stress injury to a certain extent.
Because farnesene belongs to volatile oily substances and has poor solubility and stability, cyclodextrin is used as an inclusion material to prepare the active ingredient into an inclusion compound, so that the water solubility of the farnesene is improved, the farnesene can be more conveniently prepared into eye drops, the loss of the farnesene in the preparation process can be reduced, and the treatment effect is improved.
Specifically, the inclusion material in the pharmaceutical composition is β -cyclodextrin or derivatives thereof, the β -cyclodextrin derivatives are selected from one or more of hydroxypropyl- β -cyclodextrin, hydroxyethyl- β -cyclodextrin and sulfobutyl- β -cyclodextrin, and the inclusion material is preferably hydroxypropyl- β -cyclodextrin.
Further, the pharmaceutically acceptable other ophthalmic excipients are one or more of ophthalmic solvents, surfactants, pH adjusting agents, osmotic pressure adjusting agents, preservatives, bacteriostats, viscosity adjusting agents.
Further, the pharmaceutical composition is prepared into an ophthalmic preparation.
Preferably, the ophthalmic preparation is one of eye drops, eye washes, eye ointments, eye films, eye gels, eye sustained release preparations, and eye implants.
The invention also aims to provide a preparation method of the medicine composition, which adopts a saturated water solution method to prepare the farnesene and inclusion material inclusion compound, and then prepares the medicine composition with other pharmaceutically acceptable eye excipients.
Preferably, the preparation method comprises the following steps:
(1) preparing cyclodextrin into saturated solution according to the feeding ratio of 1:2 of the molar ratio of the farnesene to the cyclodextrin, heating, dissolving, cooling, adding the farnesene, magnetically stirring at 55-65 ℃, clathrating for 2-4h, cooling, and freeze-drying to obtain the product;
(2) adding the clathrate prepared in the step (1) and other pharmaceutically acceptable excipients for eyes into a proper amount of water for injection, heating to dissolve, adjusting pH to 6.0-7.0 with hydrochloric acid, supplementing water for injection, filtering with microporous membrane under clean condition, and autoclaving at 121 deg.C for 20-30 min to obtain the final product.
The invention also aims to provide application of the pharmaceutical composition in preparing a medicinal preparation for treating cataract.
Preferably, the cataract is an senile cataract, a traumatic cataract or a diabetic cataract.
Preferred embodiments of the present invention and effects thereof will be described below with reference to specific examples. It should be understood, however, that the description is for illustrative purposes only and is not intended to limit the claims of the present invention in any way.
Detailed Description
Example 1: eye drops containing 1% farnesene
1. The prescription composition is as follows:
10g of farnesene, a proper amount of hydroxypropyl- β -cyclodextrin, 3.6g of sodium chloride, 0.2g of ethylparaben and water for injection added to 1000m of L.
2. The preparation method comprises the following steps:
(1) preparing HP- β -CD into a saturated solution according to the feeding ratio of 1:2 of the molar ratio of the aureohedron to the HP- β -CD, heating, dissolving and cooling, adding the farnesene, magnetically stirring at 60 ℃, clathrating for about 2 hours, cooling, and freeze-drying to obtain the product;
(2) adding the clathrate prepared in the step (1) and other adjuvant ingredients in the prescription into a proper amount of water for injection, heating to dissolve, adjusting pH to 6.0-7.0 with hydrochloric acid, supplementing water for injection to 1000m L, filtering with microporous membrane under clean condition, and autoclaving at 121 deg.C for 20 min to obtain the final product.
Example 2: eye drops containing 1.5% farnesene
1. The prescription composition is as follows:
15g of farnesene, a proper amount of hydroxypropyl- β -cyclodextrin, 3.6g of sodium chloride, 0.2g of ethylparaben and water for injection, wherein the total amount of the mixture is 1000m L.
2. The preparation method comprises the following steps:
(1) preparing HP- β -CD into a saturated solution according to the feeding ratio of 1:2 of the molar ratio of the aureohedron to the HP- β -CD, heating, dissolving and cooling, adding the farnesene, magnetically stirring at 60 ℃, clathrating for about 2 hours, cooling, and freeze-drying to obtain the product;
(2) adding the clathrate prepared in the step (1) and other adjuvant ingredients in the prescription into a proper amount of water for injection, heating to dissolve, adjusting pH to 6.0-7.0 with hydrochloric acid, supplementing water for injection to 1000m L, filtering with microporous membrane under clean condition, and autoclaving at 121 deg.C for 20 min to obtain the final product.
Example 3: eye drops containing 2% farnesene
1. The prescription composition is as follows:
20g of farnesene, a proper amount of hydroxypropyl- β -cyclodextrin, 3.6g of sodium chloride, 0.2g of ethylparaben and water for injection added to 1000m of L.
2. The preparation method comprises the following steps:
(1) preparing HP- β -CD into a saturated solution according to the feeding ratio of 1:2 of the molar ratio of the aureohedron to the HP- β -CD, heating, dissolving and cooling, adding the farnesene, magnetically stirring at 60 ℃, clathrating for about 2 hours, cooling, and freeze-drying to obtain the product;
(2) adding the clathrate prepared in the step (1) and other adjuvant ingredients in the prescription into a proper amount of water for injection, heating to dissolve, adjusting pH to 6.0-7.0 with hydrochloric acid, supplementing water for injection to 1000m L, filtering with microporous membrane under clean condition, and autoclaving at 121 deg.C for 20 min to obtain the final product.
Pharmacodynamic experiment
Purpose of the experiment: the eye drops containing farnesene according to the invention were tested for their therapeutic effect on cataractous rats.
Experimental animals: healthy Wistar rats of 12 days old are male and female.
The experimental method comprises the following steps:
preparing sodium selenite powder into 0.1% sodium selenite solution with normal saline, injecting sodium selenite physiological saline solution into the neck and back of a rat subcutaneously, wherein the dosage is 10 mu mol/kg body weight, 1 time every other day and 5 times continuously, preparing a selenium cataract rat model, and checking the crystal turbidity condition through a slit lamp to judge whether the molding is successful.
Rats successfully molded were randomly divided into 5 groups of 20 rats each, the model group was administered with physiological saline as eye drops, the positive control group was administered with glutathione-containing eye drops (specification: 5ml:100mg), and the examples were administered with the Albizziene-containing eye drops of the present invention prepared in examples 1 to 3, respectively, and were designated as example 1 group (low dose group), example 2 group (medium dose group) and example 3 group (high dose group). All groups were dosed 2 drops/dose, 3 times/day for 12 weeks.
The first day after the administration, the degree of lens opacity was observed under a slit lamp using a mydriasis of 1% atropine eye drops and recorded photographically. Then, the rat is killed, the eyeball is picked off, the lens is separated, 10 times of phosphate buffer solution (10mM, pH value 6.8) is added under the condition of ice bath after being sucked dry by filter paper, high-speed centrifugation (5000r/min) is carried out for 10min, the supernatant is taken, the Malondialdehyde (MDA) content is measured by adopting a thiobarbituric acid method, the SOD content is measured by adopting a xanthine oxidase method, and the GSH-Px content is measured by adopting a dithiodinitrobenzoic acid method.
Statistical analysis, data mean ± standard deviation
And (4) showing. SPSS 13.0 statistical software is adopted to carry out one-factor variance analysis on a plurality of data of each group, and P is less than 0.05 to indicate that the difference has statistical significance.
The experimental results are as follows:
1. change in opacity of rat lens: the cataract rats are graded for lenticular opacity with reference to the grading method of ophthalmic laboratory lens of oxford university, uk:
level 0, transparent; grade 1, first order nucleus and lens with slight micro-suture; level 2, secondary core; level 3, tertiary core; grade 4, tertiary nucleus and lens fissures; grade 5, quaternary nucleus and lens fissures; grade 6, quaternary nuclei and radial haze of the crystals; grade 7, the lens was completely cloudy and radial opacity was not visible. The degree of crystal turbidity was graded by double blind method. The results are shown in Table 1.
Table 1 comparison of the degree of lenticular opacity in rats (n ═ 20)
As can be seen from table 1, most lenses of rats in the example group recovered transparent after 12 weeks of continuous administration, and only a few lenses showed slight suture, wherein the lenses of rats in the high dose group completely appeared transparent (20/20), which is significantly different from the lenses of rats in the model group, while the ratio of the lenses completely recovered transparent was only 11/20 in the positive control group to which glutathione eye drops were administered, which indicates that the effect of the eye drops containing farnesene according to the present invention on the treatment of cataractous rats was significantly better than that of the positive control group.
2. Changes in MDA, SOD and GSH-Px content in rat lenses:
the results of measuring the contents of MDA, SOD and GSH-Px in the lenses of the rats in each group are shown in Table 2. Compared with the model group, the rat lenses in the example group have lower MDA content, wherein the MDA content measured in the example 2 group and the example 3 group is obviously lower than that measured in the model group, and has significant difference; in the rats of the example group, the contents of SOD and GSH-Px in the lenses are obviously increased compared with the model group, and the increase amplitude is also obviously higher than that of the positive control group which is given with glutathione.
TABLE 2 comparison of the changes in MDA, SOD and GSH-Px content in the lens of rats (n 20)
Note: p < 0.05, the difference was statistically significant.
The experimental results show that the farnesene-containing pharmaceutical composition can effectively increase the content of antioxidant enzymes in rat lens with cataract and reduce the oxidative damage of the lens, thereby playing a role in preventing and treating the development of cataract.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.
Claims (9)
1. A pharmaceutical composition for treating cataract, characterized in that: the medicine composition comprises farnesene serving as an active ingredient, an inclusion material and other pharmaceutically acceptable ophthalmic excipients, wherein the farnesene and the inclusion material form an inclusion compound in a molar ratio of 1: 2.
2. The pharmaceutical composition of claim 1, wherein the inclusion material is β -cyclodextrin or its derivative, and the β -cyclodextrin derivative is one or more selected from hydroxypropyl- β -cyclodextrin, hydroxyethyl- β -cyclodextrin, and sulfobutyl- β -cyclodextrin.
3. The pharmaceutical composition according to claim 1 or 2, characterized in that: the other pharmaceutically acceptable ophthalmic excipients are one or more of ophthalmic solvents, surfactants, pH regulators, osmotic pressure regulators, preservatives, bacteriostats and viscosity regulators.
4. The pharmaceutical composition of claim 3, wherein: the pharmaceutical composition is prepared into an ophthalmic preparation.
5. The pharmaceutical composition of claim 4, wherein: the ophthalmic preparation is one of eye drops, eye lotion, eye ointment, eye film, eye gel, eye sustained-release preparation and eye implant.
6. A process for preparing a pharmaceutical composition according to any one of claims 1 to 5, characterized in that: the clathrate compound of farnesene and the inclusion material is prepared by adopting a saturated water solution method, and then the clathrate compound is prepared into a pharmaceutical composition with other pharmaceutically acceptable ophthalmic excipients.
7. The method of claim 6, wherein: the method comprises the following steps:
(1) preparing cyclodextrin into saturated solution according to the feeding ratio of 1:2 of the molar ratio of the farnesene to the cyclodextrin, heating, dissolving, cooling, adding the farnesene, magnetically stirring at 55-65 ℃, clathrating for 2-4h, cooling, and freeze-drying to obtain the product;
(2) adding the clathrate prepared in the step (1) and other pharmaceutically acceptable excipients for eyes into a proper amount of water for injection, heating to dissolve, adjusting pH to 6.0-7.0 with hydrochloric acid, supplementing water for injection, filtering with microporous membrane under clean condition, and autoclaving at 121 deg.C for 20-30 min to obtain the final product.
8. Use of a pharmaceutical composition according to any one of claims 1 to 7 for the preparation of a pharmaceutical formulation for the treatment of cataracts.
9. Use according to claim 8, characterized in that: the cataract is senile cataract, traumatic cataract or diabetic cataract.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202010382772.1A CN111494647A (en) | 2020-05-08 | 2020-05-08 | A pharmaceutical composition for treating cataract and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010382772.1A CN111494647A (en) | 2020-05-08 | 2020-05-08 | A pharmaceutical composition for treating cataract and its preparation method |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5029724A (en) * | 1973-07-19 | 1975-03-25 | ||
| CN104693035A (en) * | 2015-02-12 | 2015-06-10 | 中国农业大学 | Salicylic acid trans-(beta)-farnesene analogues and application thereof |
| CN107998145A (en) * | 2016-10-30 | 2018-05-08 | 西北农林科技大学 | Ozonize olefin-containing double bond compound |
| CN108078919A (en) * | 2018-01-16 | 2018-05-29 | 沈阳药科大学 | A kind of Quercetin eye drops and preparation method thereof |
-
2020
- 2020-05-08 CN CN202010382772.1A patent/CN111494647A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5029724A (en) * | 1973-07-19 | 1975-03-25 | ||
| CN104693035A (en) * | 2015-02-12 | 2015-06-10 | 中国农业大学 | Salicylic acid trans-(beta)-farnesene analogues and application thereof |
| CN107998145A (en) * | 2016-10-30 | 2018-05-08 | 西北农林科技大学 | Ozonize olefin-containing double bond compound |
| CN108078919A (en) * | 2018-01-16 | 2018-05-29 | 沈阳药科大学 | A kind of Quercetin eye drops and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| MEHMET ENES ARSLAN, HASAN TÜRKEZ AND ADIL MARDINOĞLU: "In vitro neuroprotective effects of farnesene sesquiterpene on alzheimer’s disease model of differentiated neuroblastoma cell line", 《INTERNATIONAL JOURNAL OF NEUROSCIENCE》 * |
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